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Hu Y, He J, Ma Y, Ge L, Lou B, Fang X, Wang H, Xu Y. Arsenic and metabolic diseases: New insights from mesenchymal stem cells. Toxicol Appl Pharmacol 2025; 498:117299. [PMID: 40081540 DOI: 10.1016/j.taap.2025.117299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 01/27/2025] [Accepted: 03/10/2025] [Indexed: 03/16/2025]
Abstract
Arsenic is a common toxic metal contaminant in the environment. Humans are exposed to arsenic through drinking water, air, food, and medical treatment. Chronic exposure to arsenic is a well-documented risk factor of type 2 diabetes and a potential risk factor of osteoporosis and obesity. Mesenchymal stem cells (MSCs) are adult stem cells with multiple differentiation potential and immunomodulatory capacity. These cells have shown therapeutic potential in experimental studies of metabolic diseases by differentiating into parenchymal cells of damaged tissues, such as islet-like cells and osteoblasts, and resisting chronic inflammation. Meanwhile, when key functional genes were suppressed in MSCs, experimental animals showed metabolic disease-related changes, such as insulin resistance and obesity. Arsenic exposure inhibits the differentiation capacity of MSCs, leads to changes in the synthesis and secretion of immunomodulatory factors, and induces cellular senescence and apoptosis. Therefore, dysfunction and death of MSCs may be important pathogenesis of arsenic-related metabolic diseases. Future studies on the functional changes of MSCs in arsenic-related metabolic diseases and the role of MSCs in arsenic pathogenesis are worthwhile. In addition, the mechanism of arsenic-induced dysfunction in MSCs needs to be explored in depth.
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Affiliation(s)
- Yuxin Hu
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, Shenyang, People's Republic of China; School of Public Health, China Medical University, Shenyang, People's Republic of China; Key Laboratory of Toxic and Biological Effects of Arsenic (China Medical University), Shenyang, Liaoning Province, People's Republic of China
| | - Jialin He
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, Shenyang, People's Republic of China; School of Public Health, China Medical University, Shenyang, People's Republic of China; Key Laboratory of Toxic and Biological Effects of Arsenic (China Medical University), Shenyang, Liaoning Province, People's Republic of China
| | - Yue Ma
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, Shenyang, People's Republic of China; School of Public Health, China Medical University, Shenyang, People's Republic of China; Key Laboratory of Toxic and Biological Effects of Arsenic (China Medical University), Shenyang, Liaoning Province, People's Republic of China
| | - Lili Ge
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, Shenyang, People's Republic of China; School of Public Health, China Medical University, Shenyang, People's Republic of China; Key Laboratory of Toxic and Biological Effects of Arsenic (China Medical University), Shenyang, Liaoning Province, People's Republic of China
| | - Bin Lou
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, Shenyang, People's Republic of China; School of Public Health, China Medical University, Shenyang, People's Republic of China; Key Laboratory of Toxic and Biological Effects of Arsenic (China Medical University), Shenyang, Liaoning Province, People's Republic of China
| | - Xin Fang
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, Shenyang, People's Republic of China; School of Public Health, China Medical University, Shenyang, People's Republic of China; Key Laboratory of Toxic and Biological Effects of Arsenic (China Medical University), Shenyang, Liaoning Province, People's Republic of China
| | - Huihui Wang
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, Shenyang, People's Republic of China; School of Public Health, China Medical University, Shenyang, People's Republic of China; Key Laboratory of Toxic and Biological Effects of Arsenic (China Medical University), Shenyang, Liaoning Province, People's Republic of China
| | - Yuanyuan Xu
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, Shenyang, People's Republic of China; School of Public Health, China Medical University, Shenyang, People's Republic of China; Key Laboratory of Toxic and Biological Effects of Arsenic (China Medical University), Shenyang, Liaoning Province, People's Republic of China.
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Vaiasicca S, James DW, Melone G, Saeed O, Francis LW, Corradetti B. Amniotic fluid-derived mesenchymal stem cells as a therapeutic tool against cytokine storm: a comparison with umbilical cord counterparts. Stem Cell Res Ther 2025; 16:151. [PMID: 40156072 PMCID: PMC11951844 DOI: 10.1186/s13287-025-04262-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 03/04/2025] [Indexed: 04/01/2025] Open
Abstract
BACKGROUND Several immunosuppressive therapies have been proposed as key treatment options for critically ill patients since the first appearance of severe acute respiratory syndrome coronavirus 2. Mesenchymal stem cells (MSCs) from different sources have been considered for their potential to attenuate the cytokine storm associated to COVID-19 and the consequent multi-organ failure, providing evidence for safe and efficacious treatments. Among them, administration of umbilical cord-derived MSCs (UC-MSCs) has demonstrated a significant increase in survival rates, largely due to their potent immunosuppressive properties. METHODS We applied next-generation sequencing (NGS) analysis to compare the transcriptomic profiles of MSCs isolated from two gestational sources: amniotic fluid (AF) obtained during prenatal diagnosis and their clinically relevant umbilical cord counterparts, for which datasets were publicly available. A full meta-analysis was performed to identify suitable GEO and NGS datasets for comparison between AF- and UC-MSC samples. RESULTS Transcriptome analysis revelaed significant differences between groups, despite both cell lines being strongly involved in the tissue development, crucial to achieve the complex task of wound healing. Significantly enriched hallmark genes suggest AF-MSC superior immunomodulatory features against signaling pathways actively involved in the cytokine storm (i.e., IL-2/STAT, TNF-a/NFkB, IL-2/STAT5, PI3K/AKT/mTOR). CONCLUSIONS The data presented here suggest that AF-MSCs hold significant promise for treating not only COVID-19-associated cytokine storms but also a variety of other inflammatory syndromes (i.e., those induced by bacterial infections, autoimmune disorders, and therapeutic interventions). Realizing the full potential of AF-MSCs as a comprehensive therapeutic approach in inflammatory disease management will require more extensive clinical trials and in-depth mechanistic studies.
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Affiliation(s)
- Salvatore Vaiasicca
- Advanced Technology Center for Aging Research, IRCCS INRCA, Ancona, Italy
- Department of Life and Environmental Life, Polytechnic University of Marche, Ancona, Italy
| | - David W James
- Centre of NanoHealth, Swansea University Medical School, Swansea, UK
| | - Gianmarco Melone
- Centre of NanoHealth, Swansea University Medical School, Swansea, UK
| | - Omar Saeed
- Centre of NanoHealth, Swansea University Medical School, Swansea, UK
| | - Lewis W Francis
- Centre of NanoHealth, Swansea University Medical School, Swansea, UK
| | - Bruna Corradetti
- Centre of NanoHealth, Swansea University Medical School, Swansea, UK.
- Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA.
- Department of Medicine, Section Oncology/Hematology, Baylor College of Medicine, Houston, TX, USA.
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Nada AH, Ibrahim IA, Oteri V, Shalabi L, Asar NK, Aqeilan SR, Hafez W. Safety and efficacy of umbilical cord mesenchymal stem cells in the treatment of type 1 and type 2 diabetes mellitus: a systematic review and meta-analysis. Expert Rev Endocrinol Metab 2025; 20:107-117. [PMID: 39905688 DOI: 10.1080/17446651.2025.2457474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Accepted: 11/22/2024] [Indexed: 02/06/2025]
Abstract
INTRODUCTION Many patients struggle to control glucose without side effects. Due to their immunomodulatory and regenerative properties, mesenchymal stem cells (MSCs) might treat Diabetes Mellitus (DM). The authors employed this meta-analysis to evaluate the efficacy and safety of umbilical cord MSCs (UCMSCs) for DM management. METHODS The PubMed, Cochrane, WOS, Embase, and Scopus databases were searched for randomized controlled trials (RCTs) investigating the effects of UCMSCs on DM (Types 1, 2) till January 2024. Patient demographics, interventions, and outcomes, including glycated hemoglobin (HbA1c%), C-peptide levels, and insulin requirements, were extracted. A comprehensive meta-analysis software was used. RESULTS Eight CTs of 334 patients (172 experimental and 162 controls) were included. UMSCs treatment substantially lowered HbA1c levels (MD = -1.06, 95% CI [-1.27, -0.85], p < 0.00001) with consistent outcomes (i2 = 0%, p = 0.43). Fasting C-peptide levels were heterogeneous but favored placebo (MD = 0.35, 95% CI [0.15, 0.56], p = 0.0007). In T1D patients, daily insulin requirements decreased considerably (MD = -0.24, 95% CI [-0.29, -0.18], p < 0.00001), with heterogeneity addressed by sensitivity analysis. CONCLUSION UMSCs therapy reduced HbA1c and insulin requirements, and increased C-peptide levels. Multicenter clinical trials are required to confirm the long-term efficacy and safety of UMSC therapy.
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Affiliation(s)
| | - Ismail A Ibrahim
- Faculty of Health Sciences, Fenerbahce University, Istanbul, Turkey
| | - Vittorio Oteri
- Endocrine Unit, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy
| | - Laila Shalabi
- Faculty of Medicine, Gharyan University, Gharyan, Libya
| | | | | | - Wael Hafez
- Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
- NMC Royal Hospital, Khalifa City, Abu Dhabi, UAE
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Han JJ, Li J, Huang DH. Mesenchymal Stem Cell-Derived Extracellular Vesicles Carrying Circ-Tulp4 Attenuate Diabetes Mellitus with Nonalcoholic Fatty Liver Disease by Inhibiting Cell Pyroptosis through the HNRNPC/ABHD6 Axis. Tissue Eng Regen Med 2025; 22:23-41. [PMID: 39546192 PMCID: PMC11711725 DOI: 10.1007/s13770-024-00675-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 08/15/2024] [Accepted: 09/22/2024] [Indexed: 11/17/2024] Open
Abstract
BACKGROUND Diabetes mellitus with nonalcoholic fatty liver disease (DM-NAFLD) represents a complex metabolic syndrome with significant clinical challenges. This study explores the therapeutic potential and underlying mechanisms of umbilical cord-derived mesenchymal stem cells (UCMSCs)-derived extracellular vesicles (EVs) in DM-NAFLD. METHODS UCMSCs-EVs were isolated and characterized. DM-NAFLD mouse model was developed through high-energy diet and streptozotocin injection. Additionally, primary mouse hepatocytes were exposed to high glucose to simulate cellular conditions. Hepatic tissue damage, body weight changes, lipid levels, glucose and insulin homeostasis, and hepatic lipid accumulation were evaluated. The interaction between UCMSCs-EVs and hepatocytes was assessed, focusing on the localization and function of circ-Tulp4. The study also investigated the expression of circularRNA TUB-like protein 4 (circ-Tulp4), heterogeneous nuclear ribonucleoprotein C (HNRNPC), abhydrolase domain containing 6 (ABHD6), cleaved Caspase-1, NLR family pyrin domain containing 3 (NLRP3) and cleaved N-terminal gasdermin D (GSDMD-N). The binding of circ-Tulp4 to lysine demethylase 6B (KDM6B) and the subsequent epigenetic regulation of ABHD6 by H3K27me3 were analyzed. RESULTS Circ-Tulp4 was reduced, while HNRNPC and ABHD6 were elevated in DM-NAFLD models. UCMSCs-EVs attenuated hepatic steatosis and inhibited the NLRP3/cleaved Caspase-1/GSDMD-N pathway. EVs delivered circ-Tulp4 into hepatocytes, thereby restoring circ-Tulp4 expression. Elevated circ-Tulp4 enhanced the recruitment of H3K27me3 to the HNRNPC promoter through interaction with KDM6B, thus suppressing HNRNPC and ABHD6. Overexpression of HNRNPC or ABHD6 counteracted the protective effects of UCMSCs-EVs, exacerbating pyroptosis and hepatic steatosis in DM-NAFLD. CONCLUSION UCMSCs-EVs deliver circ-Tulp4 into hepatocytes, where circ-Tulp4 inhibits the HNRNPC/ABHD6 axis, thereby reducing pyroptosis and alleviating DM-NAFLD. These findings provide a novel therapeutic avenue for targeting DM-NAFLD through modulation of cell pyroptosis.
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Affiliation(s)
- Jing-Jing Han
- Department of Endocrinology, The Second Affiliated Hospital of Shandong First Medical University, Taishan Street Road No.366, Tai'an, 271000, Shandong, China
| | - Jing Li
- Department of Pediatric, The Secondary TCM Hospital of Tai'an City, Lingshan Street No.265, Tai'an, 271000, Shandong, China
| | - Dong-Hui Huang
- Department of Endocrinology, The Second Affiliated Hospital of Shandong First Medical University, Taishan Street Road No.366, Tai'an, 271000, Shandong, China.
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Liu X, Hyun Kim J, Li X, Liu R. Application of mesenchymal stem cells exosomes as nanovesicles delivery system in the treatment of breast cancer. Int J Pharm 2024; 666:124732. [PMID: 39304093 DOI: 10.1016/j.ijpharm.2024.124732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 09/09/2024] [Accepted: 09/17/2024] [Indexed: 09/22/2024]
Abstract
As people's living standards continue to improve and human life span expectancy increases, the incidence and mortality rates of breast cancer are continuously rising. Early detection of breast cancer and targeted therapy for different breast cancer subtypes can significantly reduce the mortality rate and alleviate the suffering of patients. Exosomes are extracellular vesicles secreted by various cells in the body. They participate in physiological and pathological responses by releasing active substances and play an important role in regulating intercellular communication. In recent years, research on exosomes has gradually expanded, and their special membrane structure and targetable characteristics are being increasingly applied in various clinical studies. Mesenchymal stem cells (MSCs)-derived exosomes play an important role in regulating the progression of breast cancer. In this review, we summarize the current treatment methods for breast cancer, the connection between MSCs, exosomes, and breast cancer, as well as the application of exosomes derived from MSCs from different sources in cancer treatment. We highlight how the rational design of modified MSCs-derived exosomes (MSCs-Exos) delivery systems can overcome the uncertainties of stem cell therapy and overcome the clinical translation challenges of nanomaterials. This work aims to promote future research on the application of MSCs-Exos in breast cancer treatment.
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Affiliation(s)
- Xiaofan Liu
- Department of Biotechnology, College of Engineering, The University of Suwon, Hwaseong 18323, Republic of Korea; Collaborative Innovation Center of Tumor Marker Detection Technology, Equipment and Diagnosis-Therapy Integration in Universities of Shandong, Shandong Province Key Laboratory of Detection Technology for Tumor Makers, School of Chemistry and Chemical Engineering, Linyi University, Linyi 276005, China
| | - June Hyun Kim
- Department of Biotechnology, College of Engineering, The University of Suwon, Hwaseong 18323, Republic of Korea
| | - Xuemei Li
- Collaborative Innovation Center of Tumor Marker Detection Technology, Equipment and Diagnosis-Therapy Integration in Universities of Shandong, Shandong Province Key Laboratory of Detection Technology for Tumor Makers, School of Chemistry and Chemical Engineering, Linyi University, Linyi 276005, China.
| | - Rui Liu
- Department of Biotechnology, College of Engineering, The University of Suwon, Hwaseong 18323, Republic of Korea.
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Guo X, Niu Z, Zhuang Y, Zhao Y, Ding Z, Shi J, Hou S, Fan H, Lv Q. Bone marrow mesenchymal stromal cells attenuate smoke inhalation injury by regulating the M1/M2-Th17/Treg immune homeostasis axis. Int Immunopharmacol 2024; 141:112986. [PMID: 39182266 DOI: 10.1016/j.intimp.2024.112986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 08/16/2024] [Accepted: 08/18/2024] [Indexed: 08/27/2024]
Abstract
Smoke inhalation injury (SII) is the leading cause of death in fire burn patients. The inflammatory response induced by smoke inhalation is a significant factor in the development of acute lung injury or acute respiratory distress syndrome (ALI/ARDS). Mesenchymal stem cells (MSCs) can alleviate various inflammatory diseases by regulating the polarization of macrophages from the M1 to the M2 phenotype. Moreover, MSCs can facilitate the inflammatory response by regulating Th17/Treg homeostasis. However, little is known about the associations among MSCs, M1/M2 macrophages and Th17/Treg homeostasis. Therefore, the purpose of this study was to evaluate whether MSCs affect subsequent Th17/Treg differentiation and immune homeostasis by regulating M1/M2 polarization in SII. Our results showed that bone marrow mesenchymal stem cells (BMSCs) ameliorated lung inflammatory injury and fibrosis after SII by affecting the polarization of alveolar macrophages (AMs) from the M1 to the M2 phenotype. Moreover, BMSCs maintain Th17/Treg immune homeostasis by increasing the proportion of Treg cells and decreasing the proportion of Th17 cells. In vitro, we further demonstrated that BMSCs promoted the polarization of AMs from the M1 to the M2 phenotype and decreased IL-23 levels. Reduced IL-23 decreased Th17 differentiation and promoted Th17/Treg balance. Therefore, BMSCs ameliorate the inflammatory response and lung damage after SII through regulating M1/M2 polarization and subsequent Th17/Treg immune homeostasis, which are linked to alveolar macrophage-derived IL-23. These findings provide novel insight into how BMSCs regulate the M1/M2-Th17/Treg immune homeostasis axis and provide new therapeutic targets for more effective control of the inflammatory response after SII.
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Affiliation(s)
- Xiaoqin Guo
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; Key Laboratory for Disaster Medicine Technology, Tianjin 300072, China; Wenzhou Safety (Emergency) Institute, Tianjin University, Wenzhou 325026, China
| | - Zhifang Niu
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; Key Laboratory for Disaster Medicine Technology, Tianjin 300072, China; Wenzhou Safety (Emergency) Institute, Tianjin University, Wenzhou 325026, China
| | - Yong Zhuang
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; Key Laboratory for Disaster Medicine Technology, Tianjin 300072, China; Wenzhou Safety (Emergency) Institute, Tianjin University, Wenzhou 325026, China
| | - Yunlong Zhao
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; Key Laboratory for Disaster Medicine Technology, Tianjin 300072, China; Wenzhou Safety (Emergency) Institute, Tianjin University, Wenzhou 325026, China
| | - Ziling Ding
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; Key Laboratory for Disaster Medicine Technology, Tianjin 300072, China; Wenzhou Safety (Emergency) Institute, Tianjin University, Wenzhou 325026, China
| | - Jie Shi
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; Key Laboratory for Disaster Medicine Technology, Tianjin 300072, China; Wenzhou Safety (Emergency) Institute, Tianjin University, Wenzhou 325026, China
| | - Shike Hou
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; Key Laboratory for Disaster Medicine Technology, Tianjin 300072, China; Wenzhou Safety (Emergency) Institute, Tianjin University, Wenzhou 325026, China.
| | - Haojun Fan
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; Key Laboratory for Disaster Medicine Technology, Tianjin 300072, China; Wenzhou Safety (Emergency) Institute, Tianjin University, Wenzhou 325026, China.
| | - Qi Lv
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; Key Laboratory for Disaster Medicine Technology, Tianjin 300072, China; Wenzhou Safety (Emergency) Institute, Tianjin University, Wenzhou 325026, China.
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Zeinhom A, Fadallah SA, Mahmoud M. Human mesenchymal stem/stromal cell based-therapy in diabetes mellitus: experimental and clinical perspectives. Stem Cell Res Ther 2024; 15:384. [PMID: 39468609 PMCID: PMC11520428 DOI: 10.1186/s13287-024-03974-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 10/04/2024] [Indexed: 10/30/2024] Open
Abstract
Diabetes mellitus (DM), a chronic metabolic disease, poses a significant global health challenge, with current treatments often fail to prevent the long-term disease complications. Mesenchymal stem/stromal cells (MSCs) are, adult progenitors, able to repair injured tissues, exhibiting regenerative effects and immunoregulatory and anti-inflammatory responses, so they have been emerged as a promising therapeutic approach in many immune-related and inflammatory diseases. This review summarizes the therapeutic mechanisms and outcomes of MSCs, derived from different human tissue sources (hMSCs), in the context of DM type 1 and type 2. Animal model studies and clinical trials indicate that hMSCs can facilitate pleiotropic actions in the diabetic milieu for improved metabolic indices. In addition to modulating abnormally active immune system, hMSCs can ameliorate peripheral insulin resistance, halt beta-cell destruction, preserve residual beta-cell mass, promote beta-cell regeneration and insulin production, support islet grafts, and correct lipid metabolism. Moreover, hMSC-free derivatives, importantly extracellular vesicles, have shown potent experimental anti-diabetic efficacy. Moreover, the review discusses the diverse priming strategies that are introduced to enhance the preclinical anti-diabetic actions of hMSCs. Such strategies are recommended to restore the characteristics and functions of MSCs isolated from patients with DM for autologous implications. Finally, limitations and merits for the wide spread clinical applications of MSCs in DM such as the challenge of autologous versus allogeneic MSCs, the optimal MSC tissue source and administration route, the necessity of larger clinical trials for longer evaluation duration to assess safety concerns, are briefly presented.
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Affiliation(s)
- Alaa Zeinhom
- Biotechnology Department, Faculty of Science, Cairo University, Cairo Governorate, 12316, Egypt
| | - Sahar A Fadallah
- Biotechnology Department, Faculty of Science, Cairo University, Cairo Governorate, 12316, Egypt
| | - Marwa Mahmoud
- Human Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre (NRC), Cairo, 12622, Egypt.
- Stem Cell Research Unit, Medical Research Centre of Excellence, NRC, Cairo, Egypt.
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Wu S, Zhou Z, Li Y, Jiang J. Advancements in diabetic foot ulcer research: Focus on mesenchymal stem cells and their exosomes. Heliyon 2024; 10:e37031. [PMID: 39286219 PMCID: PMC11403009 DOI: 10.1016/j.heliyon.2024.e37031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/11/2024] [Accepted: 08/26/2024] [Indexed: 09/19/2024] Open
Abstract
Diabetes represents a widely acknowledged global public health concern. Diabetic foot ulcer (DFU) stands as one of the most severe complications of diabetes, its occurrence imposing a substantial economic burden on patients, profoundly impacting their quality of life. Despite the deepening comprehension regarding the pathophysiology and cellular as well as molecular responses of DFU, the current therapeutic arsenal falls short of efficacy, failing to offer a comprehensive remedy for deep-seated chronic wounds and microvascular occlusions. Conventional treatments merely afford symptomatic alleviation or retard the disease's advancement, devoid of the capacity to effectuate further restitution of compromised vasculature and nerves. An escalating body of research underscores the prominence of mesenchymal stem cells (MSCs) owing to their paracrine attributes and anti-inflammatory prowess, rendering them a focal point in the realm of chronic wound healing. Presently, MSCs have been validated as a highly promising cellular therapeutic approach for DFU, capable of effectuating cellular repair, epithelialization, granulation tissue formation, and neovascularization by means of targeted differentiation, angiogenesis promotion, immunomodulation, and paracrine activities, thereby fostering wound healing. The secretome of MSCs comprises cytokines, growth factors, chemokines, alongside exosomes harboring mRNA, proteins, and microRNAs, possessing immunomodulatory and regenerative properties. The present study provides a systematic exposition on the etiology of DFU and elucidates the intricate molecular mechanisms and diverse functionalities of MSCs in the context of DFU treatment, thereby furnishing pioneering perspectives aimed at harnessing the therapeutic potential of MSCs for DFU management and advancing wound healing processes.
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Affiliation(s)
- ShuHui Wu
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - ZhongSheng Zhou
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yang Li
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jinlan Jiang
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
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Xia L, Yang M, Zang N, Song J, Chen J, Hu H, Wang K, Xiang Y, Yang J, Wang L, Zou Y, Lv X, Hou X, Chen L. PEGylated β-Cell-Targeting Exosomes from Mesenchymal Stem Cells Improve β Cell Function and Quantity by Suppressing NRF2-Mediated Ferroptosis. Int J Nanomedicine 2024; 19:9575-9596. [PMID: 39296939 PMCID: PMC11410040 DOI: 10.2147/ijn.s459077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 08/27/2024] [Indexed: 09/21/2024] Open
Abstract
Background The depletion of β cell mass is widely recognized as a significant contributor to the progression of type 2 diabetes mellitus (T2DM). Exosomes derived from mesenchymal stem cells (MSC-EXOs) hold promise as cell-free therapies for treating T2DM. However, the precise effects and mechanisms through which MSC-EXO affects β cell function remain incompletely understood, and the limited ability of MSC-EXO to target β cells and the short blood circulation time hampers its therapeutic effectiveness. Methods The effects of MSC-EXO were investigated in T2DM mice induced by a high-fat diet combined with STZ. Additionally, the high glucose-stimulated INS-1 cell line was used to investigate the potential mechanism of MSC-EXO. Michael addition reaction-mediated chemical coupling was used to modify the surface of the exosome membrane with a β-cell-targeting aptamer and polyethylene glycol (PEG). The β-cell targeting and blood circulation time were evaluated, and whether this modification enhanced the islet-protective effect of MSC-EXO was further analyzed. Results We observed that the therapeutic effects of MSC-EXO on T2DM manifested through the reduction of random blood glucose levels, enhancement of glucose and insulin tolerance, and increased insulin secretion. These effects were achieved by augmenting β cell mass via inhibiting nuclear factor erythroid 2-related factor 2 (NRF2)-mediated ferroptosis. Mechanistically, MSC-EXOs play a role in the NRF2-mediated anti-ferroptosis mechanism by transporting active proteins that are abundant in the AKT and ERK pathways. Moreover, compared to MSC-EXOs, aptamer- and PEG-modified exosomes (Apt-EXOs) were more effective in islet protection through PEG-mediated cycle prolongation and aptamer-mediated β-cell targeting. Conclusion MSC-EXO suppresses NRF2-mediated ferroptosis by delivering bioactive proteins to regulate the AKT/ERK signaling pathway, thereby improving the function and quantity of β cells. Additionally, Apt-EXO may serve as a novel drug carrier for islet-targeted therapy.
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Affiliation(s)
- Longqing Xia
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, People's Republic of China
| | - Mengmeng Yang
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, People's Republic of China
| | - Nan Zang
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, People's Republic of China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, People's Republic of China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, People's Republic of China
- Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 250012, People's Republic of China
| | - Jia Song
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, People's Republic of China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, People's Republic of China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, People's Republic of China
- Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 250012, People's Republic of China
| | - Jun Chen
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, People's Republic of China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, People's Republic of China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, People's Republic of China
- Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 250012, People's Republic of China
| | - Huiqing Hu
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, People's Republic of China
| | - Kewei Wang
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, People's Republic of China
| | - Yingyue Xiang
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, People's Republic of China
| | - Jingwen Yang
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, People's Republic of China
| | - Liming Wang
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, People's Republic of China
| | - Ying Zou
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, People's Republic of China
| | - Xiaoyu Lv
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, People's Republic of China
| | - Xinguo Hou
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, People's Republic of China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, People's Republic of China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, People's Republic of China
- Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 250012, People's Republic of China
| | - Li Chen
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, People's Republic of China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, People's Republic of China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, People's Republic of China
- Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 250012, People's Republic of China
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Song J, Wang L, Wang L, Guo X, He Q, Cui C, Hu H, Zang N, Yang M, Yan F, Liang K, Wang C, Liu F, Sun Y, Sun Z, Lai H, Hou X, Chen L. Mesenchymal stromal cells ameliorate mitochondrial dysfunction in α cells and hyperglucagonemia in type 2 diabetes via SIRT1/FoxO3a signaling. Stem Cells Transl Med 2024; 13:776-790. [PMID: 38864709 PMCID: PMC11328933 DOI: 10.1093/stcltm/szae038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 04/24/2024] [Indexed: 06/13/2024] Open
Abstract
Dysregulation of α cells results in hyperglycemia and hyperglucagonemia in type 2 diabetes mellitus (T2DM). Mesenchymal stromal cell (MSC)-based therapy increases oxygen consumption of islets and enhances insulin secretion. However, the underlying mechanism for the protective role of MSCs in α-cell mitochondrial dysfunction remains unclear. Here, human umbilical cord MSCs (hucMSCs) were used to treat 2 kinds of T2DM mice and αTC1-6 cells to explore the role of hucMSCs in improving α-cell mitochondrial dysfunction and hyperglucagonemia. Plasma and supernatant glucagon were detected by enzyme-linked immunosorbent assay (ELISA). Mitochondrial function of α cells was assessed by the Seahorse Analyzer. To investigate the underlying mechanisms, Sirtuin 1 (SIRT1), Forkhead box O3a (FoxO3a), glucose transporter type1 (GLUT1), and glucokinase (GCK) were assessed by Western blotting analysis. In vivo, hucMSC infusion improved glucose and insulin tolerance, as well as hyperglycemia and hyperglucagonemia in T2DM mice. Meanwhile, hucMSC intervention rescued the islet structure and decreased α- to β-cell ratio. Glucagon secretion from αTC1-6 cells was consistently inhibited by hucMSCs in vitro. Meanwhile, hucMSC treatment activated intracellular SIRT1/FoxO3a signaling, promoted glucose uptake and activation, alleviated mitochondrial dysfunction, and enhanced ATP production. However, transfection of SIRT1 small interfering RNA (siRNA) or the application of SIRT1 inhibitor EX-527 weakened the therapeutic effects of hucMSCs on mitochondrial function and glucagon secretion. Our observations indicate that hucMSCs mitigate mitochondrial dysfunction and glucagon hypersecretion of α cells in T2DM via SIRT1/FoxO3a signaling, which provides novel evidence demonstrating the potential for hucMSCs in treating T2DM.
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Affiliation(s)
- Jia Song
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Lingshu Wang
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Liming Wang
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Xinghong Guo
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Qin He
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Chen Cui
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Huiqing Hu
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Nan Zang
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Mengmeng Yang
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Fei Yan
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Kai Liang
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Chuan Wang
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Fuqiang Liu
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Yujing Sun
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Zheng Sun
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Hong Lai
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan 250012, Shandong, People's Republic of China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine and Health, Jinan 250012, Shandong, People's Republic of China
- Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan 250012, Shandong, People's Republic of China
| | - Xinguo Hou
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan 250012, Shandong, People's Republic of China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine and Health, Jinan 250012, Shandong, People's Republic of China
- Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan 250012, Shandong, People's Republic of China
| | - Li Chen
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan 250012, Shandong, People's Republic of China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine and Health, Jinan 250012, Shandong, People's Republic of China
- Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan 250012, Shandong, People's Republic of China
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11
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Luo W, Zhou Y, Wang LY, Ai L. Interactions between myoblasts and macrophages under high glucose milieus result in inflammatory response and impaired insulin sensitivity. World J Diabetes 2024; 15:1589-1602. [PMID: 39099815 PMCID: PMC11292338 DOI: 10.4239/wjd.v15.i7.1589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 04/28/2024] [Accepted: 05/20/2024] [Indexed: 07/08/2024] Open
Abstract
BACKGROUND Skeletal muscle handles about 80% of insulin-stimulated glucose uptake and become the major organ occurring insulin resistance (IR). Many studies have confirmed the interactions between macrophages and skeletal muscle regulated the inflammation and regeneration of skeletal muscle. However, despite of the decades of research, whether macrophages infiltration and polarization in skeletal muscle under high glucose (HG) milieus results in the development of IR is yet to be elucidated. C2C12 myoblasts are well-established and excellent model to study myogenic regulation and its responses to stimulation. Further exploration of macrophages' role in myoblasts IR and the dynamics of their infiltration and polarization is warranted. AIM To evaluate interactions between myoblasts and macrophages under HG, and its effects on inflammation and IR in skeletal muscle. METHODS We detected the polarization status of macrophages infiltrated to skeletal muscles of IR mice by hematoxylin and eosin and immunohistochemical staining. Then, we developed an in vitro co-culture system to study the interactions between myoblasts and macrophages under HG milieus. The effects of myoblasts on macrophages were explored through morphological observation, CCK-8 assay, Flow Cytometry, and enzyme-linked immunosorbent assay. The mediation of macrophages to myogenesis and insulin sensitivity were detected by morphological observation, CCK-8 assay, Immunofluorescence, and 2-NBDG assay. RESULTS The F4/80 and co-localization of F4/80 and CD86 increased, and the myofiber size decreased in IR group (P < 0.01, g = 6.26). Compared to Mc group, F4/80+CD86+CD206- cells, tumor necrosis factor-α (TNFα), inerleukin-1β (IL-1β) and IL-6 decreased, and IL-10 increased in McM group (P < 0.01, g > 0.8). In McM + HG group, F4/80+CD86+CD206- cells, monocyte chemoattractant protein 1, TNFα, IL-1β and IL-6 were increased, and F4/80+CD206+CD86- cells and IL-10 were decreased compared with Mc + HG group and McM group (P < 0.01, g > 0.8). Compered to M group, myotube area, myotube number and E-MHC were increased in MMc group (P < 0.01, g > 0.8). In MMc + HG group, myotube area, myotube number, E-MHC, GLUT4 and glucose uptake were decreased compared with M + HG group and MMc group (P < 0.01, g > 0.8). CONCLUSION Interactions between myoblasts and macrophages under HG milieus results in inflammation and IR, which support that the macrophage may serve as a promising therapeutic target for skeletal muscle atrophy and IR.
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Affiliation(s)
- Wei Luo
- Department of Sports and Health Sciences, Nanjing Sport Institute, Nanjing 210014, Jiangsu Province, China
| | - Yue Zhou
- Department of Exercise Physiology, Beijing Sport University, Beijing 100084, China
| | - Li-Ying Wang
- Department of Exercise Physiology, Beijing Sport University, Beijing 100084, China
| | - Lei Ai
- Department of Sports Physiology Research, Jiangsu Research Institute of Sports Science, Nanjing 210033, Jiangsu Province, China
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Liu L, Chen Y, Li X, Wang J, Yang L. Therapeutic potential: The role of mesenchymal stem cells from diverse sources and their derived exosomes in diabetic nephropathy. Biomed Pharmacother 2024; 175:116672. [PMID: 38677249 DOI: 10.1016/j.biopha.2024.116672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 04/17/2024] [Accepted: 04/24/2024] [Indexed: 04/29/2024] Open
Abstract
Diabetic nephropathy (DN) is one of the most common microvascular complications in diabetic patients, with its incidence continuously increasing in recent years. DN causes renal tissue damage and functional decline, expedites the aging process of the kidneys, and may ultimately progress leading to end-stage renal disease, severely impacting the patient's quality of life and prognosis. Mesenchymal stem cells (MSCs) are highly valued for their multipotent differentiation, paracrine functions, immunomodulatory effects, and capacity for tissue repair. Particularly, exosomes (Exo) derived from MSCs (MSCs-Exo) are rich in bioactive molecules and facilitate intercellular communication, participating in various physiological and pathological processes. MSCs and MSCs-Exo, in particular, have been demonstrated to have therapeutic effects in DN treatment research by encouraging tissue repair, fibrosis inhibition, and inflammation reduction. Research has shown that MSCs and MSCs-Exo have therapeutic effects in DN treatment by promoting tissue repair, inhibiting fibrosis, and reducing inflammation. Recent studies underscore the potential of MSCs and MSCs-Exo, highlighting their broad applicability in DN treatment. This review aims to provide a comprehensive summary of the scientific developments in treating DN using MSCs and MSCs-Exo from diverse sources, while also exploring their future therapeutic possibilities in detail.
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Affiliation(s)
- Lixin Liu
- Departments of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning 110001, PR China
| | - Yiman Chen
- Departments of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning 110001, PR China
| | - Xuan Li
- Department of Vascular and Thyroid Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, PR China.
| | - Juan Wang
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, PR China.
| | - Lina Yang
- Departments of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning 110001, PR China; Department of International Physical Examination Center, The First Hospital of China Medical University, Shenyang, Liaoning 110001, PR China.
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Ryu S, Lee EK. The Pivotal Role of Macrophages in the Pathogenesis of Pancreatic Diseases. Int J Mol Sci 2024; 25:5765. [PMID: 38891952 PMCID: PMC11171839 DOI: 10.3390/ijms25115765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 05/20/2024] [Accepted: 05/23/2024] [Indexed: 06/21/2024] Open
Abstract
The pancreas is an organ with both exocrine and endocrine functions, comprising a highly organized and complex tissue microenvironment composed of diverse cellular and non-cellular components. The impairment of microenvironmental homeostasis, mediated by the dysregulation of cell-to-cell crosstalk, can lead to pancreatic diseases such as pancreatitis, diabetes, and pancreatic cancer. Macrophages, key immune effector cells, can dynamically modulate their polarization status between pro-inflammatory (M1) and anti-inflammatory (M2) modes, critically influencing the homeostasis of the pancreatic microenvironment and thus playing a pivotal role in the pathogenesis of the pancreatic disease. This review aims to summarize current findings and provide detailed mechanistic insights into how alterations mediated by macrophage polarization contribute to the pathogenesis of pancreatic disorders. By analyzing current research comprehensively, this article endeavors to deepen our mechanistic understanding of regulatory molecules that affect macrophage polarity and the intricate crosstalk that regulates pancreatic function within the microenvironment, thereby facilitating the development of innovative therapeutic strategies that target perturbations in the pancreatic microenvironment.
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Affiliation(s)
- Seungyeon Ryu
- Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
- Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Eun Kyung Lee
- Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
- Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
- Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
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14
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Yang J, Xie Y, Xia Z, Ji S, Yang X, Yue D, Liu Y, Yang R, Fan Y. HucMSC-Exo Induced N2 Polarization of Neutrophils: Implications for Angiogenesis and Tissue Restoration in Wound Healing. Int J Nanomedicine 2024; 19:3555-3575. [PMID: 38638364 PMCID: PMC11024985 DOI: 10.2147/ijn.s458295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 04/10/2024] [Indexed: 04/20/2024] Open
Abstract
Background Neutrophils rapidly accumulate in large numbers at sites of tissue damage, exhibiting not only their well-known bactericidal capabilities but also playing crucial roles in angiogenesis and tissue repair. While exosomes derived from human umbilical cord mesenchymal stem cells (HucMSC-Exo) have emerged as a promising therapeutic tool, their exact mechanisms of action remain partly elusive. We hypothesize that HucMSC-Exo treatment may modulate neutrophil phenotypes, thereby significantly influencing wound healing outcomes. Methods HucMSC-Exo were isolated via ultracentrifugation and subsequently administered through subcutaneous injection into full-thickness cutaneous wounds in mice. To determine the impact of host neutrophils on the healing effects of HucMSC-Exo in skin injuries, strategies including neutrophil depletion and adoptive transfer were employed. Flow cytometry was used to evaluate the proportion of N2 subtype neutrophils in both normal and diabetic wounds, and the effect of HucMSC-Exo on this proportion was assessed. Furthermore, the mitochondrial metabolic reprogramming driven by HucMSC-Exo during N2 polarization was investigated through JC1 staining, ATP quantification, fatty acid uptake assays, and assessment of FAO-related genes (Cpt1b, Acadm, and Acadl). Results Depleting host neutrophils strikingly dampened prohealing effect of HucMSC-Exo on skin injury, while adoptive transfer of bone marrow neutrophils rescued this process. During normal healing process, some neutrophils expressed N2 markers, in contrast, diabetic wounds exhibited a reduced expression of N2 markers. After treatment with HucMSC-Exo, most neutrophils increased the phosphorylation of STAT6, leading to mitochondrial metabolic reprogramming and thus acquired an N2 phenotype. These N2 neutrophils, polarized by HucMSC-Exo, boosted the release of proangiogenic factors, particularly BV8, a myeloid cell-derived proangiogenic factor, and induced angiogenesis thereby favoring tissue restoration. Conclusion This research uniquely demonstrates the identification of N2 neutrophils in skin injury and shows that HucMSC-Exo could skew neutrophils toward N2 phenotype, enhancing our insight into how cells react to HucMSC-Exo.
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Affiliation(s)
- Jiaman Yang
- Department of Dermatology, the Seventh Medical Center of Chinese PLA General Hospital, Beijing, 100700, People’s Republic of China
- The Second School of Clinical Medicine, SouThern Medical University, Guangzhou, 510599, People’s Republic of China
| | - Yulin Xie
- Department of Dermatology, the Seventh Medical Center of Chinese PLA General Hospital, Beijing, 100700, People’s Republic of China
- The Second School of Clinical Medicine, SouThern Medical University, Guangzhou, 510599, People’s Republic of China
| | - Zhikuan Xia
- Department of Dermatology, the Seventh Medical Center of Chinese PLA General Hospital, Beijing, 100700, People’s Republic of China
| | - Shuaifei Ji
- Chinese PLA Medical School, Beijing, 100853, People’s Republic of China
| | - Xin Yang
- Department of Dermatology, the Seventh Medical Center of Chinese PLA General Hospital, Beijing, 100700, People’s Republic of China
| | - Danxia Yue
- Department of Dermatology, the Seventh Medical Center of Chinese PLA General Hospital, Beijing, 100700, People’s Republic of China
| | - Yuanyuan Liu
- Department of Dermatology, the Seventh Medical Center of Chinese PLA General Hospital, Beijing, 100700, People’s Republic of China
- Chinese PLA Medical School, Beijing, 100853, People’s Republic of China
| | - Rongya Yang
- Department of Dermatology, the Seventh Medical Center of Chinese PLA General Hospital, Beijing, 100700, People’s Republic of China
- The Second School of Clinical Medicine, SouThern Medical University, Guangzhou, 510599, People’s Republic of China
- Chinese PLA Medical School, Beijing, 100853, People’s Republic of China
| | - Yunlong Fan
- Department of Dermatology, the Seventh Medical Center of Chinese PLA General Hospital, Beijing, 100700, People’s Republic of China
- Chinese PLA Medical School, Beijing, 100853, People’s Republic of China
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Su W, Yin Y, Cheng Y, Yu S, Hu R, Zhang H, Hu J, Ren R, Zhang Y, Zhao J, Wang A, Lyu Z, Mu Y, Gao J. The phenotype and related gene expressions of macrophages in adipose tissue of T2D mice following MSCs infusion. Immunobiology 2024; 229:152788. [PMID: 38309141 DOI: 10.1016/j.imbio.2024.152788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 12/28/2023] [Accepted: 01/24/2024] [Indexed: 02/05/2024]
Abstract
BACKGROUND Infusion of mesenchymal stem cells (MSCs) induces polarization of M2 macrophages in adipose tissue of type 2 diabetes (T2D) mice. Studies have shown that M2 macrophages were divided into four sub-phenotypes (M2a, M2b, M2c and M2d) with different functions, and manuscripts have also confirmed that macrophages co-cultured with MSCs were not matched with known four phenotype macrophages. Therefore, our study explored the phenotype and related gene expressions of macrophages in the adipose tissue of T2D mice with/without MSCs infusion. METHODS We induced a T2D mouse model by using high-fat diets and streptozotocin (STZ) injection. The mice were divided into three groups: the control group, the T2D group, and the MSCs group. MSCs were systemically injected once a week for 6 weeks. The phenotype of macrophages in adipose tissue was detected via flow cytometric analysis. We also investigated the gene expression of macrophages in different groups via SMART-RNA-sequencing and quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR). RESULTS The present study found that the macrophages of adipose tissue in the MSCs group were polarized to the M2 phenotype mixed with four sub-phenotypes. Besides, M2a and M2c held a dominant position, while M2b and M2d (tumor-associated macrophages, TAMs) exhibited a decreasing trend after infusion of MSCs. Moreover, the MSCs group did not appear to express higher levels of tumor-associated, inflammation-associated, or fibrosis-associated genes in comparison to the T2D group. CONCLUSION The present results unveiled that the macrophage phenotype was inclined to be present in a hybridity state of four M2 sub-phenotypes and the genes related to tumor-promoting, pro-inflammation and pro-fibrosis were not increased after MSCs injection.
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Affiliation(s)
- Wanlu Su
- School of Medicine, Nankai University, No. 94 Weijin Road, Tianjin 300071, China; Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Yaqi Yin
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Yu Cheng
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Songyan Yu
- Department of Endocrinology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
| | - Ruofan Hu
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Haixia Zhang
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Jia Hu
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Rui Ren
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Yue Zhang
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Jian Zhao
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Anning Wang
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Zhaohui Lyu
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China.
| | - Yiming Mu
- School of Medicine, Nankai University, No. 94 Weijin Road, Tianjin 300071, China; Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China.
| | - Jieqing Gao
- Department of Endocrinology, Beijing Rehabilitation Hospital of Capital Medical University, Beijing, China.
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Wang Y, Chen H, Li Y, Hao H, Liu J, Chen Y, Meng J, Zhang S, Gu W, Lyu Z, Zang L, Mu Y. Predictive factors that influence the clinical efficacy of umbilical cord-derived mesenchymal stromal cells in the treatment of type 2 diabetes mellitus. Cytotherapy 2024; 26:311-316. [PMID: 38219142 DOI: 10.1016/j.jcyt.2023.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 11/20/2023] [Accepted: 12/26/2023] [Indexed: 01/15/2024]
Abstract
BACKGROUND Our previous single-center, randomized, double-blinded, placebo-controlled phase 2 study evaluated the safety and effectiveness of human umbilical cord mesenchymal stromal cell (UC-MSC) transfusion for treating patients with type 2 diabetes mellitus (T2DM). Indeed, this potential treatment strategy was able to reduce insulin use by half in a considerable number of patients. However, many other patients' responses to UC-MSC transfusion were insignificant. The selection of patients who might benefit from UC-MSC treatment is crucial from a clinical standpoint. METHODS In this post hoc analysis, 37 patients who received UC-MSC transfusions were divided into two groups based on whether their glycated hemoglobin (hemoglobin A1c, or HbA1c) level was less than 7% after receiving UC-MSC treatment. The baseline differences between the two groups were summarized, and potential factors influencing efficacy of UC-MSCs for T2DM were analyzed by univariate and multivariate logistic regression. The correlations between the relevant hormone levels and the treatment effect were further analyzed. RESULTS At the 9-week follow-up, 59.5% of patients achieved their targeted HbA1c level. Male patients with lower baseline HbA1c and greater C-peptide area under the curve (AUCC-pep) values responded favorably to UC-MSC transfusion, according to multivariate analysis. The effectiveness of UC-MSCs transfusion was predicted by AUCC-pep (cutoff value: 14.22 ng/h/mL). Further investigation revealed that AUCC-pep was increased in male patients with greater baseline testosterone levels. CONCLUSIONS Male patients with T2DM with greater AUCC-pep may be more likely to respond clinically to UC-MSC therapy, and further large-scale multi-ethnic clinical studies should be performed to confirm the conclusion.
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Affiliation(s)
- Yuepeng Wang
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China; School of Medicine, Nankai University, Tianjin, China
| | - Haixu Chen
- Institute of Geriatrics & National Clinical Research Center of Geriatrics Disease, The Second Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yijun Li
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Haojie Hao
- Department of Biotherapy, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jiejie Liu
- Department of Biotherapy, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yulong Chen
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Junhua Meng
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Saichun Zhang
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Weijun Gu
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zhaohui Lyu
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Li Zang
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China.
| | - Yiming Mu
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China.
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Li L, Hua S, You L, Zhong T. Secretome Derived from Mesenchymal Stem/Stromal Cells: A Promising Strategy for Diabetes and its Complications. Curr Stem Cell Res Ther 2024; 19:1328-1350. [PMID: 37711134 DOI: 10.2174/1574888x19666230913154544] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 07/06/2023] [Accepted: 07/24/2023] [Indexed: 09/16/2023]
Abstract
Diabetes is a complex metabolic disease with a high global prevalence. The health and quality of life of patients with diabetes are threatened by many complications, including diabetic foot ulcers, diabetic kidney diseases, diabetic retinopathy, and diabetic peripheral neuropathy. The application of mesenchymal stem/stromal cells (MSCs) in cell therapies has been recognized as a potential treatment for diabetes and its complications. MSCs were originally thought to exert biological effects exclusively by differentiating and replacing specific impaired cells. However, the paracrine function of factors secreted by MSCs may exert additional protective effects. MSCs secrete multiple compounds, including proteins, such as growth factors, chemokines, and other cytokines; nucleic acids, such as miRNAs; and lipids, extracellular vesicles (EVs), and exosomes (Exos). Collectively, these secreted compounds are called the MSC secretome, and usage of these chemicals in cell-free therapies may provide stronger effects with greater safety and convenience. Recent studies have demonstrated positive effects of the MSC secretome, including improved insulin sensitivity, reduced inflammation, decreased endoplasmic reticulum stress, enhanced M2 polarization of macrophages, and increased angiogenesis and autophagy; however, the mechanisms leading to these effects are not fully understood. This review summarizes the current research regarding the secretome derived from MSCs, including efforts to quantify effectiveness and uncover potential molecular mechanisms in the treatment of diabetes and related disorders. In addition, limitations and challenges are also discussed so as to facilitate applications of the MSC secretome as a cell-free therapy for diabetes and its complications.
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Affiliation(s)
- Ling Li
- Nanjing Maternity and Child Health Care Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, 210004, China
| | - Siyu Hua
- Nanjing Maternity and Child Health Care Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, 210004, China
| | - Lianghui You
- Nanjing Maternity and Child Health Care Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, 210004, China
| | - Tianying Zhong
- Nanjing Maternity and Child Health Care Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, 210004, China
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Ti D, Yi J, Chen H, Hao H, Shi C. The Role of Mesenchymal Stem/Stromal Cells Secretome in Macrophage Polarization: Perspectives on Treating Inflammatory Diseases. Curr Stem Cell Res Ther 2024; 19:894-905. [PMID: 37723965 DOI: 10.2174/1574888x18666230811093101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 06/25/2023] [Accepted: 06/28/2023] [Indexed: 09/20/2023]
Abstract
Mesenchymal stem/stromal cells (MSCs) have exhibited potential for treating multiple inflammation- related diseases (IRDs) due to their easy acquisition, unique immunomodulatory and tissue repair properties, and immune-privileged characteristics. It is worth mentioning that MSCs release a wide array of soluble bioactive components in the secretome that modulate host innate and adaptive immune responses and promote the resolution of inflammation. As the first line of defense, macrophages exist throughout the entire inflammation process. They continuously switch their molecular phenotypes accompanied by complementary functional regulation ranging from classically activated pro-inflammatory M1-type (M1) to alternatively activated anti-inflammatory M2-type macrophages (M2). Recent studies have shown that the active intercommunication between MSCs and macrophages is indispensable for the immunomodulatory and regenerative behavior of MSCs in pharmacological cell therapy products. In this review, we systematically summarized the emerging capacities and detailed the molecular mechanisms of the MSC-derived secretome (MSC-SE) in immunomodulating macrophage polarization and preventing excessive inflammation, providing novel insights into the clinical applications of MSC-based therapy in IRD management.
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Affiliation(s)
| | - Jun Yi
- Newlife R&D Center, Beijing, China
| | | | | | - Chunmeng Shi
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
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Yang LF, He JD, Jiang WQ, Wang XD, Yang XC, Liang Z, Zhou YK. Interferon-gamma Treatment of Human Umbilical Cord Mesenchymal Stem Cells can Significantly Reduce Damage Associated with Diabetic Peripheral Neuropathy in Mice. Curr Stem Cell Res Ther 2024; 19:1129-1141. [PMID: 37644749 DOI: 10.2174/1574888x19666230829155046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 07/17/2023] [Accepted: 07/24/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUND Diabetic peripheral neuropathy causes significant pain to patients. Umbilical cord mesenchymal stem cells have been shown to be useful in the treatment of diabetes and its complications. The aim of this study was to investigate whether human umbilical cord mesenchymal stem cells treated with interferon-gamma can ameliorate nerve injury associated with diabetes better than human umbilical cord mesenchymal stem cells without interferon-gamma treatment. METHODS Human umbilical cord mesenchymal stem cells were assessed for adipogenic differentiation, osteogenic differentiation, and proliferation ability. Vonfry and a hot disc pain tester were used to evaluate tactile sensation and thermal pain sensation in mice. Hematoxylin-eosin and TUNEL staining were performed to visualize sciatic nerve fiber lesions and Schwann cell apoptosis in diabetic mice. Western blotting was used to detect expression of the apoptosis-related proteins Bax, B-cell lymphoma-2, and caspase-3 in mouse sciatic nerve fibers and Schwann cells. Real-Time Quantitative PCR was used to detect mRNA levels of the C-X-C motif chemokine ligand 1, C-X-C motif chemokine ligand 2, C-X-C motif chemokine ligand 9, and C-X-C motif chemokine ligand 10 in mouse sciatic nerve fibers and Schwann cells. Enzyme-linked immunosorbent assay was used to detect levels of the inflammatory cytokines, interleukin- 1β, interleukin-6, and tumor necrosis factor-α in serum and Schwann cells. RESULTS The adipogenic differentiation capacity, osteogenic differentiation capacity, and proliferation ability of human umbilical cord mesenchymal stem cells were enhanced after interferon-gamma treatment. Real-Time Quantitative PCR revealed that interferon-gamma promoted expression of the adipogenic markers, PPAR-γ and CEBP-α, as well as of the osteogenic markers secreted phosphoprotein 1, bone gamma-carboxyglutamate protein, collagen type I alpha1 chain, and Runt-related transcription factor 2. The results of hematoxylin-eosin and TUNEL staining showed that pathological nerve fiber damage and Schwann cell apoptosis were reduced after the injection of interferon-gamma-treated human umbilical cord mesenchymal stem cells. Expression of the apoptosis-related proteins, caspase-3 and Bax, was significantly reduced, while expression of the anti-apoptotic protein B-cell lymphoma-2 was significantly increased. mRNA levels of the cell chemokines, C-X-C motif chemokine ligand 1, C-X-C motif chemokine ligand 2, C-X-C motif chemokine ligand 9, and C-X-C motif chemokine ligand 10, were significantly reduced, and levels of the inflammatory cytokines, interleukin-1β, interleukin-6, and tumor necrosis factor-α, were decreased. Tactile and thermal pain sensations were improved in diabetic mice. CONCLUSION Interferon-gamma treatment of umbilical cord mesenchymal stem cells enhanced osteogenic differentiation, adipogenic differentiation, and proliferative potential. It can enhance the ability of human umbilical cord mesenchymal stem cells to alleviate damage to diabetic nerve fibers and Schwann cells, in addition to improving the neurological function of diabetic mice.
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Affiliation(s)
- Li-Fen Yang
- Department of Endocrinology and Metabolism, First People's Hospital of Yunnan Province, China
| | - Jun-Dong He
- Department of Endocrinology and Metabolism, First People's Hospital of Yunnan Province, China
- Medical School, Kunming University of Science and Technology, Kunming, 650300, Yunnan Province, People's Republic of China
| | - Wei-Qi Jiang
- The First Clinical Medical College, Kunming Medical University, Kunming, 650050, People's Republic of China
| | - Xiao-Dan Wang
- Kunming Yan'an Hospital Kunming, 650051, People's Republic of China
| | - Xiao-Chun Yang
- Department of Ophthalmology First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, 650032, People's Republic of China
| | - Zhi Liang
- Department of Information Center, First People's Hospital of Yunnan Province, China
| | - Yi-Kun Zhou
- Department of Endocrinology and Metabolism, First People's Hospital of Yunnan Province, China
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Arte PA, Tungare K, Bhori M, Jobby R, Aich J. Treatment of type 2 diabetes mellitus with stem cells and antidiabetic drugs: a dualistic and future-focused approach. Hum Cell 2024; 37:54-84. [PMID: 38038863 DOI: 10.1007/s13577-023-01007-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 10/31/2023] [Indexed: 12/02/2023]
Abstract
Type 2 Diabetes Mellitus (T2DM) accounts for more than 90% of total diabetes mellitus cases all over the world. Obesity and lack of balance between energy intake and energy expenditure are closely linked to T2DM. Initial pharmaceutical treatment and lifestyle interventions can at times lead to remission but usually help alleviate it to a certain extent and the condition remains, thus, recurrent with the patient being permanently pharmaco-dependent. Mesenchymal stromal cells (MSCs) are multipotent, self-renewing cells with the ability to secrete a variety of biological factors that can help restore and repair injured tissues. MSC-derived exosomes possess these properties of the original stem cells and are potentially able to confer superior effects due to advanced cell-to-cell signaling and the presence of stem cell-specific miRNAs. On the other hand, the repository of antidiabetic agents is constantly updated with novel T2DM disease-modifying drugs, with higher efficacy and increasingly convenient delivery protocols. Delving deeply, this review details the latest progress and ongoing studies related to the amalgamation of stem cells and antidiabetic drugs, establishing how this harmonized approach can exert superior effects in the management and potential reversal of T2DM.
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Affiliation(s)
- Priyamvada Amol Arte
- School of Biotechnology and Bioinformatics, DY Patil Deemed to Be University, CBD Belapur, Navi Mumbai, Maharashtra, 400614, India.
- Anatek Services PVT LTD, Sai Chamber, 10, Near Santacruz Railway Bridge, Sen Nagar, Santacruz East, Mumbai, Maharashtra, 400055, India.
| | - Kanchanlata Tungare
- School of Biotechnology and Bioinformatics, DY Patil Deemed to Be University, CBD Belapur, Navi Mumbai, Maharashtra, 400614, India
| | - Mustansir Bhori
- Inveniolife Technology PVT LTD, Office No.118, Grow More Tower, Plot No.5, Sector 2, Kharghar, Navi Mumbai, Maharashtra, 410210, India
| | - Renitta Jobby
- Amity Institute of Biotechnology, Amity University Maharashtra, Mumbai-Pune Expressway, Bhatan, Panvel, Navi Mumbai, Maharashtra, 410206, India
- Amity Centre of Excellence in Astrobiology, Amity University Maharashtra, Mumbai-Pune Expressway, Bhatan, Panvel, Navi Mumbai, Maharashtra, 410206, India
| | - Jyotirmoi Aich
- School of Biotechnology and Bioinformatics, DY Patil Deemed to Be University, CBD Belapur, Navi Mumbai, Maharashtra, 400614, India
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21
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Lin X, Qu J, Yin L, Wang R, Wang X. Aerobic exercise-induced decrease of chemerin improved glucose and lipid metabolism and fatty liver of diabetes mice through key metabolism enzymes and proteins. Biochim Biophys Acta Mol Cell Biol Lipids 2023; 1868:159409. [PMID: 37871796 DOI: 10.1016/j.bbalip.2023.159409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 10/18/2023] [Accepted: 10/20/2023] [Indexed: 10/25/2023]
Abstract
Our previous studies have implicated an important role of adipokine chemerin in exercise-induced improvements of glycolipid metabolism and fatty liver in diabetes rat, but the underlying mechanisms remain unknown. This study first used an exogenous chemerin supplement to clarify the roles of decreased chemerin in exercised diabetes mice and possible mechanisms of glucose and lipid metabolism key enzymes and proteins [such as adipose triglyceride lipase (ATGL), lipoprotein lipase (LPL), phosphoenolpyruvate carboxykinase (PEPCK), and glucose transporter 4 (GLUT4)]. In addition, two kinds of adipose-specific chemerin knockout mice were generated to demonstrate the regulation of chemerin on glucose and lipid metabolism enzymes and proteins. We found that in diabetes mice, exercise-induced improvements of glucose and lipid metabolism and fatty liver, and exercise-induced increases of ATGL, LPL, and GLUT4 in liver, gastrocnemius and fat were reversed by exogenous chemerin. Furthermore, in chemerin knockdown mice, chemerin(-/-)∙adiponectin mice had lower body fat mass, improved blood glucose and lipid, and no fatty liver; while chemerin(-/-)∙fabp4 mice had hyperlipemia and unchanged body fat mass. Peroxisome proliferator-activated receptor γ (PPARγ), ATGL, LPL, GLUT4 and PEPCK in the liver and gastrocnemius had improve changes in chemerin(-/-)·adiponectin mice while deteriorated alterations in chemerin(-/-)·fabp4 mice, although PPARγ, ATGL, LPL, and GLUT4 increased in the fat of two kinds of chemerin(-/-) mice. CONCLUSIONS: Decreased chemerin exerts an important role in exercise-induced improvements of glucose and lipid metabolism and fatty liver in diabetes mice, which was likely to be through PPARγ mediating elevations of ATGL, LPL and GLUT4 in peripheral metabolic organs.
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Affiliation(s)
- Xiaojing Lin
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China
| | - Jing Qu
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China
| | - Lijun Yin
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China
| | - Ru Wang
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China.
| | - Xiaohui Wang
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China.
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Bajetto A, Pattarozzi A, Sirito R, Barbieri F, Florio T. Metformin potentiates immunosuppressant activity and adipogenic differentiation of human umbilical cord-mesenchymal stem cells. Int Immunopharmacol 2023; 124:111078. [PMID: 37844465 DOI: 10.1016/j.intimp.2023.111078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 09/25/2023] [Accepted: 10/11/2023] [Indexed: 10/18/2023]
Abstract
Metformin, a first-line drug for type-2 diabetes, displays pleiotropic effects on inflammation, aging, and cancer. Obesity triggers a low-grade chronic inflammation leading to insulin resistance, characterized by increased pro-inflammatory cytokines produced by adipocytes and infiltrated immune cells, which contributes to metabolic syndrome. We investigated metformin's differentiation and immunoregulatory properties of human umbilical cord-mesenchymal stem cells (UC-MSC), as cellular basis of its beneficial role in metabolic dysfunctions. Isolation, characterization and multilineage differentiation of UC-MSC were performed using standard protocols and flow-cytometry. Metformin effects on UC-MSC growth was assessed by colony formation and MTT assay, gene and protein expression by qRT-PCR, and western blot analysis. Proliferation of peripheral blood mononuclear cells (PBMCs) co-cultured with metformin-treated UC-MSC-conditioned media was evaluated by dye dilution assay. We show that metformin decreases proliferation and colony formation of UC-MSCs and enhances their adipogenic lineage commitment. Metformin (3 mM) increases PPARγ and downregulates FABP4 mRNA both in basal and in adipogenic culture conditions; however, the modulation of PPARγ expression is unrelated to the antiproliferative effects. Moreover, metformin inhibits UC-MSC inflammatory activity reducing the expression of IL-6, MCP-1, and COX-2. Conditioned media, collected from metformin-treated UC-MSCs, down-regulate CD3+ T lymphocyte growth in stimulated PBMCs and, in particular, reduce the CD8+ T cell population. These results indicate that metformin may favor new adipocyte formation and potentiate immune suppressive properties of UC-MSCs. Thus, adipose tissue regeneration and anti-inflammatory activity may represent possible mechanisms by which metformin exerts its positive effect on lipid metabolism.
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Affiliation(s)
- Adriana Bajetto
- Section of Pharmacology, Department of Internal Medicine, University of Genova, 16132 Genova, Italy
| | - Alessandra Pattarozzi
- Section of Pharmacology, Department of Internal Medicine, University of Genova, 16132 Genova, Italy
| | - Rodolfo Sirito
- Section of Obstetrics and Gynaecology, International Evangelical Hospital, 16122 Genova, Italy
| | - Federica Barbieri
- Section of Pharmacology, Department of Internal Medicine, University of Genova, 16132 Genova, Italy
| | - Tullio Florio
- Section of Pharmacology, Department of Internal Medicine, University of Genova, 16132 Genova, Italy; IRCCS, Ospedale Policlinico San Martino, 16132 Genova, Italy.
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Liang Z, Zhang G, Gan G, Liu X, Liu H, Nie D, Ma L. Mesenchymal Stromal Cells Regulate M1/M2 Macrophage Polarization in Mice with Immune Thrombocytopenia. Stem Cells Dev 2023; 32:703-714. [PMID: 37606909 DOI: 10.1089/scd.2023.0154] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2023] Open
Abstract
Mesenchymal stromal cells have shown promising effects in the treatment of immune thrombocytopenia. However, the underlying mechanisms are not fully understood. In this study, we investigated the therapeutic effects of human bone marrow mesenchymal stromal cells (hBMSCs) and analyzed their unique role in regulating the M1/M2 macrophage ratio. We established a passive immune thrombocytopenia (ITP) mouse model and showed that there was a significant M1/M2 imbalance in ITP model mice by assessing the M1/M2 ratios in the liver, spleen, and bone marrow; we observed excessive activation of M1 cells and decreased M2 cell numbers in vivo. We have shown that systemic infusion of hBMSCs effectively elevated platelet levels after disease onset. Further analysis revealed that hBMSCs treatment significantly suppressed the number of proinflammatory M1 macrophages and enhanced the number of anti-inflammatory M2 macrophages; in addition, the levels of proinflammatory factors, such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), were significantly decreased in vivo, while the levels of the anti-inflammatory factor interleukin-10 (IL-10) were increased. In conclusion, our data suggest that hBMSCs treatment can effectively increase platelet counts, and the mechanism is related to the induction of macrophage polarization toward the anti-inflammatory M2 phenotype and the decrease in proinflammatory cytokine production, which together ameliorate innate immune disorders.
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Affiliation(s)
- Ziyang Liang
- Department of Hematology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Guoyang Zhang
- Department of Hematology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - GuangTing Gan
- Department of Oncology, Guizhou Provincial People's Hospital, Guiyang, China
| | - Xiaoyan Liu
- Department of Hematology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Hongyun Liu
- Department of Hematology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Danian Nie
- Department of Hematology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Liping Ma
- Department of Hematology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
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Li L, Li J, Guan H, Oishi H, Takahashi S, Zhang C. Human umbilical cord mesenchymal stem cells in diabetes mellitus and its complications: applications and research advances. Int J Med Sci 2023; 20:1492-1507. [PMID: 37790847 PMCID: PMC10542192 DOI: 10.7150/ijms.87472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 08/22/2023] [Indexed: 10/05/2023] Open
Abstract
Diabetes mellitus and its complications pose a major threat to global health and affect the quality of life and life expectancy of patients. Currently, the application of traditional therapeutic drugs for diabetes mellitus has great limitations and can only temporarily control blood glucose but not fundamentally cure it. Mesenchymal stem cells, as pluripotent stromal cells, have multidirectional differentiation potential, high self-renewal, immune regulation, and low immunogenicity, which provide a new idea and possible development direction for diabetes mellitus treatment. Regenerative medicine with mesenchymal stem cells treatment as the core treatment will become another treatment option for diabetes mellitus after traditional treatment. Recently, human umbilical cord mesenchymal stem cells have been widely used in basic and clinical research on diabetes mellitus and its complications because of their abundance, low ethical controversy, low risk of infection, and high proliferation and differentiation ability. This paper reviews the therapeutic role and mechanism of human umbilical cord mesenchymal stem cells in diabetes mellitus and its complications and highlights the challenges faced by the clinical application of human umbilical cord mesenchymal stem cells to provide a more theoretical basis for the application of human umbilical cord mesenchymal stem cells in diabetes mellitus patients.
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Affiliation(s)
- Luyao Li
- Department of Endocrinology, the Second Hospital of Jilin University, Changchun 130041, Jilin, P.R. China
| | - Jicui Li
- Department of Nephrology, the Second Hospital of Jilin University, Changchun 130041, Jilin, P.R. China
| | - Haifei Guan
- Department of Endocrinology, the Second Hospital of Jilin University, Changchun 130041, Jilin, P.R. China
| | - Hisashi Oishi
- Department of Comparative and Experimental Medicine, Nagoya City University Graduate 24 School of Medical Sciences, Aichi 467-8601, Nagoya, Japan
| | - Satoru Takahashi
- Institute of Basic Medical Sciences and Laboratory Animal Resource Center, University of Tsukuba, Ibaraki 305-8575, Tsukuba, Japan
| | - Chuan Zhang
- Department of Endocrinology, the Second Hospital of Jilin University, Changchun 130041, Jilin, P.R. China
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Extracellular Vesicles Derived from Three-Dimensional-Cultured Human Umbilical Cord Blood Mesenchymal Stem Cells Prevent Inflammation and Dedifferentiation in Pancreatic Islets. Stem Cells Int 2023; 2023:5475212. [PMID: 36860546 PMCID: PMC9970714 DOI: 10.1155/2023/5475212] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 12/16/2022] [Accepted: 02/08/2023] [Indexed: 02/22/2023] Open
Abstract
It is unclear whether extracellular vesicles (EVs) from mesenchymal stem cells (MSCs) have a direct protective effect on pancreatic islets. In addition, whether culturing MSCs in three dimensions (3D) instead of a monolayer (2D) can induce changes in the cargo of EVs that facilitate the polarization of macrophages into an M2 phenotype has not been investigated. We sought to determine whether EVs from MSCs cultured in 3D can prevent inflammation and dedifferentiation in pancreatic islets and, if so, whether the protective effect is superior to that of EVs from 2D MSCs. Human umbilical cord blood- (hUCB-) MSCs cultured in 3D were optimized according to cell density, exposure to hypoxia, and cytokine treatment based on the ability of the hUCB-MSC-derived EVs to induce the M2 polarization of macrophages. Islets isolated from human islet amyloid polypeptide (hIAPP) heterozygote transgenic mice were cultured in serum-deprived conditions with hUCB-MSC-derived EVs. EVs derived from 3D hUCB-MSCs had more abundant microRNAs involved in M2 polarization of macrophages and had an enhanced M2 polarization ability on macrophages, which was optimized when the 3D culture condition was 2.5 × 104 cells per spheroid without preconditioning with hypoxia and cytokine exposure. When islets isolated from hIAPP heterozygote transgenic mice were cultured in serum-deprived conditions with hUCB-MSC-derived EVs, the EVs derived from 3D hUCB-MSCs suppressed the expression of proinflammatory cytokines and caspase-1 in pancreatic islets and increased the proportion of M2-polarized islet-resident macrophages. They improved glucose-stimulated insulin secretion, reduced the expression of Oct4 and NGN3, and induced the expression of Pdx1 and FoxO1. The greater suppression of IL-1β, NLRP3 inflammasome, caspase-1, and Oct4 and induction of Pdx1 and FoxO1 were found in islets cultured with the EVs derived from 3D hUCB-MSCs. In conclusion, EVs derived from 3D hUCB-MSCs optimized for M2 polarization attenuated nonspecific inflammation and preserved β-cell identity of pancreatic islets.
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Liang ZH, Lin SS, Pan NF, Zhong GY, Qiu ZY, Kuang SJ, Lin ZH, Zhang Z, Pan YC. UCMSCs-derived exosomal circHIPK3 promotes ulcer wound angiogenesis of diabetes mellitus via miR-20b-5p/Nrf2/VEGFA axis. Diabet Med 2023; 40:e14968. [PMID: 36209373 DOI: 10.1111/dme.14968] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 09/14/2022] [Accepted: 10/07/2022] [Indexed: 01/17/2023]
Abstract
AIMS Experiments confirmed that circular RNAs contributed to the pathogenesis of diabetic foot ulcers (DFUs). CircHIPK3 was upregulated in type 2 diabetes mellitus (T2DM), but its role in DFU remained unknown. Our study aimed to investigate the regulatory functions of exosomal circHIPK3 and its potential mechanisms in DFU. METHODS Exosomal size and distribution, marker proteins, and circHIPK3 levels were evaluated by transmission electron microscope, ExoView R200, western blot, and qRT-PCR. Flow cytometry, MTT, Wound healing assays, and tube formation assays were used to assess the roles of exosomal circHIPK3 in high glucose (HG)-treated human umbilical vein endothelial cells (HUVECs). The relationships between Nrf2/VEGFA/circHIPK3 and miR-20b-5p, and between Nrf2 and VEGFA were determined by luciferase reporter assay and RNA immunoprecipitation. We used cell and mice models to investigate the mechanisms of exosomal circHIPK3 under diabetic conditions. RESULTS CircHIPK3 was significantly upregulated in exo-circHIPK3 rather than exo-vector. Exo-circHIPK3 remarkably inhibited cell apoptosis but promoted cell proliferation, migration, and tube formation in HG-treated HUVECs. Luciferase reporter and RIP assays showed that miR-20b-5p targeted and inhibited Nrf2 and VEGFA, and circHIPK3 acted as a ceRNA of miR-20b-5p to inhibit the binding to its downstream genes Nrf2 and VEGFA. Mechanistically, circHIPK3 promoted cell proliferation, migration, and angiogenesis via downregulating miR-20b-5p to upregulate Nrf2 and VEGFA. However, the overexpressed miR-20b-5p could abolish the promoting effects of circHIPK3 overexpression on cell proliferation, migration, and tube formation under HG conditions. CONCLUSION UCMSCs-derived exosomal circHIPK3 protected HG-treated HUVECs via miR-20b-5p/Nrf2/VEGFA axis. The exosomal circHIPK3 might be a therapeutic candidate to treat DFU.
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Affiliation(s)
- Zun-Hong Liang
- Department of Burn & Skin Repair Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, People's Republic of China
| | - Shi-Shuai Lin
- Department of Burn & Skin Repair Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, People's Republic of China
| | - Nan-Fang Pan
- Department of Burn & Skin Repair Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, People's Republic of China
| | - Guo-Yu Zhong
- Department of Burn & Skin Repair Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, People's Republic of China
| | - Zhi-Yang Qiu
- Department of Burn & Skin Repair Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, People's Republic of China
| | - Shao-Jia Kuang
- Department of Burn & Skin Repair Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, People's Republic of China
| | - Zhi-Hu Lin
- Department of Burn & Skin Repair Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, People's Republic of China
| | - Zhi Zhang
- Department of Burn and Plastic Surgery, Guangzhou Red Cross Hospital Affifiliated to Jinan University, Guangzhou, People's Republic of China
| | - Yun-Chuan Pan
- Department of Burn & Skin Repair Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, People's Republic of China
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Marson RF, Regner AP, da Silva Meirelles L. Mesenchymal "stem" cells, or facilitators for the development of regenerative macrophages? Pericytes at the interface of wound healing. Front Cell Dev Biol 2023; 11:1148121. [PMID: 36936686 PMCID: PMC10017474 DOI: 10.3389/fcell.2023.1148121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 02/10/2023] [Indexed: 03/06/2023] Open
Abstract
Cultured mesenchymal stromal cells are among the most used cells in clinical trials. Currently, their potential benefits include provision of mature cell types through differentiation, and secretion of various types of paracrine signaling molecules. Even though research on these cells has spanned some decades now, surprisingly, their therapeutic potential has not been fully translated into clinical practice yet, which calls for further understanding of their intrinsic nature and modes of action. In this review, after discussing pieces of evidence that suggest that some perivascular cells may exhibit mesenchymal stem cell characteristics in vivo, we examine the possibility that subpopulations of perivascular and/or adventitial cells activated after tissue injury behave as MSCs and contribute to the resolution of tissue injury by providing cues for the development of regenerative macrophages at injured sites. Under this perspective, an important contribution of cultured MSCs (or their acellular products, such as extracellular vesicles) used in cell therapies would be to instigate the development of M2-like macrophages that support the tissue repair process.
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Affiliation(s)
- Renan Fava Marson
- Graduate Program in Cellular and Molecular Biology Applied to Health—PPGBioSaúde, Lutheran University of Brazil, Canoas, Brazil
| | - Andrea Pereira Regner
- Graduate Program in Cellular and Molecular Biology Applied to Health—PPGBioSaúde, Lutheran University of Brazil, Canoas, Brazil
- School of Medicine, Lutheran University of Brazil, Canoas, Brazil
| | - Lindolfo da Silva Meirelles
- Graduate Program in Cellular and Molecular Biology Applied to Health—PPGBioSaúde, Lutheran University of Brazil, Canoas, Brazil
- School of Medicine, Lutheran University of Brazil, Canoas, Brazil
- *Correspondence: Lindolfo da Silva Meirelles, ,
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Wang W, Wang Y, Chi J, Tan X, Hu J, Ma X, Sun X, Che K, Lv W, Wang Y. hUCMSCs carrying exenatide prevent T1DM by improving intestinal microflora composition and islet tissue damage repair. Mol Med 2022; 28:155. [PMID: 36514009 PMCID: PMC9746121 DOI: 10.1186/s10020-022-00526-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 08/04/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Exenatide is a stable analogue of glucagon-like peptide 1 that can reduce postprandial hyperglycemia and has been utilized as adjunctive therapy for type 1 diabetes mellitus (T1DM). The human umbilical cord is a rich source of MSCs, and human umbilical cord mesenchymal stem cells (hUCMSCs) also show potential to enhance insulin secretion. Here, we aimed to explore the effects of hUCMSCs carrying exenatide in T1DM and further identify the possible mechanisms involved. METHODS hUCMSCs were isolated from human umbilical cord tissues, identified, and transduced with recombinant lentivirus carrying exenatide to obtain exenatide-carrying hUCMSCs (hUCMSCs@Ex-4). RESULTS The results showed that hUCMSCs@Ex-4 restored the blood glucose levels and body weight of NOD mice, and repressed immune cell infiltration and islet tissue changes. Additionally, in T1DM mice, treatment with hUCMSCs@Ex-4 reduced the blood glucose levels and promoted repair of islet tissue damage. Moreover, hUCMSCs@Ex-4 attenuated renal tissue lesions in T1DM mice. Applying bioinformatic analysis, the effects of hUCMSCs@Ex-4 were suggested to correlate with decreased abundance of pro-inflammatory intestinal bacteria and increased abundance of anti-inflammatory intestinal bacteria. CONCLUSION Overall, the study indicated that hUCMSCs carrying exenatide might improve beneficial intestinal microflora abundance and promote islet tissue damage repair, thereby alleviating T1DM.
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Affiliation(s)
- Wei Wang
- grid.412521.10000 0004 1769 1119Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao, 266000 People’s Republic of China
| | - Yahao Wang
- grid.410645.20000 0001 0455 0905Medical College, Qingdao University, Qingdao, 266071 People’s Republic of China
| | - Jingwei Chi
- grid.412521.10000 0004 1769 1119Key Laboratory of Thyroid Diseases, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266000 People’s Republic of China
| | - Xiaojun Tan
- grid.510325.0Department of Endocrinology, Yidu Central Hospital of Weifang City, Weifang, 261000 People’s Republic of China
| | - Jianxia Hu
- grid.412521.10000 0004 1769 1119The Laboratory of Thyroid Disease, The Affiliated Hospital of Qingdao University, Qingdao, 266000 People’s Republic of China
| | - Xiaolong Ma
- grid.415912.a0000 0004 4903 149XDepartment of Endocrinology, Liaocheng People’s Hospital, Liaocheng, 252000 People’s Republic of China
| | - Xiaofang Sun
- grid.412521.10000 0004 1769 1119Department of Endocrinology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, South District, Qingdao, 266000 Shandong People’s Republic of China
| | - Kui Che
- grid.412521.10000 0004 1769 1119Key Laboratory of Thyroid Diseases, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266000 People’s Republic of China
| | - Wenshan Lv
- grid.412521.10000 0004 1769 1119Department of Endocrinology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, South District, Qingdao, 266000 Shandong People’s Republic of China
| | - Yangang Wang
- grid.412521.10000 0004 1769 1119Department of Endocrinology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, South District, Qingdao, 266000 Shandong People’s Republic of China
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Bai J, Liu F. The Yin-Yang functions of macrophages in metabolic disorders. LIFE MEDICINE 2022; 1:319-332. [PMID: 39872753 PMCID: PMC11749365 DOI: 10.1093/lifemedi/lnac035] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 08/29/2022] [Indexed: 01/30/2025]
Abstract
Macrophages are widely distributed in various metabolic tissues/organs and play an essential role in the immune regulation of metabolic homeostasis. Macrophages have two major functions: adaptive defenses against invading pathogens by triggering inflammatory cytokine release and eliminating damaged/dead cells via phagocytosis to constrain inflammation. The pro-inflammatory role of macrophages in insulin resistance and related metabolic diseases is well established, but much less is known about the phagocytotic function of macrophages in metabolism. In this review, we review our current understanding of the ontogeny, tissue distribution, and polarization of macrophages in the context of metabolism. We also discuss the Yin-Yang functions of macrophages in the regulation of energy homeostasis. Third, we summarize the crosstalk between macrophages and gut microbiota. Lastly, we raise several important but remain to be addressed questions with respect to the mechanisms by which macrophages are involved in immune regulation of metabolism.
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Affiliation(s)
- Juli Bai
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha 410011, China
- Department of Pharmacology, University of Texas Health at San Antonio, San Antonio, TX 78229, USA
| | - Feng Liu
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha 410011, China
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30
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Enhancement of Tendon Repair Using Tendon-Derived Stem Cells in Small Intestinal Submucosa via M2 Macrophage Polarization. Cells 2022; 11:cells11172770. [PMID: 36078178 PMCID: PMC9454771 DOI: 10.3390/cells11172770] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/08/2022] [Accepted: 07/10/2022] [Indexed: 11/17/2022] Open
Abstract
(1) Background: Reconstruction of Achilles tendon defects and prevention of postoperative tendon adhesions were two serious clinical problems. In the treatment of Achilles tendon defects, decellularized matrix materials and mesenchymal stem cells (MSCs) were thought to address both problems. (2) Methods: In vitro, cell adhesion, proliferation, and tenogenic differentiation of tendon-derived stem cells (TDSCs) on small intestinal submucosa (SIS) were evaluated. RAW264.7 was induced by culture medium of TDSCs and TDSCs–SIS scaffold groups. A rat Achilles tendon defect model was used to assess effects on tendon regeneration and antiadhesion in vivo. (3) Results: SIS scaffold facilitated cell adhesion and tenogenic differentiation of TDSCs, while SIS hydrogel coating promoted proliferation of TDSCs. The expression of TGF-β and ARG-1 in the TDSCs-SIS scaffold group were higher than that in the TDSCs group on day 3 and 7. In vivo, the tendon regeneration and antiadhesion capacity of the implanted TDSCs–SIS scaffold was significantly enhanced. The expression of CD163 was significantly highest in the TDSCs–SIS scaffold group; meanwhile, the expression of CD68 decreased more significantly in the TDSCs–SIS scaffold group than the other two groups. (4) Conclusion: This study showed that biologically prepared SIS scaffolds synergistically promote tendon regeneration with TDSCs and achieve antiadhesion through M2 polarization of macrophages.
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31
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Wu X, Xu X, Xiang Y, Fan D, An Q, Yue G, Jin Z, Ding J, Hu Y, Du Q, Xu J, Xie R. Exosome-mediated effects and applications in inflammatory diseases of the digestive system. Eur J Med Res 2022; 27:163. [PMID: 36045437 PMCID: PMC9429695 DOI: 10.1186/s40001-022-00792-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 08/17/2022] [Indexed: 11/24/2022] Open
Abstract
Exosomes are membranous vesicles containing RNA and proteins that are specifically secreted in vivo. Exosomes have many functions, such as material transport and signal transduction between cells. Many studies have proven that exosomes can not only be used as biomarkers for disease diagnosis but also as carriers to transmit information between cells. Exosomes participate in a variety of physiological and pathological processes, including the immune response, antigen presentation, cell migration, cell differentiation, and tumour development. Differences in exosome functions depend on cell type. In recent years, exosome origin, cargo composition, and precise regulatory mechanisms have been the focus of research. Although exosomes have been extensively reported in digestive tumours, few articles have reviewed their roles in inflammatory diseases of the digestive system, especially inflammatory-related diseases (such as reflux oesophagitis, gastritis, inflammatory bowel disease, hepatitis, and pancreatitis). This paper briefly summarizes the roles of exosomes in inflammatory diseases of the digestive system to provide a basis for research on the mechanism of inflammatory diseases of the digestive system targeted by exosomes.
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Affiliation(s)
- Xianli Wu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Xiaolin Xu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Yiwei Xiang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Dongdong Fan
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Qiming An
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Gengyu Yue
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Zhe Jin
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Jianhong Ding
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Yanxia Hu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Qian Du
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Jingyu Xu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China. .,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China.
| | - Rui Xie
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China. .,The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China.
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32
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Gao S, Zhang Y, Liang K, Bi R, Du Y. Mesenchymal Stem Cells (MSCs): A Novel Therapy for Type 2 Diabetes. Stem Cells Int 2022; 2022:8637493. [PMID: 36045953 PMCID: PMC9424025 DOI: 10.1155/2022/8637493] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 02/15/2022] [Accepted: 07/05/2022] [Indexed: 11/25/2022] Open
Abstract
Although plenty of drugs are currently available for type 2 diabetes mellitus (T2DM), a subset of patients still failed to restore normoglycemia. Recent studies proved that symptoms of T2DM patients who are unresponsive to conventional medications could be relieved with mesenchymal stem/stromal cell (MSC) therapy. However, the lack of systematic summary and analysis for animal and clinical studies of T2DM has limited the establishment of standard guidelines in anti-T2DM MSC therapy. Besides, the therapeutic mechanisms of MSCs to combat T2DM have not been thoroughly understood. In this review, we present an overview of the current status of MSC therapy in treating T2DM for both animal studies and clinical studies. Potential mechanisms of MSC-based intervention on multiple pathological processes of T2DM, such as β-cell exhaustion, hepatic dysfunction, insulin resistance, and systemic inflammation, are also delineated. Moreover, we highlight the importance of understanding the pharmacokinetics (PK) of transplanted cells and discuss the hurdles in MSC-based T2DM therapy toward future clinical applications.
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Affiliation(s)
- Shuang Gao
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Yuanyuan Zhang
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Kaini Liang
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Ran Bi
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Yanan Du
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
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33
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Su W, Yu S, Yin Y, Li B, Xue J, Wang J, Gu Y, Zhang H, Lyu Z, Mu Y, Cheng Y. Diabetic microenvironment preconditioning of adipose tissue-derived mesenchymal stem cells enhances their anti-diabetic, anti-long-term complications, and anti-inflammatory effects in type 2 diabetic rats. STEM CELL RESEARCH & THERAPY 2022; 13:422. [PMID: 35986406 PMCID: PMC9389728 DOI: 10.1186/s13287-022-03114-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 08/04/2022] [Indexed: 11/25/2022]
Abstract
Background Mesenchymal stem cells (MSCs) exert anti-diabetic effects and improve long-term complications via secretory effects that regulate macrophage polarisation and attenuate inflammation. Enhancing the efficacy of MSCs needs to be explored further. The in vitro culture microenvironment influences the secretory profile of MSCs. Therefore, we hypothesised that a diabetic microenvironment would promote the secretion of cytokines responsible for macrophage polarisation, further attenuating systemic inflammation and enhancing the effects of MSCs on type 2 diabetes (T2D) and long-term diabetic complications. Methods Preconditioned adipose-derived mesenchymal stem cells (pre-ADSCs) were obtained after co-cultivating ADSCs in a diabetic metabolic environment (including high sugar, advanced glycation end-product, and lipopolysaccharides). The regulatory effects of pre-ADSCs on macrophages were observed in vitro. A T2D rat model was induced with a high-fat diet for 32 weeks combined with an intraperitoneal injection of streptozotocin. Sprague–Dawley (SD) rats were divided into four groups: normal group, diabetes without treatment group (PBS), ADSC treatment group, and pre-ADSC treatment group. ADSCs and pre-ADSCs were intravenously administered weekly to SD rats for 6 months, and then glucose homeostasis and long-term diabetic complications were evaluated in each group. Results The secretion of cytokines related to M2 macrophage polarisation (IL-6, MCP-1, etc.) was increased in the pre-ADSC group in the in vitro model. Pre-ADSC treatment significantly maintained blood glucose homeostasis, reduced insulin resistance, promoted islet regeneration, and ameliorated the complications related to diabetes in rats (chronic kidney disease, non-alcoholic steatohepatitis, lung fibrosis, and cataract) compared to the ADSC group (P < 0.05). Additionally, the number of anti-inflammatory M2 macrophage phenotypes was enhanced in tissues following pre-ADSC injections. Moreover, the expression of pro-inflammatory genes (iNOS, TNF-α, IL-1β) was reduced whereas that of anti-inflammatory genes (Arg1, CD206, and Il-10) was increased after cultivation with pre-ADSCs. Conclusion Diabetic microenvironment-preconditioned ADSCs effectively strengthen the capacity against inflammation and modulate the progress of long-term T2D complications. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03114-5.
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34
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Park YM, Yang CM, Cho HY. Therapeutic Effects of Insulin-Producing Human Umbilical Cord-Derived Mesenchymal Stem Cells in a Type 1 Diabetes Mouse Model. Int J Mol Sci 2022; 23:6877. [PMID: 35805883 PMCID: PMC9266974 DOI: 10.3390/ijms23136877] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 06/17/2022] [Accepted: 06/18/2022] [Indexed: 02/01/2023] Open
Abstract
In patients with type 1 diabetes (T1D), compromised pancreatic β-cell functions are compensated through daily insulin injections or the transplantation of pancreatic tissue or islet cells. However, both approaches are associated with specific challenges. The transplantation of mesenchymal stem cells (MSCs) represents a potential alternative, as MSCs have tissue-forming capacity and can be isolated from various tissues. The human umbilical cord (hUC) is a good source of freely available MSCs, which can be collected through pain-free, non-invasive methods subject to minimal ethical concerns. We sought to develop a method for the in vitro generation of insulin-producing cells (IPCs) using MSCs. We examined the potential therapeutic uses and efficacy of IPCs generated from hUC-derived MSCs (hUC-IPCs) and human adipose tissue (hAD)-derived MSCs (hAD-IPCs) through in vitro experiments and streptozotocin (STZ)-induced C57BL/6 T1D mouse models. We discovered that compared to hAD-IPCs, hUC-IPCs exhibited a superior insulin secretion capacity. Therefore, hUC-IPCs were selected as candidates for T1D cell therapy in mice. Fasting glucose and intraperitoneal glucose tolerance test levels were lower in hUC-IPC-transplanted mice than in T1D control mice and hAD-IPC-transplanted mice. Our findings support the potential use of MSCs for the treatment of T1D.
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Affiliation(s)
- Yu Mi Park
- CHA Advanced Research Institute, 335, Pangyo-ro, Bundang-gu, Seongnam-si 13488, Gyeonggi-do, Korea
- Department of Biomedical Science, CHA University, 335, Pangyo-ro, Bundang-gu, Seongnam-si 13488, Gyeonggi-do, Korea
- Cell Therapy R&D Center, HansBiomed Corp, 7, Jeongui-ro 8-gil, Songpa-gu, Seoul 05836, Gyeonggi-do, Korea; (C.M.Y.); (H.Y.C.)
| | - Chang Mo Yang
- Cell Therapy R&D Center, HansBiomed Corp, 7, Jeongui-ro 8-gil, Songpa-gu, Seoul 05836, Gyeonggi-do, Korea; (C.M.Y.); (H.Y.C.)
| | - Hee Yeon Cho
- Cell Therapy R&D Center, HansBiomed Corp, 7, Jeongui-ro 8-gil, Songpa-gu, Seoul 05836, Gyeonggi-do, Korea; (C.M.Y.); (H.Y.C.)
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35
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Zang L, Li Y, Hao H, Liu J, Cheng Y, Li B, Yin Y, Zhang Q, Gao F, Wang H, Gu S, Li J, Lin F, Zhu Y, Tian G, Chen Y, Gu W, Du J, Chen K, Guo Q, Yang G, Pei Y, Yan W, Wang X, Meng J, Zhang S, Ba J, Lyu Z, Dou J, Han W, Mu Y. Efficacy and safety of umbilical cord-derived mesenchymal stem cells in Chinese adults with type 2 diabetes: a single-center, double-blinded, randomized, placebo-controlled phase II trial. Stem Cell Res Ther 2022; 13:180. [PMID: 35505375 PMCID: PMC9066971 DOI: 10.1186/s13287-022-02848-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 04/14/2022] [Indexed: 12/26/2022] Open
Abstract
Background To determine the efficacy and safety of umbilical cord-derived mesenchymal stem cells (UC-MSCs) in Chinese adults with type 2 diabetes mellitus (T2DM). Methods In this single-center, double-blinded, randomized, placebo-controlled phase II trial, 91 patients were randomly assigned to receive intravenous infusion of UC-MSCs (n = 45) or placebo (n = 46) three times with 4-week intervals and followed up for 48 weeks from October 2015 to December 2018. The primary endpoint was the percentage of patients with glycated hemoglobin (HbA1c) levels of < 7.0% and daily insulin reduction of ≥ 50% at 48 weeks. Additional endpoints were changes of metabolic control, islet β-cell function, insulin resistance, and safety. Results At 48 weeks, 20% of the patients in the UC-MSCs group and 4.55% in the placebo group reached the primary endpoint (p < 0.05, 95% confidence interval (CI) 2.25–28.66%). The percentage of insulin reduction of the UC-MSCs group was significantly higher than that of the placebo group (27.78% versus 15.62%, p < 0.05). The levels of HbA1c decreased 1.31% (9.02 ± 1.27% to 7.52 ± 1.07%, p < 0.01) in the UC-MSCs group, and only 0.63% in the placebo group (8.89 ± 1.11% to 8.19 ± 1.02%, p˃0.05; p = 0.0081 between both groups). The glucose infusion rate (GIR) increased significantly in the UC-MSCs group (from 3.12 to 4.76 mg/min/kg, p < 0.01), whereas no significant change was observed in the placebo group (from 3.26 to 3.60 mg/min/kg, p ˃ 0.05; p < 0.01 between both groups). There was no improvement in islet β-cell function in both groups. No major UC-MSCs transplantation-related adverse events occurred. Conclusions UC-MSCs transplantation could be a potential therapeutic approach for Chinese adults with T2DM. Trial registration This study was registered on ClinicalTrials.gov (identifier: NCT02302599). Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02848-6.
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Affiliation(s)
- Li Zang
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Yijun Li
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Haojie Hao
- Department of Biotherapy, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Jiejie Liu
- Department of Biotherapy, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Yu Cheng
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Bing Li
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Yaqi Yin
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Qian Zhang
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Fei Gao
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Haibin Wang
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Shi Gu
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Jia Li
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Fengxiang Lin
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Yingfei Zhu
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Guanglei Tian
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Yulong Chen
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Weijun Gu
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Jin Du
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Kang Chen
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Qinghua Guo
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Guoqing Yang
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Yu Pei
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Wenhua Yan
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Xianling Wang
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Junhua Meng
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Saichun Zhang
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Jianming Ba
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Zhaohui Lyu
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Jingtao Dou
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Weidong Han
- Department of Biotherapy, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China.
| | - Yiming Mu
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China.
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Xin DQ, Zhao YJ, Li TT, Ke HF, Gai CC, Guo XF, Chen WQ, Liu DX, Wang Z. The delivery of miR-21a-5p by extracellular vesicles induces microglial polarization via the STAT3 pathway following hypoxia-ischemia in neonatal mice. Neural Regen Res 2022; 17:2238-2246. [PMID: 35259844 PMCID: PMC9083169 DOI: 10.4103/1673-5374.336871] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Extracellular vesicles (EVs) from mesenchymal stromal cells (MSCs) have previously been shown to protect against brain injury caused by hypoxia-ischemia (HI). The neuroprotective effects have been found to relate to the anti-inflammatory effects of EVs. However, the underlying mechanisms have not previously been determined. In this study, we induced oxygen-glucose deprivation in BV-2 cells (a microglia cell line), which mimics HI in vitro, and found that treatment with MSCs-EVs increased the cell viability. The treatment was also found to reduce the expression of pro-inflammatory cytokines, induce the polarization of microglia towards the M2 phenotype, and suppress the phosphorylation of selective signal transducer and activator of transcription 3 (STAT3) in the microglia. These results were also obtained in vivo using neonatal mice with induced HI. We investigated the potential role of miR-21a-5p in mediating these effects, as it is the most highly expressed miRNA in MSCs-EVs and interacts with the STAT3 pathway. We found that treatment with MSCs-EVs increased the levels of miR-21a-5p in BV-2 cells, which had been lowered following oxygen-glucose deprivation. When the level of miR-21a-5p in the MSCs-EVs was reduced, the effects on microglial polarization and STAT3 phosphorylation were reduced, for both the in vitro and in vivo HI models. These results indicate that MSCs-EVs attenuate HI brain injury in neonatal mice by shuttling miR-21a-5p, which induces microglial M2 polarization by targeting STAT3.
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Affiliation(s)
- Dan-Qing Xin
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Yi-Jing Zhao
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Ting-Ting Li
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Hong-Fei Ke
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Cheng-Cheng Gai
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Xiao-Fan Guo
- Department of Neurology, Loma Linda University Health, Loma Linda, CA, USA
| | - Wen-Qiang Chen
- Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - De-Xiang Liu
- Department of Medical Psychology and Ethics, School of Basic Medicine Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Zhen Wang
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
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Tian G, Liu C, Gong Q, Yu Z, Wang H, Zhang D, Cong H. Human Umbilical Cord Mesenchymal Stem Cells Improve the Necrosis and Osteocyte Apoptosis in Glucocorticoid-Induced Osteonecrosis of the Femoral Head Model through Reducing the Macrophage Polarization. Int J Stem Cells 2021; 15:195-202. [PMID: 34965999 PMCID: PMC9148830 DOI: 10.15283/ijsc21120] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 10/01/2021] [Accepted: 10/25/2021] [Indexed: 11/16/2022] Open
Abstract
Background and Objectives Apoptosis is an outstanding determinant of glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH). Human umbilical cord mesenchymal stem cells (hUC-MSCs) have been demonstrated to be associated with apoptosis in diseases models. However, the role of hUC-MSCs in GC-induced ONFH via regulating apoptosis still needs further study. Methods and Results In the present study, a GC-induced ONFH model was built in vivo through a consecutive injection with lipopolysaccharide (LPS) and methylprednisolone. The necrosis and apoptosis of the femoral head was evaluated by histological and Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) assay. The level of collagen and TRAP positive cells were determined by Masson and TRAP staining, respectively. M1 macrophage polarization was assessed using immunofluorescence assay. The level of proinflammatory cytokines including tumor necrosis factor (TNF)‐α, Interleukin (IL)‐1β and IL-6 of femoral head was determined by enzyme-linked immunosorbent assay (ELISA) kits. The protein expression of AKT, mTOR, p-AKT and p-mTOR was detected using western blot assay. The results showed that hUC-MSCs treatment prominently promoted the GC-induced the decrease of the collagen level and the increase of TRAP positive cells. Besides, hUC-MSCs treatment decreased necrosis and apoptosis, macrophage polarization, the level of TNF‐α, IL‐1β and IL-6, the protein expression of p-AKT and p-mTOR, and the radio of p-AKT to AKT and p-mTOR to mTOR of femoral head in vivo. Conclusions Therefore, the present study revealed that hUC-MSCs improved the necrosis and osteocyte apoptosis in GC-induced ONFH model through reducing the macrophage polarization, which was associated with the inhibition of AKT/mTOR signaling pathway.
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Affiliation(s)
- Gang Tian
- Department of Orthopedics, Weihai Central Hospital Affiliated to Qingdao University & Qingdao University, Weihai, China
| | - Chuanjie Liu
- Xinxiang Medical University, Xinxiang, China.,Weihai Key Laboratory of Autoimmunity & Central Laboratory of Weihai Central Hospital, Weihai, China
| | - Qi Gong
- Weihai Key Laboratory of Autoimmunity & Central Laboratory of Weihai Central Hospital, Weihai, China
| | - Zhiping Yu
- Department of Sports Medicine, Weihai Central Hospital Affiliated to Qingdao University, Weihai, China
| | - Haitao Wang
- Department of Trauma Surgery, Weihai Central Hospital Affiliated to Qingdao University, Weihai, China
| | - Daoqiang Zhang
- Weihai Key Laboratory of Autoimmunity & Central Laboratory of Weihai Central Hospital, Weihai, China
| | - Haibo Cong
- Department of Orthopedics, Weihai Central Hospital Affiliated to Qingdao University & Weihai Key Laboratory of Autoimmunity, Weihai, China
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Wang YN, Wu X, Jia TT, Feng Y, Liu SY, Xu X, Zhang DJ. Effect of type 2 diabetes mellitus on mandibular bone regeneration and the expression of T helper cell 17/regulat-ory T cell-related factors in mice. HUA XI KOU QIANG YI XUE ZA ZHI = HUAXI KOUQIANG YIXUE ZAZHI = WEST CHINA JOURNAL OF STOMATOLOGY 2021; 39:642-650. [PMID: 34859623 PMCID: PMC8703102 DOI: 10.7518/hxkq.2021.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 09/14/2021] [Indexed: 01/24/2023]
Abstract
OBJECTIVES To observe the effect of type 2 diabetes mellitus (T2DM) on mandibular bone regeneration and the expression of factors related to T helper cell 17 (Th17 cell) and regulatory T cell (Treg cell) in mice. METHODS Thirty-six 6-week-old C57BL/6J male mice were randomly divided into normal control (NC) and T2DM groups. Fasting blood glucose levels were detected 0 d, 7 d, 14 d, and 28 d after surgery for mandibular defects. Hematoxylin-eosin (HE) staining was used in observing the bone after 7 d, 14 d, and 28 d of the healing process. Immunohistochemical staining was used in observing the expression of alkaline phosphatase (ALP), Runt-related transcription factor 2 (RUNX2), forkhead box protein P3 (Foxp3), retinoic acid related orphan receptor gamma T (RORγt), and protein tyrosine phosphatase non-receptor type 2 (PTPN2) after 7 d, 14 d, and 28 d of healing. RESULTS HE staining showed that the area with new bones in the T2DM group was significantly smaller than that in the NC group. Immunohistochemical staining showed that the expression of osteogenesis related proteins ALP and RUNX2 were significantly reduced in the T2DM group. In addition, the number of RORγt positive cells increased, whereas the number of Foxp3 positive cells and the expression PTPN2 decreased significantly in the mandibular bone defect in mice with T2DM. CONCLUSIONS T2DM significantly inhibit mandibular bone regeneration in mice. Decline in PTPN2 expression and the transition of Treg and Th17 may be the underlying molecular mechanisms.
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Affiliation(s)
- Ya Nan Wang
- Dept. of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan 250012, China
| | - Xuan Wu
- Dept. of Implantology, Yuehu Branch, Ningbo Dental Hospital, Ningbo 315000, China
| | - Ting Ting Jia
- Dept. of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan 250012, China
| | - Yao Feng
- Dept. of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan 250012, China
| | - Shi Yue Liu
- Dept. of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan 250012, China
| | - Xin Xu
- Dept. of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan 250012, China
| | - Dong Jiao Zhang
- Dept. of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan 250012, China
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Cheng L, Yu P, Li F, Jiang X, Jiao X, Shen Y, Lai X. Human umbilical cord-derived mesenchymal stem cell-exosomal miR-627-5p ameliorates non-alcoholic fatty liver disease by repressing FTO expression. Hum Cell 2021; 34:1697-1708. [PMID: 34410623 DOI: 10.1007/s13577-021-00593-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 08/11/2021] [Indexed: 01/17/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs)-based therapy is currently considered to be an effective treatment for NAFLD. The present study aimed to determine whether hUC-MSCs-exosomes have a hepatoprotective effect on NAFLD. We constructed NAFLD rat model by high-fat high-fructose feeding. Liver cells (L-O2) were treated with palmitic acid (PA) to mimic NAFLD model. NAFLD rats and PA-treated L-O2 cells were treated with hUC-MSCs-exosomes, and then we determined the influence of exosomes on liver damage and glucose and lipid metabolism in vivo and in vitro. We found that hUC-MSCs-exosomes exhibited an up-regulation of miR-627-5p. Exosomal miR-627-5p promoted cell viability and repressed apoptosis of PA-treated L-O2 cells. Exosomal miR-627-5p also enhanced the expression of G6Pc, PEPCK, FAS and SREBP-1c and suppressed PPARα expression in PA-treated L-O2 cells. Moreover, miR-627-5p interacted with fat mass and obesity-associated gene (FTO) and inhibited FTO expression in L-O2 cells. MiR-627-5p-enriched exosomes improved glucose and lipid metabolism in L-O2 cells by targeting FTO. In vivo, exosomal miR-627-5p ameliorated insulin tolerance, liver damage, glucose and lipid metabolism and reduced lipid deposition in NAFLD rats. Exosomal miR-627-5p also reduced body weight, liver weight, and liver index (body weight/liver weight) in NAFLD rats. In conclusion, these data demonstrate that HUC-MSCs-derived exosomal miR-627-5p improves glucose and lipid metabolism and alleviate liver damage by repressing FTO expression, thereby ameliorating NAFLD progression. Thus, hUC-MSCs-exosomes may be a potential treatment for NAFLD.
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Affiliation(s)
- Lidan Cheng
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang, 330006, China
- Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang, 330006, China
| | - Peng Yu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang, 330006, China
- Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang, 330006, China
| | - Fangfang Li
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang, 330006, China
- Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang, 330006, China
| | - Xueling Jiang
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang, 330006, China
- Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang, 330006, China
| | - Xiaojuan Jiao
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang, 330006, China
- Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang, 330006, China
| | - Yunfeng Shen
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang, 330006, China.
- Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang, 330006, China.
| | - Xiaoyang Lai
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang, 330006, China.
- Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang, 330006, China.
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Dymowska M, Aksamit A, Zielniok K, Kniotek M, Kaleta B, Roszczyk A, Zych M, Dabrowski F, Paczek L, Burdzinska A. Interaction between Macrophages and Human Mesenchymal Stromal Cells Derived from Bone Marrow and Wharton's Jelly-A Comparative Study. Pharmaceutics 2021; 13:pharmaceutics13111822. [PMID: 34834238 PMCID: PMC8624657 DOI: 10.3390/pharmaceutics13111822] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/27/2021] [Accepted: 10/28/2021] [Indexed: 01/15/2023] Open
Abstract
Despite intensive clinical research on the use of mesenchymal stromal cells (MSCs), further basic research in this field is still required. Herein, we compared human bone marrow MSCs (BM-MSCs, n = 6) and Wharton’s jelly MSCs (WJ-MSCs, n = 6) in their ability to interact with human primary macrophages. Evaluation of secretory potential revealed that under pro-inflammatory stimulation, WJ-MSCs secreted significantly more IL-6 than BM-MSCs (2-fold). This difference did not translate into the effect of MSCs on macrophages: both types of MSCs significantly directed M1-like macrophages toward the M2 phenotype (based on CD206 expression) to a similar extent. This observation was consistent both in flow cytometry analysis and immunocytochemical assessment. The effect of MSCs on macrophages was sustained when IL-6 signaling was blocked with Tocilizumab. Macrophages, regardless of polarization status, enhanced chemotaxis of both BM-MSCs and WJ-MSCs (p < 0.01; trans-well assay), with WJ-MSCs being significantly more responsive to M1-derived chemotactic signals than BM-MSCs. Furthermore, WJ-MSCs increased their motility (scratch assay) when exposed to macrophage-conditioned medium while BM-MSCs did not. These results indicate that although both BM-MSCs and WJ-MSCs have the ability to reciprocally interact with macrophages, the source of MSCs could slightly but significantly modify the response under clinical settings.
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Affiliation(s)
- Marta Dymowska
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (M.D.); (A.A.); (L.P.)
- Laboratory of Cell Research and Application, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland
| | - Aleksandra Aksamit
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (M.D.); (A.A.); (L.P.)
| | - Katarzyna Zielniok
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (M.D.); (A.A.); (L.P.)
- Department of Clinical Immunology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (M.K.); (B.K.); (A.R.); (M.Z.)
- Correspondence: (K.Z.); (A.B.)
| | - Monika Kniotek
- Department of Clinical Immunology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (M.K.); (B.K.); (A.R.); (M.Z.)
| | - Beata Kaleta
- Department of Clinical Immunology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (M.K.); (B.K.); (A.R.); (M.Z.)
| | - Aleksander Roszczyk
- Department of Clinical Immunology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (M.K.); (B.K.); (A.R.); (M.Z.)
| | - Michal Zych
- Department of Clinical Immunology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (M.K.); (B.K.); (A.R.); (M.Z.)
| | - Filip Dabrowski
- Department of Gynecology and Obstetrics, Medical University of Silesia, Medykow 14, 40-752 Katowice, Poland;
| | - Leszek Paczek
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (M.D.); (A.A.); (L.P.)
- Department of Bioinformatics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5A, 02-106 Warsaw, Poland
| | - Anna Burdzinska
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (M.D.); (A.A.); (L.P.)
- Correspondence: (K.Z.); (A.B.)
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MSC-derived immunomodulatory extracellular matrix functionalized electrospun fibers for mitigating foreign-body reaction and tendon adhesion. Acta Biomater 2021; 133:280-296. [PMID: 33894349 DOI: 10.1016/j.actbio.2021.04.035] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 03/28/2021] [Accepted: 04/15/2021] [Indexed: 12/17/2022]
Abstract
Adhesion formation during tendon healing remains a severe problem in clinical practice. Multiple factors contribute to postoperative adhesion formation, and macrophage-driven inflammation is thought to be greatly involved in this process. We hypothesize that reducing macrophage-mediated inflammation in the injured tendon by regulating M1 to M2 macrophage polarization may effectively inhibit adhesion formation. Here, we developed an acellular immunomodulatory biomaterial consisting of an electrospun polycaprolactone/silk fibroin (PCL/SF) composite fibrous scaffold functionalized with mesenchymal stem cell (MSC)-derived extracellular matrix (ECM). To enhance the immunoregulatory potential of MSCs, we performed inflammatory licensing with IFN-γ to obtain immunomodulatory ECM (iECM). Proteomic analyses of MSCs and their secreted ECM components from different culture conditions revealed the MSC-ECM molecular signatures and the potential mechanism of ECM immunoregulation. Then, the immunoregulatory potential of the iECM-modified scaffold was evaluated in vitro and in vivo. Relative to the PCL/SF fibrous scaffold, the iECM-functionalized scaffold facilitated M2 macrophage polarization and inhibited the expression of multiple cytokines (IL-1β, IL-6, CXCL11, IL-10, IL-1R2, and TGF-β1) in vitro, strongly suggesting the immunosuppressive ability of iECM derived from inflammatory licensed MSCs. Consistent with the in vitro findings, the results of rat subcutaneous implantation indicated that a markedly lower foreign-body reaction (FBR) was obtained in the PCL/SF-iECM group than in the other groups, as evidenced by thinner fibrotic capsule formation, less type I collagen production and more M2-type macrophage polarization. In the rat Achilles tendon injury model, the PCL/SF-iECM scaffold greatly mitigated tendon adhesion with clear sheath space formation between the tendon and the scaffold. These data highlight the immunomodulatory potential of iECM-functionalized fibrous scaffolds to attenuate FBR by modulating M2 macrophage polarization, thereby preventing tendon adhesion. STATEMENT OF SIGNIFICANCE: Electrospun PCL/SF fibrous scaffolds functionalized with ECM secreted by MSCs stimulated by inflammatory factor IFN-γ was developed that combined physical barrier and immunomodulatory functions to prevent tendon adhesion formation. PCL/SF micro-nanoscale bimodal fibrous scaffolds prepared by emulsion electrospinning possess high porosity and a large pore size beneficial for nutrient transport to promote intrinsic healing; moreover, surface modification with immunomodulatory ECM (iECM) mitigates the FBR of fibrous scaffolds to prevent tendon adhesion. The iECM-functionalized electrospun scaffolds exhibit powerful immunomodulatory potency in vitro and in vivo. Moreover, the iECM-modified scaffolds, as an anti-adhesion physical barrier with immunomodulatory ability, have an excellent performance in a rat Achilles tendon adhesion model. MSC secretome-based therapeutics, as an acellular regenerative medicine strategy, are expected to be applied to other inflammatory diseases due to its strong immunoregulatory potential.
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Sant'Ana AN, Araújo AB, Gonçalves FDC, Paz AH. Effects of living and metabolically inactive mesenchymal stromal cells and their derivatives on monocytes and macrophages. World J Stem Cells 2021; 13:1160-1176. [PMID: 34630856 PMCID: PMC8474715 DOI: 10.4252/wjsc.v13.i9.1160] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/01/2021] [Accepted: 09/03/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are multipotent and self-renewing stem cells that have great potential as cell therapy for autoimmune and inflammatory disorders, as well as for other clinical conditions, due to their immunoregulatory and regenerative properties. MSCs modulate the inflammatory milieu by releasing soluble factors and acting through cell-to-cell mechanisms. MSCs switch the classical inflammatory status of monocytes and macrophages towards a non-classical and anti-inflammatory phenotype. This is characterized by an increased secretion of anti-inflammatory cytokines, a decreased release of pro-inflammatory cytokines, and changes in the expression of cell membrane molecules and in metabolic pathways. The MSC modulation of monocyte and macrophage phenotypes seems to be critical for therapy effectiveness in several disease models, since when these cells are depleted, no immunoregulatory effects are observed. Here, we review the effects of living MSCs (metabolically active cells) and metabolically inactive MSCs (dead cells that lost metabolic activity by induced inactivation) and their derivatives (extracellular vesicles, soluble factors, extracts, and microparticles) on the profile of macrophages and monocytes and the implications for immunoregulatory and reparative processes. This review includes mechanisms of action exhibited in these different therapeutic approaches, which induce the anti-inflammatory properties of monocytes and macrophages. Finally, we overview several possibilities of therapeutic applications of these cells and their derivatives, with results regarding monocytes and macrophages in animal model studies and some clinical trials.
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Affiliation(s)
- Alexia Nedel Sant'Ana
- Laboratório de Células Tecidos e Genes, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, RS, Brazil
| | - Anelise Bergmann Araújo
- Centro de Processamento Celular, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, RS, Brazil.
| | | | - Ana Helena Paz
- Laboratório de Células Tecidos e Genes, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, RS, Brazil
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CGF Membrane Promotes Periodontal Tissue Regeneration Mediated by hUCMSCs through Upregulating TAZ and Osteogenic Differentiation Genes. Stem Cells Int 2021; 2021:6644366. [PMID: 34394357 PMCID: PMC8360720 DOI: 10.1155/2021/6644366] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 06/22/2021] [Accepted: 07/19/2021] [Indexed: 01/11/2023] Open
Abstract
Concentrated growth factor (CGF) membranes are widely used in basic and clinical research of soft and hard tissue regeneration, but its effect on periodontal tissue regeneration is less studied. This study explored the role of CGF membranes in periodontal tissue regeneration mediated by human umbilical cord mesenchymal stem cells (hUCMSCs). HUCMSCs and human periodontal ligament fibroblasts (HPLFs) were extracted and identified by microscope and flow cytometry. The effects of the extracted CGF membrane on cell viability, osteogenic differentiation ability, osteopontin (OPN) expression, alkaline phosphatase (ALP) content, and osteogenic differentiation-related genes (Runt-related transcription factor 2 (RUNX2); osteocalcin (OCN); ALP), Tafazzin (TAZ) expression, and nuclear transfer were examined by MTT assay, alizarin red staining, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot. Rescue experiments were performed to examine the effects of TAZ transfection and cell coculture. In the identified hUCMSCs (positive expressions of CD29, CD44, CD146, and CD105), overexpressed TAZ (pc-TAZ) enhanced the promotive effect of CGF membrane on cell viability, cell cycle, mineralization, ALP content and expressions of OPN, TAZ and osteogenic differentiation-related genes, and nuclear transfer. However, silencing TAZ showed opposite effects. The coculture of hUCMSCs and HPLFs further promoted the basic biological functions of HPLFs by upregulating osteogenic differentiation-related genes and COL-1 but downregulated MMP1 expression. Pc-TAZ could enhance the effect of CGF membrane on promoting periodontal tissue regeneration. CGF membrane promoted periodontal tissue regeneration through upregulating TAZ and osteogenic differentiation-related genes.
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Ma Y, Wang L, Yang S, Liu D, Zeng Y, Lin L, Qiu L, Lu J, Chang J, Li Z. The tissue origin of human mesenchymal stem cells dictates their therapeutic efficacy on glucose and lipid metabolic disorders in type II diabetic mice. Stem Cell Res Ther 2021; 12:385. [PMID: 34233739 PMCID: PMC8261817 DOI: 10.1186/s13287-021-02463-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 06/15/2021] [Indexed: 12/12/2022] Open
Abstract
Background The therapeutic efficacy of mesenchymal stem cells (MSCs) of different tissue origins on metabolic disorders can be varied in many ways but remains poorly defined. Here we report a comprehensive comparison of human MSCs derived from umbilical cord Wharton’s jelly (UC-MSCs), dental pulp (PU-MSCs), and adipose tissue (AD-MSCs) on the treatment of glucose and lipid metabolic disorders in type II diabetic mice. Methods Fourteen-to-fifteen-week-old male C57BL/6 db/db mice were intravenously administered with human UC-MSCs, PU-MSCs, and AD-MSCs at various doses or vehicle control once every 2 weeks for 6 weeks. Metformin (MET) was given orally to animals in a separate group once a day at weeks 4 to 6 as a positive control. Body weight, blood glucose, and insulin levels were measured every week. Glucose tolerance tests (GTT) and insulin tolerance tests (ITT) were performed every 2 weeks. All the animals were sacrificed at week 6 and the blood and liver tissues were collected for biochemical and histological examinations. Results UC-MSCs showed the strongest efficacy in reducing fasting glucose levels, increasing fasting insulin levels, and improving GTT and ITT in a dose-dependent manner, whereas PU-MSCs showed an intermediate efficacy and AD-MSCs showed the least efficacy on these parameters. Moreover, UC-MSCs also reduced the serum low-density lipoprotein cholesterol (LDL-C) levels with the most prominent potency and AD-MSCs had only very weak effect on LDL-C. In contrast, AD-MSCs substantially reduced the lipid content and histological lesion of liver and accompanying biomarkers of liver injury such as serum aspartate transaminase (AST) and alanine aminotransferase (ALT) levels, whereas UC-MSCs and PU-MSCs displayed no or modest effects on these parameters, respectively. Conclusions Taken together, our results demonstrated that MSCs of different tissue origins can confer substantially different therapeutic efficacy in ameliorating glucose and lipid metabolic disorders in type II diabetes. MSCs with different therapeutic characteristics could be selected according to the purpose of the treatment in the future clinical practice.
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Affiliation(s)
- Yinzhong Ma
- SIAT-GHMSCB Biomedical Laboratory for Major Diseases, Dongguan Enlife Stem Cell Biotechnology Institute, Dongguan Avenue 430, Dongguan, Guangdong, China.,Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Xueyuan Blvd 1068, Shenzhen, Guangdong, China
| | - Lisha Wang
- SIAT-GHMSCB Biomedical Laboratory for Major Diseases, Dongguan Enlife Stem Cell Biotechnology Institute, Dongguan Avenue 430, Dongguan, Guangdong, China
| | - Shilun Yang
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Xueyuan Blvd 1068, Shenzhen, Guangdong, China
| | - Dongyu Liu
- SIAT-GHMSCB Biomedical Laboratory for Major Diseases, Dongguan Enlife Stem Cell Biotechnology Institute, Dongguan Avenue 430, Dongguan, Guangdong, China
| | - Yi Zeng
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Xueyuan Blvd 1068, Shenzhen, Guangdong, China
| | - Lilong Lin
- SIAT-GHMSCB Biomedical Laboratory for Major Diseases, Dongguan Enlife Stem Cell Biotechnology Institute, Dongguan Avenue 430, Dongguan, Guangdong, China
| | - Linhui Qiu
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Xueyuan Blvd 1068, Shenzhen, Guangdong, China
| | - Jiahao Lu
- SIAT-GHMSCB Biomedical Laboratory for Major Diseases, Dongguan Enlife Stem Cell Biotechnology Institute, Dongguan Avenue 430, Dongguan, Guangdong, China
| | - Junlei Chang
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Xueyuan Blvd 1068, Shenzhen, Guangdong, China.
| | - Zhihuan Li
- SIAT-GHMSCB Biomedical Laboratory for Major Diseases, Dongguan Enlife Stem Cell Biotechnology Institute, Dongguan Avenue 430, Dongguan, Guangdong, China.
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Human umbilical cord mesenchymal stem cells in type 2 diabetes mellitus: the emerging therapeutic approach. Cell Tissue Res 2021; 385:497-518. [PMID: 34050823 DOI: 10.1007/s00441-021-03461-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 04/11/2021] [Indexed: 12/14/2022]
Abstract
The umbilical cord has been proved to be an easy-access, reliable, and useful source of mesenchymal stem cells (MSC) for clinical applications due to its primitive, immunomodulatory, non-immunogenic, secretory and paracrine, migratory, proliferative, and multipotent properties. This set of characteristics has recently attracted great research interest in the fields of nanotechnology and regenerative medicine and cellular therapy. Accumulating evidence supports a pronounced therapeutic potential of MSC in many different pathologies, from hematology to immunology, wound-healing, tissue regeneration, and oncology. Diabetes mellitus, branded the epidemic of the century, is considered a chronic metabolic disorder, representing a major burden for health system sustainability and an important public health challenge to modern societies. The available treatments for type 2 diabetes mellitus (T2DM) still rely mainly on combinations of oral antidiabetic agents with lifestyle and nutritional adjustments. Despite the continuous development of novel and better hypoglycemic drugs, their efficacy is limited in the installment and progression of silent T2DM complications. T2DM comorbidities and mortality rates still make it a serious, common, costly, and long-term manageable disease. Recently, experimental models, preclinical observations, and clinical studies have provided some insights and preliminary promising results using umbilical cord MSCs to treat and manage diabetes. This review focuses on the latest research and applications of human-derived umbilical cord MSC in the treatment and management of T2DM, exploring and systematizing the key effects of both umbilical cord MSC and its factor-rich secretome accordingly with the major complications associated to T2DM.
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Jaber H, Issa K, Eid A, Saleh FA. The therapeutic effects of adipose-derived mesenchymal stem cells on obesity and its associated diseases in diet-induced obese mice. Sci Rep 2021; 11:6291. [PMID: 33737713 PMCID: PMC7973738 DOI: 10.1038/s41598-021-85917-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 03/08/2021] [Indexed: 12/15/2022] Open
Abstract
Obesity is a global public health concern associated with increased risk of several comorbidities. Due to the limited effectiveness of current therapies, new treatment strategies are needed. Our aim was to examine the effect of adipose-derived mesenchymal stem cells (AD-MSCs) on obesity and its associated diseases in a diet-induced obese (DIO) animal model. C57BL6 mice were fed with either high fat diet (HFD) or CHOW diet for 15 weeks. Obese and lean mice were then subjected to two doses of AD-MSCs intraperitoneally. Mice body weight and composition; food intake; blood glucose levels; glycated hemoglobin (HbA1c), intraperitoneal glucose tolerance test and atherogenic index of plasma (AIP) were measured. Pro-inflammatory cytokines, tumor necrosis factor-α and interleukin-6, were also determined. AD-MSCs treatment reduced blood glucose levels, HbA1c and AIP as well as improved glucose tolerance in DIO mice. In addition, MSCs caused significant attenuation in the levels of inflammatory mediators in HFD-fed mice. Taken together, AD-MSCs were effective in treating obesity-associated diabetes in an animal model as well as protective against cardiovascular diseases as shown by AIP, which might be partly due to the attenuation of inflammatory mediators. Thus, AD-MSCs may offer a promising therapeutic potential in counteracting obesity-related diseases in patients.
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Affiliation(s)
- Hala Jaber
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Beirut Arab University, Beirut, Lebanon
| | - Khodr Issa
- Department of Molecular Diagnostics, Doctors' Center Laboratories, Beirut, Lebanon.,Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Ali Eid
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.,Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar.,Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar
| | - Fatima A Saleh
- Department of Medical Laboratory Technology, Faculty of Health Sciences, Beirut Arab University, Beirut, 115020, Lebanon.
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van de Vyver M, Powrie YSL, Smith C. Targeting Stem Cells in Chronic Inflammatory Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1286:163-181. [PMID: 33725353 DOI: 10.1007/978-3-030-55035-6_12] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Mesenchymal stem cell (MSC) dysfunction is a serious complication in ageing and age-related inflammatory diseases such as type 2 diabetes mellitus. Inflammation and oxidative stress-induced cellular senescence alter the immunomodulatory ability of MSCs and hamper their pro-regenerative function, which in turn leads to an increase in disease severity, maladaptive tissue damage and the development of comorbidities. Targeting stem/progenitor cells to restore their function and/or protect them against impairment could thus improve healing outcomes and significantly enhance the quality of life for diabetic patients. This review discusses the dysregulation of MSCs' immunomodulatory capacity in the context of diabetes mellitus and focuses on intervention strategies aimed at MSC rejuvenation. Research pertaining to the potential therapeutic use of either pharmacological agents (NFкB antagonists), natural products (phytomedicine) or biological agents (exosomes, probiotics) to improve MSC function is discussed and an overview of the most pertinent methodological considerations given. Based on in vitro studies, numerous anti-inflammatory agents, antioxidants and biological agents show tremendous potential to revitalise MSCs. An integrated systems approach and a thorough understanding of complete disease pathology are however required to identify feasible candidates for in vivo targeting of MSCs.
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Affiliation(s)
- Mari van de Vyver
- Department of Medicine, Faculty of Medicine & Health Sciences, Stellenbosch University, Cape Town, South Africa.
| | - Yigael S L Powrie
- Department of Medicine, Faculty of Medicine & Health Sciences, Stellenbosch University, Cape Town, South Africa.,Department of Physiological Sciences, Science Faculty, Stellenbosch University, Stellenbosch, South Africa
| | - Carine Smith
- Department of Physiological Sciences, Science Faculty, Stellenbosch University, Stellenbosch, South Africa
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Li B, Cheng Y, Yin Y, Xue J, Yu S, Gao J, Liu J, Zang L, Mu Y. Reversion of early- and late-stage β-cell dedifferentiation by human umbilical cord-derived mesenchymal stem cells in type 2 diabetic mice. Cytotherapy 2021; 23:510-520. [PMID: 33736932 DOI: 10.1016/j.jcyt.2021.01.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 01/11/2021] [Accepted: 01/20/2021] [Indexed: 01/08/2023]
Abstract
BACKGROUND AIMS The authors aimed to observe β-cell dedifferentiation in type 2 diabetes mellitus (T2DM) and investigate the reversal effect of umbilical cord-derived mesenchymal stem cells (UC-MSCs) on early- and late-stage β-cell dedifferentiation. METHODS In high-fat diet (HFD)/streptozotocin (STZ)-induced T2DM mice, the authors examined the predominant role of β-cell dedifferentiation over apoptosis in the development of T2DM and observed the reversion of β-cell dedifferentiation by UC-MSCs. Next, the authors used db/db mice to observe the progress of β-cell dedifferentiation from early to late stage, after which UC-MSC infusions of the same amount were performed in the early and late stages of dedifferentiation. Improvement in metabolic indices and restoration of β-cell dedifferentiation markers were examined. RESULTS In HFD/STZ-induced T2DM mice, the proportion of β-cell dedifferentiation was much greater than that of apoptosis, demonstrating that β-cell dedifferentiation was the predominant contributor to T2DM. UC-MSC infusions significantly improved glucose homeostasis and reversed β-cell dedifferentiation. In db/db mice, UC-MSC infusions in the early stage significantly improved glucose homeostasis and reversed β-cell dedifferentiation. In the late stage, UC-MSC infusions mildly improved glucose homeostasis and partially reversed β-cell dedifferentiation. Combining with other studies, the authors found that the reversal effect of UC-MSCs on β-cell dedifferentiation relied on the simultaneous relief of glucose and lipid metabolic disorders. CONCLUSIONS UC-MSC therapy is a promising strategy for reversing β-cell dedifferentiation in T2DM, and the reversal effect is greater in the early stage than in the late stage of β-cell dedifferentiation.
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Affiliation(s)
- Bing Li
- Department of Endocrinology, First Medical Center of People's Liberation Army General Hospital, Beijing, China
| | - Yu Cheng
- Department of Endocrinology, First Medical Center of People's Liberation Army General Hospital, Beijing, China
| | - Yaqi Yin
- Department of Endocrinology, First Medical Center of People's Liberation Army General Hospital, Beijing, China
| | - Jing Xue
- Department of Endocrinology, First Medical Center of People's Liberation Army General Hospital, Beijing, China
| | - Songyan Yu
- Department of Endocrinology, First Medical Center of People's Liberation Army General Hospital, Beijing, China
| | - Jieqing Gao
- Department of Endocrinology, Beijing Rehabilitation Hospital of Capital Medical University, Beijing, China
| | - Jiejie Liu
- Department of Molecular Biology, Institute of Basic Medicine, School of Life Science, People's Liberation Army General Hospital, Beijing, China
| | - Li Zang
- Department of Endocrinology, First Medical Center of People's Liberation Army General Hospital, Beijing, China.
| | - Yiming Mu
- Department of Endocrinology, First Medical Center of People's Liberation Army General Hospital, Beijing, China.
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Li H, Zhu H, Ge T, Wang Z, Zhang C. Mesenchymal Stem Cell-Based Therapy for Diabetes Mellitus: Enhancement Strategies and Future Perspectives. Stem Cell Rev Rep 2021; 17:1552-1569. [PMID: 33675006 DOI: 10.1007/s12015-021-10139-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2021] [Indexed: 12/11/2022]
Abstract
Diabetes mellitus (DM), a chronic disorder of carbohydrate metabolism, is characterized by the unbridled hyperglycemia resulted from the impaired ability of the body to either produce or respond to insulin. As a cell-based regenerative therapy, mesenchymal stem cells (MSCs) hold immense potency for curing DM duo to their easy isolation, multi-differentiation potential, and immunomodulatory property. However, despite the promising efficacy in pre-clinical animal models, naive MSC administration fails to exhibit clinically satisfactory therapeutic outcomes, which varies greatly among individuals with DM. Recently, numbers of innovative strategies have been applied to improve MSC-based therapy. Preconditioning, genetic modification, combination therapy and exosome application are representative strategies to maximize the therapeutic benefits of MSCs. Therefore, in this review, we summarize recent advancements in mechanistic studies of MSCs-based treatment for DM, and mainly focus on the novel approaches aiming to improve the anti-diabetic potentials of naive MSCs. Additionally, the potential directions of MSCs-based therapy for DM are also proposed at a glance.
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Affiliation(s)
- Haisen Li
- Department of Plastic and Reconstructive Surgery, Shanghai Institute of Precision Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China.,Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.,Sinoneural Cell Engineering Group Holdings Co., Ltd., Shanghai 201100, China
| | - Hao Zhu
- Sinoneural Cell Engineering Group Holdings Co., Ltd., Shanghai 201100, China
| | - Ting Ge
- Xinxiang First People's Hospital, Xinxiang 453000, China
| | - Zhifeng Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Institute of Precision Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China. .,Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. .,Sinoneural Cell Engineering Group Holdings Co., Ltd., Shanghai 201100, China.
| | - Chao Zhang
- Department of Plastic and Reconstructive Surgery, Shanghai Institute of Precision Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China. .,Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
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50
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Li W, Jiao X, Song J, Sui B, Guo Z, Zhao Y, Li J, Shi S, Huang Q. Therapeutic potential of stem cells from human exfoliated deciduous teeth infusion into patients with type 2 diabetes depends on basal lipid levels and islet function. Stem Cells Transl Med 2021; 10:956-967. [PMID: 33660433 PMCID: PMC8235136 DOI: 10.1002/sctm.20-0303] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 01/02/2021] [Accepted: 02/06/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) hold great potential in treating patients with diabetes, but the therapeutic effects are not always achieved. Particularly, the clinical factors regulating MSC therapy in this setting are largely unknown. In this study, 24 patients with type 2 diabetes mellitus (T2DM) treated with insulin were selected to receive three intravenous infusions of stem cells from human exfoliated deciduous teeth (SHED) over the course of 6 weeks and were followed up for 12 months. We observed a significant reduction of glycosylated serum albumin level (P < .05) and glycosylated hemoglobin level (P < .05) after SHED transplantation. The total effective rate was 86.36% and 68.18%, respectively, at the end of treatment and follow‐up periods. Three patients ceased insulin injections after SHED transplantation. A steamed bread meal test showed that the serum levels of postprandial C‐peptide at 2 hours were significantly higher than those at the baseline (P < .05). Further analysis showed that patients with a high level of blood cholesterol and a low baseline level of C‐peptide had poor response to SHED transplantation. Some patients experienced a transient fever (11.11%), fatigue (4.17%), or rash (1.39%) after SHED transplantation, which were easily resolved. In summary, SHED infusion is a safe and effective therapy to improve glucose metabolism and islet function in patients with T2DM. Blood lipid levels and baseline islet function may serve as key factors contributing to the therapeutic outcome of MSC transplantation in patients with T2DM.
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Affiliation(s)
- Wenwen Li
- Department of Endocrinology, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Xuan Jiao
- Department of Endocrinology, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Jingyun Song
- Department of Endocrinology, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Bingdong Sui
- South China Center of Craniofacial Stem Cell Research, Guanghua School and Hospital of Stomatology, Sun Yat-sen University, Guangzhou, People's Republic of China.,Research and Development Center for Tissue Engineering, School of Stomatology, Air Force Medical University, People's Republic of China
| | - Zhili Guo
- Department of Dermatology, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Yingji Zhao
- South China Center of Craniofacial Stem Cell Research, Guanghua School and Hospital of Stomatology, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Jun Li
- Easter Greenland Hospital, People's Republic of China
| | - Songtao Shi
- South China Center of Craniofacial Stem Cell Research, Guanghua School and Hospital of Stomatology, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Qin Huang
- Department of Endocrinology, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China
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