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Isildar B, Ozkan S, Neccar D, Koyuturk M. Preconditioning and post-preconditioning states of mesenchymal stem cells with deferoxamine: A comprehensive analysis. Eur J Pharmacol 2025; 996:177574. [PMID: 40180273 DOI: 10.1016/j.ejphar.2025.177574] [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: 01/29/2025] [Revised: 03/17/2025] [Accepted: 03/31/2025] [Indexed: 04/05/2025]
Abstract
Mesenchymal stem cells (MSCs) derive their therapeutic potential from their secretomes, which can be modulated by external stimuli. Hypoxia is one such stimulus, and research on preconditioning MSCs with hypoxia-mimetic agents is rising. However, the effects of these preconditioning processes and the resulting metabolic status require further investigation. This study evaluated the effects of deferoxamine (DFX), a hypoxia-mimetic agent, preconditioning on MSCs in serum and serum-free environments. The influence of hypoxia on cell metabolism was examined during and after preconditioning by assessing cytotoxicity, proliferation, migration, secretomes, senescence, autophagy, and apoptosis mechanisms. The optimal DFX dose and duration for preconditioning were determined as 150 μM and 24 h based on cytotoxicity testing. Accordingly, DFX preconditioning significantly upregulated HIF-1α expression, increasing protein secretion and reducing total oxidant status. DFX appears to enhance the therapeutic potential of MSCs by increasing their secretome and antioxidant capacity. However, upon DFX removal, HIF-1α levels returned to normal, and the associated positive effects diminished. Autophagy was markedly enhanced during DFX preconditioning, potentially improving metabolic activity, preserving cellular integrity, and preparing MSCs for ischemic environments. Autophagy returned to baseline after DFX withdrawal, indicating a temporary hypoxia-mimetic response. In a serum-containing medium, specific effects of preconditioning were relatively weak to be observed. This study demonstrates that DFX-preconditioning increases MSCs' metabolic activity and enhances their adaptive cellular response. However, the effect may be transient, which provides insights into the behavior of MSCs in ischemic environments and emphasizes the need to evaluate the long-term effects of hypoxia-mimetic agents.
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Affiliation(s)
- Basak Isildar
- Balıkesir University, Histology and Embryology Department, Balıkesir, Turkey.
| | - Serbay Ozkan
- İzmir Katip Çelebi University, Histology and Embryology Department, Izmir, Turkey.
| | - Duygu Neccar
- İstanbul University-Cerrahpaşa, Cerrahpaşa Faculty of Medicine, Department of Histology and Embryology, Istanbul, Turkey.
| | - Meral Koyuturk
- İstanbul University-Cerrahpaşa, Cerrahpaşa Faculty of Medicine, Department of Histology and Embryology, Istanbul, Turkey.
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2
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Bonfield TL, Lazarus HM. Human mesenchymal stem cell therapy: Potential advances for reducing cystic fibrosis infection and organ inflammation. Best Pract Res Clin Haematol 2025; 38:101602. [PMID: 40274338 DOI: 10.1016/j.beha.2025.101602] [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: 11/20/2024] [Revised: 02/11/2025] [Accepted: 03/04/2025] [Indexed: 04/26/2025]
Abstract
Innovation in cystic fibrosis (CF) supportive care, including implementing new antimicrobial agents, improved physiotherapy, and highly effective modulators therapy, has advanced patient survival into the 4th and 5th decades of life. However, even with these remarkable improvements in therapy, CF patients continue to suffer from pulmonary infection and other visceral organ complications associated with long-term deficient cystic fibrosis transmembrane conductance regulator (CFTR) expression. Human mesenchymal stem cells (MSCs) have been utilized in tissue engineering based upon their capacity to provide structural components of mesenchymal tissues. An alternative role of MSCs, however is their versatile utilization as cell-based infusion powerhouses due to the unique capacity to deliver milieu specific soluble biologic factors, promoting immune supportive antimicrobial and anti-inflammatory potency. MSCs derived from umbilical cord blood, bone marrow, adipose and other tissues can be expanded in ex vivo using good manufacturing procedure facilities for a safe, unique therapeutic to reduce and limit CF infection and facilitate the resolution of multi-organ inflammation. In our efforts, we conducted extensive preclinical development and validation of an allogeneic derived bone marrow derived MSC product in preparation for a clinical trial in CF. In this process, potency models were developed to ensure the functional capacity of the MSC product to provide clinical benefit. In vitro, murine in vivo and patient tissue ex vivo potency models were utilized to follow MSC anti-infective and anti-inflammatory potency associated with the CFTR deficient environment. We showed in our "First in CF" clinical trial that the allogeneic MSCs obtained from healthy volunteer bone marrow samples were safe. The advent of improved CF care measures and exciting new small molecules has changed the survival and morbidity phenotype of patients with CF, however, there are CF patients who cannot tolerate or have genotypes that are non-responsive to modulators. Additionally, even with the small molecule therapy, CF patients are living longer, but without genetic correction, with the CF disease manifestation aggravated by the continuance of pre-existing CFTR-associated clinical issues such as ongoing inflammation. MSCs secrete bio-active factors that enhance and protect tissue function and can promote "self-immune" regulation. These properties can provide therapeutic support for the traditional and changing face of CF disease clinical complications. Further, MSC-derived bio-active factors can directly mitigate colonizing pathogens' survival by producing antimicrobial peptides (AMPs) which change the pathogen surface and increase host recognition, elimination, and sensitivity to antibiotics. Herein, we review the potential of MSC therapeutics for treating many facets of CF, emphasizing the potential for providing great additive therapeutics for managing morbidity and quality of life.
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Affiliation(s)
- Tracey L Bonfield
- Genetics and Genome Sciences, National Center for Regenerative Medicine, Pediatrics and Pathology, Case Western Reserve University, Cleveland, Ohio, 44106, USA.
| | - Hillard M Lazarus
- Department of Medicine, Hematology and National Center for Regenerative Medicine, Case Western Reserve University, Cleveland, Ohio, 44106, USA
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Sajjad U, Ahmed M, Iqbal MZ, Riaz M, Mustafa M, Biedermann T, Klar AS. Exploring mesenchymal stem cells homing mechanisms and improvement strategies. Stem Cells Transl Med 2024; 13:1161-1177. [PMID: 39550211 PMCID: PMC11631218 DOI: 10.1093/stcltm/szae045] [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: 07/26/2023] [Accepted: 05/16/2024] [Indexed: 11/18/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent cells with high self-renewal and multilineage differentiation abilities, playing an important role in tissue healing. Recent advancements in stem cell-based technologies have offered new and promising therapeutic options in regenerative medicine. Upon tissue damage, MSCs are immediately mobilized from the bone marrow and move to the injury site via blood circulation. Notably, allogenically transplanted MSCs can also home to the damaged tissue site. Therefore, MSCs hold great therapeutic potential for curing various diseases. However, one major obstacle to this approach is attracting MSCs specifically to the injury site following systemic administration. In this review, we describe the molecular pathways governing the homing mechanism of MSCs and various strategies for improving this process, including targeted stem cell administration, target tissue modification, in vitro priming, cell surface engineering, genetic modifications, and magnetic guidance. These strategies are crucial for directing MSCs precisely to the injury site and, consequently, enhancing their migration and local tissue repair properties. Specifically, our review provides a guide to improving the therapeutic efficacy of clinical applications of MSCs through optimized in vivo administration and homing capacities.
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Affiliation(s)
- Umar Sajjad
- National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Muhammad Ahmed
- National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - M Zohaib Iqbal
- Tissue Biology Research Unit, Department of Surgery, University Children’s Hospital Zurich, Wagistrasse 12, CH-8952, Zurich, Switzerland
- Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland
- University of Zurich, Zurich, Switzerland
| | - Mahrukh Riaz
- Tissue Biology Research Unit, Department of Surgery, University Children’s Hospital Zurich, Wagistrasse 12, CH-8952, Zurich, Switzerland
- Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland
- University of Zurich, Zurich, Switzerland
| | - Muhammad Mustafa
- KAM School of Life Sciences, Forman Christian College University, Lahore, Pakistan
| | - Thomas Biedermann
- Tissue Biology Research Unit, Department of Surgery, University Children’s Hospital Zurich, Wagistrasse 12, CH-8952, Zurich, Switzerland
- Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland
- University of Zurich, Zurich, Switzerland
| | - Agnes S Klar
- Tissue Biology Research Unit, Department of Surgery, University Children’s Hospital Zurich, Wagistrasse 12, CH-8952, Zurich, Switzerland
- Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland
- University of Zurich, Zurich, Switzerland
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Shan Y, Zhang M, Tao E, Wang J, Wei N, Lu Y, Liu Q, Hao K, Zhou F, Wang G. Pharmacokinetic characteristics of mesenchymal stem cells in translational challenges. Signal Transduct Target Ther 2024; 9:242. [PMID: 39271680 PMCID: PMC11399464 DOI: 10.1038/s41392-024-01936-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 07/04/2024] [Accepted: 07/23/2024] [Indexed: 09/15/2024] Open
Abstract
Over the past two decades, mesenchymal stem/stromal cell (MSC) therapy has made substantial strides, transitioning from experimental clinical applications to commercial products. MSC therapies hold considerable promise for treating refractory and critical conditions such as acute graft-versus-host disease, amyotrophic lateral sclerosis, and acute respiratory distress syndrome. Despite recent successes in clinical and commercial applications, MSC therapy still faces challenges when used as a commercial product. Current detection methods have limitations, leaving the dynamic biodistribution, persistence in injured tissues, and ultimate fate of MSCs in patients unclear. Clarifying the relationship between the pharmacokinetic characteristics of MSCs and their therapeutic effects is crucial for patient stratification and the formulation of precise therapeutic regimens. Moreover, the development of advanced imaging and tracking technologies is essential to address these clinical challenges. This review provides a comprehensive analysis of the kinetic properties, key regulatory molecules, different fates, and detection methods relevant to MSCs and discusses concerns in evaluating MSC druggability from the perspective of integrating pharmacokinetics and efficacy. A better understanding of these challenges could improve MSC clinical efficacy and speed up the introduction of MSC therapy products to the market.
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Affiliation(s)
- Yunlong Shan
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
| | - Mengying Zhang
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Enxiang Tao
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Jing Wang
- Jiangsu Renocell Biotech Co. Ltd., Nanjing, China
| | - Ning Wei
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
- Jiangsu Renocell Biotech Co. Ltd., Nanjing, China
| | - Yi Lu
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Qing Liu
- Jiangsu Renocell Biotech Co. Ltd., Nanjing, China
| | - Kun Hao
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
| | - Fang Zhou
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
| | - Guangji Wang
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
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Park N, Kim KS, Park CG, Jung HD, Park W, Na K. Adipose-derived stem cell-based anti-inflammatory paracrine factor regulation for the treatment of inflammatory bowel disease. J Control Release 2024; 374:384-399. [PMID: 39173953 DOI: 10.1016/j.jconrel.2024.08.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 07/17/2024] [Accepted: 08/19/2024] [Indexed: 08/24/2024]
Abstract
Stem cell-based therapies offer promising avenues for treating inflammatory diseases owing to their immunomodulatory properties. However, challenges persist regarding their survival and efficacy in inflamed tissues. Our study introduces a novel approach by engineering adipose-derived stem cells (ADSCs) to enhance their viability in inflammatory environments and boost the secretion of paracrine factors for treating inflammatory bowel disease (IBD). An arginine-glycine-aspartate peptide-poly (ethylene glycol)-chlorin e6 conjugate (RPC) was synthesized and coupled with ADSCs, resulting in RPC-labeled ADSCs (ARPC). This conjugation strategy employed RGD-integrin interaction to shield stem cells and allowed visualization and tracking using chlorin e6. The engineered ARPC demonstrated enhanced viability and secretion of paracrine factors upon light irradiation, regulating the inflammatory microenvironment. RNA-sequencing analysis unveiled pathways favoring angiogenesis, DNA repair, and exosome secretion in ARPC(+) while downregulating inflammatory pathways. In in vivo models of acute and chronic IBD, ARPC(+) treatment led to reduced inflammation, preserved colon structure, and increased populations of regulatory T cells, highlighting its therapeutic potential. ARPC(+) selectively homed to inflammatory sites, demonstrating its targeted effect. Overall, ARPC(+) exhibits promise as an effective and safe therapeutic strategy for managing inflammatory diseases like IBD by modulating immune responses and creating an anti-inflammatory microenvironment.
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Affiliation(s)
- Naeun Park
- Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 14662, Republic of Korea; Department of Biomedical-Chemical Engineering, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 14662, Republic of Korea
| | - Kyoung Sub Kim
- Department of Biomedical-Chemical Engineering, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 14662, Republic of Korea
| | - Chun Gwon Park
- Department of Biomedical Engineering, SKKU Institute for Convergence, Sungkyunkwan University (SKKU), Seobu-ro 2066, Suwon, Gyeonggi 16419, Republic of Korea; Department of Intelligent Precision Healthcare Convergence, SKKU Institute for Convergence, Sungkyunkwan University (SKKU), Seobu-ro 2066, Suwon, Gyeonggi 16419, Republic of Korea
| | - Hyun-Do Jung
- Division of Materials Science and Engineering, Hanyang University, Seoul 04763, Republic of Korea
| | - Wooram Park
- Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Seoburo 2066, Suwon, Gyeonggi 16419, Republic of Korea
| | - Kun Na
- Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 14662, Republic of Korea; Department of Biomedical-Chemical Engineering, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 14662, Republic of Korea.
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Česnik AB, Švajger U. The issue of heterogeneity of MSC-based advanced therapy medicinal products-a review. Front Cell Dev Biol 2024; 12:1400347. [PMID: 39129786 PMCID: PMC11310176 DOI: 10.3389/fcell.2024.1400347] [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: 03/13/2024] [Accepted: 07/15/2024] [Indexed: 08/13/2024] Open
Abstract
Mesenchymal stromal stem cells (MSCs) possess a remarkable potential for numerous clinical applications due to their unique properties including self-renewal, immunomodulation, paracrine actions and multilineage differentiation. However, the translation of MSC-based Advanced Therapy Medicinal Products (ATMPs) into the clinic has frequently met with inconsistent outcomes. One of the suspected reasons for this issue is the inherent and extensive variability that exists among such ATMPs, which makes the interpretation of their clinical efficacy difficult to assess, as well as to compare the results of various studies. This variability stems from numerous reasons including differences in tissue sources, donor attributes, variances in manufacturing protocols, as well as modes of administration. MSCs can be isolated from various tissues including bone marrow, umbilical cord, adipose tissue and others, each with its unique phenotypic and functional characteristics. While MSCs from different sources do share common features, they also exhibit distinct gene expression profiles and functional properites. Donor-specific factors such as age, sex, body mass index, and underlying health conditions can influence MSC phenotype, morphology, differentiation potential and function. Moreover, variations in preparation of MSC products introduces additional heterogeneity as a result of cell culture media composition, presence or absence of added growth factors, use of different serum supplements and culturing techniques. Once MSC products are formulated, storage protocols play a pivotal role in its efficacy. Factors that affect cell viability include cell concentration, delivery solution and importantly, post-thawing protocols where applicable. Ensuing, differences in administration protocols can critically affect the distribution and functionallity of administered cells. As MSC-based therapies continue to advance through numerous clinical trials, implication of strategies to reduce product heterogeneity is imperative. Central to addressing these challenges is the need for precise prediction of clinical responses, which require well-defined MSC populations and harmonized assessment of their specific functions. By addressing these issues by meaningful approaches, such as, e.g., MSC pooling, the field can overcome barriers to advance towards more consistent and effective MSC-based therapies.
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Affiliation(s)
- Ana Bajc Česnik
- Slovenian Institute for Transfusion Medicine, Department for Therapeutic Services, Ljubljana, Slovenia
| | - Urban Švajger
- Slovenian Institute for Transfusion Medicine, Department for Therapeutic Services, Ljubljana, Slovenia
- Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
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Wu X, Tang Y, Lu X, Liu Y, Liu X, Sun Q, Wang L, Huang W, Liu A, Liu L, Chao J, Zhang X, Qiu H. Endothelial cell-derived extracellular vesicles modulate the therapeutic efficacy of mesenchymal stem cells through IDH2/TET pathway in ARDS. Cell Commun Signal 2024; 22:293. [PMID: 38802896 PMCID: PMC11129421 DOI: 10.1186/s12964-024-01672-0] [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: 03/12/2024] [Accepted: 05/20/2024] [Indexed: 05/29/2024] Open
Abstract
BACKGROUND Acute respiratory distress syndrome (ARDS) is a severe and fatal disease. Although mesenchymal stem cell (MSC)-based therapy has shown remarkable efficacy in treating ARDS in animal experiments, clinical outcomes have been unsatisfactory, which may be attributed to the influence of the lung microenvironment during MSC administration. Extracellular vesicles (EVs) derived from endothelial cells (EC-EVs) are important components of the lung microenvironment and play a crucial role in ARDS. However, the effect of EC-EVs on MSC therapy is still unclear. In this study, we established lipopolysaccharide (LPS) - induced acute lung injury model to evaluate the impact of EC-EVs on the reparative effects of bone marrow-derived MSC (BM-MSC) transplantation on lung injury and to unravel the underlying mechanisms. METHODS EVs were isolated from bronchoalveolar lavage fluid of mice with LPS - induced acute lung injury and patients with ARDS using ultracentrifugation. and the changes of EC-EVs were analysed using nanoflow cytometry analysis. In vitro assays were performed to establish the impact of EC-EVs on MSC functions, including cell viability and migration, while in vivo studies were performed to validate the therapeutic effect of EC-EVs on MSCs. RNA-Seq analysis, small interfering RNA (siRNA), and a recombinant lentivirus were used to investigate the underlying mechanisms. RESULTS Compared with that in non-ARDS patients, the quantity of EC-EVs in the lung microenvironment was significantly greater in patients with ARDS. EVs derived from lipopolysaccharide-stimulated endothelial cells (LPS-EVs) significantly decreased the viability and migration of BM-MSCs. Furthermore, engrafting BM-MSCs pretreated with LPS-EVs promoted the release of inflammatory cytokines and increased pulmonary microvascular permeability, aggravating lung injury. Mechanistically, LPS-EVs reduced the expression level of isocitrate dehydrogenase 2 (IDH2), which catalyses the formation of α-ketoglutarate (α-KG), an intermediate product of the tricarboxylic acid (TCA) cycle, in BM-MSCs. α-KG is a cofactor for ten-eleven translocation (TET) enzymes, which catalyse DNA hydroxymethylation in BM-MSCs. CONCLUSIONS This study revealed that EC-EVs in the lung microenvironment during ARDS can affect the therapeutic efficacy of BM-MSCs through the IDH2/TET pathway, providing potential strategies for improving the therapeutic efficacy of MSC-based therapy in the clinic.
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Affiliation(s)
- Xiao Wu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China
| | - Ying Tang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China
| | - Xinxing Lu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China
| | - Yigao Liu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China
| | - Xu Liu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China
| | - Qin Sun
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China
| | - Lu Wang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China
| | - Wei Huang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China
| | - Airan Liu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China
| | - Ling Liu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China
| | - Jie Chao
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China
- Department of Physiology, School of Medicine, Southeast University, Nanjing, 210009, China
| | - Xiwen Zhang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China.
| | - Haibo Qiu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China
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Cheng F, Ji L, Li P, Han Z, He Y, Yang F, Xu Z, Li Y, Ruan T, Zhu X, Lin J. Enhanced therapeutic potential of Flotillins-modified MenSCs by improve the survival, proliferation and migration. Mol Biol Rep 2024; 51:680. [PMID: 38796595 DOI: 10.1007/s11033-024-09624-0] [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: 12/07/2023] [Accepted: 05/08/2024] [Indexed: 05/28/2024]
Abstract
Menstrual blood-derived endometrial stem cells (MenSCs) have attracted increasing interest due to their excellent safety, and lack of ethical dilemma as well as their ability to be periodically obtained in a noninvasive manner. However, although preclinical research as shown the therapeutic potential of MenSCs in several diseases, their poor cell survival and low engraftment at disease sites reduce their clinical efficacy. Flotillins (including Flot1 and Flot2) are implicated in various cellular processes, such as vesicular trafficking, signal transduction, cell proliferation, migration and apoptosis. In this study, we aimed to determine the effects of Flotillins on MenSCs survival, proliferation and migration. Our experimental results show that MenSCs were modified to overexpress Flot1 and/or Flot2 without altering their intrinsic characteristics. Flot1 and Flot2 co-overexpression promoted MenSC viability and proliferation capacity. Moreover, Flot1 or Flot2 overexpression significantly promoted the migration and inhibited the apoptosis of MenSCs compared with the negative control group, and these effects were stronger in the Flot1 and Flot2 gene co-overexpression group. However, these effects were significantly reversed after Flot1 and/or Flot2 knockdown. In conclusion, our results indicate that Flot1 and Flot2 overexpression in MenSCs improved their proliferation and migration and inhibited their apoptosis, and this might be an effective approach to improve the efficiency of cell-based therapies.
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Affiliation(s)
- Fangfang Cheng
- Stem Cell and Biotherapy Engineering Research Center of Henan, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, China
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang, 453003, China
| | - Longkai Ji
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang, 453003, China
| | - Pan Li
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang, 453003, China
| | - Zhisheng Han
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang, 453003, China
| | - Yanan He
- Zhongyuan Stem Cell Research Institute, Xinxiang, 453003, China
| | - Fen Yang
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang, 453003, China
| | - Zhihao Xu
- Stem Cell and Biotherapy Engineering Research Center of Henan, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, China
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang, 453003, China
| | - Yonghai Li
- Stem Cell and Biotherapy Engineering Research Center of Henan, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, China
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang, 453003, China
| | - Tao Ruan
- Stem Cell and Biotherapy Engineering Research Center of Henan, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, China
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang, 453003, China
| | - Xinxing Zhu
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang, 453003, China
| | - Juntang Lin
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang, 453003, China.
- Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road #601, Xinxiang, Henan Province, China.
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He Y, Li J, Liang Z, Tang H, Shi J, Cai J, Liao Y. Internal Expansion Preconditioning of Recipient Site Increases Fat Graft Retention by Enriching Stem Cell Pool and Inducing Browning in Rats. Plast Reconstr Surg 2024; 153:1055-1065. [PMID: 37285020 DOI: 10.1097/prs.0000000000010770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
BACKGROUND Fat grafting has an unsatisfactory retention rate for breast reconstruction because of poor recipient conditions. The contribution of the recipient site to fat grafts is unknown. In this study, the authors hypothesize that tissue expansion could improve fat graft retention by preconditioning the recipient fat pad. METHODS Overexpansion was achieved using 10-mL cylindrical soft-tissue expanders implanted beneath the left inguinal fat flaps of 16 Sprague-Dawley rats (weighing 250 to 300 g), whose contralateral parts were implanted with a silicone sheet as a control. After 7 days of expansion, the implants were removed and both inguinal fat flaps received 1 mL of fat grafts from eight donor rats. Fluorescent dye-labeled mesenchymal stromal cells were injected into rats and tracked in vivo by fluorescence imaging. Transplanted adipose tissue was harvested at 4 and 10 weeks ( n = 8 per time point). RESULTS After 7 days of expansion, OCT4 + ( P = 0.0002) and Ki67 + ( P = 0.0004) areas were increased with up-regulated expression of CXCL12 in recipient adipose flaps. An increasing number of CM-DiI-positive mesenchymal stromal cells were observed in the expanded fat pad. At 10 weeks after fat grafting, retention rate, measured using the Archimedes principle, was much higher in the expanded group than in the nonexpanded group (0.3019 ± 0.0680 versus 0.1066 ± 0.0402; P = 0.0005). Histologic and transcriptional analyses revealed that angiogenesis was enhanced, and macrophage infiltration was decreased in the expanded group. CONCLUSION Internal expansion preconditioning increased circulating stem cells into the recipient fat pad and contributed to improved fat graft retention. CLINICAL RELEVANCE STATEMENT Patients who have limited soft tissue after mastectomy are encouraged to undergo fat grafting. Then, an internal expander could be placed beneath the transferred fat. After internal expansion preconditioning of the recipient site, fat grafting could be performed again for soft-tissue volumization.
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Affiliation(s)
- Yufei He
- From the Departments of Plastic and Cosmetic Surgery
| | - Jian Li
- From the Departments of Plastic and Cosmetic Surgery
| | - Zhuokai Liang
- From the Departments of Plastic and Cosmetic Surgery
| | - Haojing Tang
- From the Departments of Plastic and Cosmetic Surgery
| | - Jiaolong Shi
- General Surgery, Nanfang Hospital, Southern Medical University
| | - Junrong Cai
- From the Departments of Plastic and Cosmetic Surgery
| | - Yunjun Liao
- From the Departments of Plastic and Cosmetic Surgery
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10
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Liu J, Qi L, Bao S, Yan F, Chen J, Yu S, Dong C. The acute spinal cord injury microenvironment and its impact on the homing of mesenchymal stem cells. Exp Neurol 2024; 373:114682. [PMID: 38199509 DOI: 10.1016/j.expneurol.2024.114682] [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: 11/07/2023] [Revised: 12/08/2023] [Accepted: 01/02/2024] [Indexed: 01/12/2024]
Abstract
Spinal cord injury (SCI) is a highly debilitating condition that inflicts devastating harm on the lives of affected individuals, underscoring the urgent need for effective treatments. By activating inflammatory cells and releasing inflammatory factors, the secondary injury response creates an inflammatory microenvironment that ultimately determines whether neurons will undergo necrosis or regeneration. In recent years, mesenchymal stem cells (MSCs) have garnered increasing attention for their therapeutic potential in SCI. MSCs not only possess multipotent differentiation capabilities but also have homing abilities, making them valuable as carriers and mediators of therapeutic agents. The inflammatory microenvironment induced by SCI recruits MSCs to the site of injury through the release of various cytokines, chemokines, adhesion molecules, and enzymes. However, this mechanism has not been previously reported. Thus, a comprehensive exploration of the molecular mechanisms and cellular behaviors underlying the interplay between the inflammatory microenvironment and MSC homing is crucial. Such insights have the potential to provide a better understanding of how to harness the therapeutic potential of MSCs in treating inflammatory diseases and facilitating injury repair. This review aims to delve into the formation of the inflammatory microenvironment and how it influences the homing of MSCs.
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Affiliation(s)
- Jinyi Liu
- Department of Anatomy, Medical College of Nantong University, Nantong, China
| | - Longju Qi
- Affiliated Nantong Hospital 3 of Nantong University, Nantong, China
| | - Shengzhe Bao
- Department of Anatomy, Medical College of Nantong University, Nantong, China
| | - Fangsu Yan
- Department of Anatomy, Medical College of Nantong University, Nantong, China
| | - Jiaxi Chen
- Department of Anatomy, Medical College of Nantong University, Nantong, China
| | - Shumin Yu
- Department of Anatomy, Medical College of Nantong University, Nantong, China
| | - Chuanming Dong
- Department of Anatomy, Medical College of Nantong University, Nantong, China; Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China.
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11
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Xiong Z, Hu Y, Jiang M, Liu B, Jin W, Chen H, Yang L, Han X. Hypoxic bone marrow mesenchymal stem cell exosomes promote angiogenesis and enhance endometrial injury repair through the miR-424-5p-mediated DLL4/Notch signaling pathway. PeerJ 2024; 12:e16953. [PMID: 38406291 PMCID: PMC10894593 DOI: 10.7717/peerj.16953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 01/25/2024] [Indexed: 02/27/2024] Open
Abstract
Background Currently, bone marrow mesenchymal stem cells (BMSCs) have been reported to promote endometrial regeneration in rat models of mechanically injury-induced uterine adhesions (IUAs), but the therapeutic effects and mechanisms of hypoxic BMSC-derived exosomes on IUAs have not been elucidated. Objective To investigate the potential mechanism by which the BMSCS-derived exosomal miR-424-5p regulates IUA angiogenesis through the DLL4/Notch signaling pathway under hypoxic conditions and promotes endometrial injury repair. Methods The morphology of the exosomes was observed via transmission electron microscopy, and the expression of exosome markers (CD9, CD63, CD81, and HSP70) was detected via flow cytometry and Western blotting. The expression of angiogenesis-related genes (Ang1, Flk1, Vash1, and TSP1) was detected via RT‒qPCR, and the expression of DLL4/Notch signaling pathway-related proteins (DLL4, Notch1, and Notch2) was detected via Western blotting. Cell proliferation was detected by a CCK-8 assay, and angiogenesis was assessed via an angiogenesis assay. The expression of CD3 was detected by immunofluorescence. The endometrial lesions of IUA rats were observed via HE staining, and the expression of CD3 and VEGFA was detected via immunohistochemistry. Results Compared with those in exosomes from normoxic conditions, miR-424-5p was more highly expressed in the exosomes from hypoxic BMSCs. Compared with those in normoxic BMSC-derived exosomes, the proliferation and angiogenesis of HUVECs were significantly enhanced after treatment with hypoxic BMSC-derived exosomes, and these effects were weakened after inhibition of miR-424-5p. miR-424-5p can target and negatively regulate the expression of DLL4, promote the expression of the proangiogenic genes Ang1 and Flk1, and inhibit the expression of the antiangiogenic genes Vash1 and TSP1. The effect of miR-424-5p can be reversed by overexpression of DLL4. In IUA rats, treatment with hypoxic BMSC exosomes and the miR-424-5p mimic promoted angiogenesis and improved endometrial damage. Conclusion The hypoxic BMSC-derived exosomal miR-424-5p promoted angiogenesis and improved endometrial injury repair by regulating the DLL4/Notch signaling pathway, which provides a new idea for the treatment of IUAs.
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Affiliation(s)
- Zhenghua Xiong
- Department of Gynecology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
- Department of Gynecology, Yan’an Hospital Affiliated to Kunming Medical University/Yan’an Hospital of Kunming City, Kunming, Yunnan, China
| | - Yong Hu
- Department of Gynecology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Min Jiang
- Department of Gynecology, Women and Children’s Hospital Affiliated to Qingdao University, Qingdao, Shandong, China
| | - Beibei Liu
- Department of Gynecology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Wenjiao Jin
- Department of Gynecology, Yan’an Hospital Affiliated to Kunming Medical University/Yan’an Hospital of Kunming City, Kunming, Yunnan, China
| | - Huiqin Chen
- Department of Gynecology, Chuxiong Hospital of Traditional Chinese Medicine, Chuxiong, Yunnan, China
| | - Linjuan Yang
- Department of Gynecology and Obstetrics, Baoshan Hospital of Traditional Chinese Medicine, Baoshan, Yunnan, China
| | - Xuesong Han
- Department of Gynecology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
- Department of Gynecology, Yan’an Hospital Affiliated to Kunming Medical University/Yan’an Hospital of Kunming City, Kunming, Yunnan, China
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12
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Yang K, Xiao Y, Zhong L, Zhang W, Wang P, Ren Y, Shi L. p53-regulated lncRNAs in cancers: from proliferation and metastasis to therapy. Cancer Gene Ther 2023; 30:1456-1470. [PMID: 37679529 DOI: 10.1038/s41417-023-00662-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 08/19/2023] [Accepted: 08/29/2023] [Indexed: 09/09/2023]
Abstract
Long non-coding RNAs (lncRNAs) have been identified as master gene regulators through various mechanisms such as transcription, translation, protein modification and RNA-protein complexes. LncRNA dysregulation is frequently associated with a variety of biological functions and human diseases including cancer. The p53 network is a key tumor-suppressive mechanism that transcriptionally activates target genes to suppress cellular proliferation in human malignancies. Recent research indicates that lncRNAs play an important role in the p53 signaling pathway. In this review, we summarize the current knowledge of lncRNAs in p53-relevant functions and provide an overview of how these altered lncRNAs contribute to tumor initiation and progression. We also discuss the association between lncRNA and up- or downstream genes of p53. These findings imply that lncRNAs can help identify cellular vulnerabilities that may prove to be promising potential biomarkers and therapeutic targets for cancer treatment.
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Affiliation(s)
- Kaixin Yang
- RNA Oncology Group, School of Public Health, Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Yinan Xiao
- RNA Oncology Group, School of Public Health, Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Linghui Zhong
- RNA Oncology Group, School of Public Health, Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Wenyang Zhang
- RNA Oncology Group, School of Public Health, Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Peng Wang
- College of Animal Science and Technology, Hebei North University, Zhangjiakou, 075131, People's Republic of China
| | - Yaru Ren
- RNA Oncology Group, School of Public Health, Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Lei Shi
- RNA Oncology Group, School of Public Health, Lanzhou University, Lanzhou, 730000, People's Republic of China.
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13
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Liu T, Guo S, Ji Y, Zhu W. Role of cancer-educated mesenchymal stromal cells on tumor progression. Biomed Pharmacother 2023; 166:115405. [PMID: 37660642 DOI: 10.1016/j.biopha.2023.115405] [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: 06/16/2023] [Revised: 08/28/2023] [Accepted: 08/28/2023] [Indexed: 09/05/2023] Open
Abstract
The malignant tumor is the main cause of human deaths worldwide. Current therapies focusing on the tumor itself have achieved unprecedented benefits. Various pro-tumorigenic factors in the tumor microenvironment (TME) could abolish the effect of cancer therapy. Mesenchymal stromal cells (MSCs) are one of the substantial components in the tumor microenvironment, contributing to tumor progression. However, MSCs are not inherently tumor-promoting. Indeed, they acquire pro-tumorigenic properties under the education of the TME. We herein review how various elements in the TME including tumor cells, immune cells, pro-inflammatory factors, hypoxia, and extracellular matrix influence the biological characteristics of MSCs through complex interactions and demonstrate the underlying mechanisms. We also highlight the importance of tumor-associated mesenchymal stromal cells (TA-MSCs) in promoting tumor progression. Our review gives a new insight into the TA-MSCs as a potential tumor therapeutic target. It is anticipated that subverting MSCs education will facilitate the outbreak of therapeutic strategies against tumors.
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Affiliation(s)
- Ting Liu
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu 212013, China
| | - Shuwei Guo
- Department of Clinical Laboratory, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China
| | - Yong Ji
- Department of Surgery, Jingjiang People's Hospital, Jingjiang 214500, China
| | - Wei Zhu
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu 212013, China.
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14
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Zhuang X, Jiang Y, Yang X, Fu L, Luo L, Dong Z, Zhao J, Hei F. Advances of mesenchymal stem cells and their derived extracellular vesicles as a promising therapy for acute respiratory distress syndrome: from bench to clinic. Front Immunol 2023; 14:1244930. [PMID: 37711624 PMCID: PMC10497773 DOI: 10.3389/fimmu.2023.1244930] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 08/14/2023] [Indexed: 09/16/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is an acute inflammatory lung injury characterized by diffuse alveolar damage. The period prevalence of ARDS was 10.4% of ICU admissions in 50 countries. Although great progress has been made in supportive care, the hospital mortality rate of severe ARDS is still up to 46.1%. Moreover, up to now, there is no effective pharmacotherapy for ARDS and most clinical trials focusing on consistently effective drugs have met disappointing results. Mesenchymal stem cells (MSCs) and their derived extracellular vesicles (EVs) have spawned intense interest of a wide range of researchers and clinicians due to their robust anti-inflammatory, anti-apoptotic and tissue regeneration properties. A growing body of evidence from preclinical studies confirmed the promising therapeutic potential of MSCs and their EVs in the treatment of ARDS. Based on the inspiring experimental results, clinical trials have been designed to evaluate safety and efficacy of MSCs and their EVs in ARDS patients. Moreover, trials exploring their optimal time window and regimen of drug administration are ongoing. Therefore, this review aims to present an overview of the characteristics of mesenchymal stem cells and their derived EVs, therapeutic mechanisms for ARDS and research progress that has been made over the past 5 years.
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Affiliation(s)
| | | | | | | | | | | | | | - Feilong Hei
- Department of Cardiopulmonary Bypass, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
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15
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Huang X, Liu C, Li H, Dai T, Luo G, Zhang C, Li T, Lü M. Hypoxia-responsive lncRNA G077640 promotes ESCC tumorigenesis via the H2AX-HIF1α-glycolysis axis. Carcinogenesis 2023; 44:383-393. [PMID: 37248865 DOI: 10.1093/carcin/bgad036] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 01/12/2023] [Accepted: 05/29/2023] [Indexed: 05/31/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) contribute to esophageal squamous cell carcinoma (ESCC) progression, but the underlying mechanisms remain elusive. In this study, we verified a hitherto uncharacterized hypoxia-responsive lncRNA, G077640, which is upregulated in human ESCC cells and tissues, supporting the proliferation and migration of ESCC cells. Mechanistically, G077640 prevented hypoxia-inducible factor-1α (HIF1α) from being degraded by directly interacting with histone H2AX and further modulated the interaction of HIF1α and H2AX. In addition, G077640 reprogrammed glycolytic metabolism by regulating the expression of glucose transporter 4 (GLUT4), hexokinase 2 (HK2) and pyruvate dehydrogenase kinase 1 (PDK1) for ESCC proliferation and migration. Clinically, G077640 was associated with poor prognosis in ESCC patients. Taken together, our findings identified a hypoxia-responsive lncRNA that contributes to ESCC cells proliferation and migration, and targeting G077640 and its pathway might be a potential therapeutic strategy for ESCC.
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Affiliation(s)
- Xiaomei Huang
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Gastroenterology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Chunxia Liu
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Gastroenterology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Hao Li
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Tianyang Dai
- Department of Cardiothoracic Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Gang Luo
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Chunxiang Zhang
- Key Laboratory of Medical Electrophysiology of the Ministry of Education, and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Tao Li
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
| | - Muhan Lü
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
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16
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Yang G, Fan X, Liu Y, Jie P, Mazhar M, Liu Y, Dechsupa N, Wang L. Immunomodulatory Mechanisms and Therapeutic Potential of Mesenchymal Stem Cells. Stem Cell Rev Rep 2023; 19:1214-1231. [PMID: 37058201 PMCID: PMC10103048 DOI: 10.1007/s12015-023-10539-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/29/2023] [Indexed: 04/15/2023]
Abstract
Mesenchymal stem cells (MSCs) are regarded as highly promising cells for allogeneic cell therapy, owing to their multipotent nature and ability to display potent and varied functions in different diseases. The functions of MSCs, including native immunomodulation, high self-renewal characteristic, and secretory and trophic properties, can be employed to improve the immune-modulatory functions in diseases. MSCs impact most immune cells by directly contacting and/or secreting positive microenvironmental factors to influence them. Previous studies have reported that the immunomodulatory role of MSCs is basically dependent on their secretion ability from MSCs. This review discusses the immunomodulatory capabilities of MSCs and the promising strategies to successfully improve the potential utilization of MSCs in clinical research.
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Affiliation(s)
- Guoqiang Yang
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
- Acupuncture and Rehabilitation Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Xuehui Fan
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention of Cardiovascular Diseases, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany
| | - Yingchun Liu
- Department of Magnetic Resonance Imaging, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Pingping Jie
- Department of Magnetic Resonance Imaging, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Maryam Mazhar
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Yong Liu
- Department of Magnetic Resonance Imaging, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China.
| | - Nathupakorn Dechsupa
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.
| | - Li Wang
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China.
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China.
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17
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Yaylacı S, Kaçaroğlu D, Hürkal Ö, Ulaşlı AM. An enzyme-free technique enables the isolation of a large number of adipose-derived stem cells at the bedside. Sci Rep 2023; 13:8005. [PMID: 37198228 DOI: 10.1038/s41598-023-34915-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 05/09/2023] [Indexed: 05/19/2023] Open
Abstract
Adipose tissue derived stromal cells (ADSCs) play a crucial role in research and applications of regenerative medicine because they can be rapidly isolated in high quantities. Nonetheless, their purity, pluripotency, differentiation capacity, and stem cell marker expression might vary greatly depending on technique and tools used for extraction and harvesting. There are two methods described in the literature for isolating regenerative cells from adipose tissue. The first technique is enzymatic digestion, which utilizes many enzymes to remove stem cells from the tissue they reside in. The second method involves separating the concentrated adipose tissue using non-enzymatic, mechanical separation methods. ADSCs are isolated from the stromal-vascular fraction (SVF) of processed lipoaspirate, which is the lipoaspirate's aqueous portion. The purpose of this work was to evaluate a unique device 'microlyzer' for generating SVF from adipose tissue using a mechanical technique that required minimal intervention. The Microlyzer was examined using tissue samples from ten different patients. The cells that were retrieved were characterized in terms of their cell survival, phenotype, proliferation capacity, and differentiation potential. The number of progenitor cells extracted only from the microlyzed tissue was in comparable amount to the number of progenitor cells acquired by the gold standard enzymatic approach. The cells that were collected from each group exhibit similar levels of viability as well as proliferation rates. In addition, the differentiation potentials of the cells derived from the microlyzed tissue were investigated, and it was discovered that cells isolated through microlyzer entered the differentiation pathways more quickly and displayed a greater level of marker gene expression than cells isolated by enzymatic methods. These findings suggest that microlyzer, particularly in regeneration investigations, will allow quick and high rate cell separation at the bedside.
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Affiliation(s)
- Seher Yaylacı
- Department of Medical Biology, Faculty of Medicine, Lokman Hekim University, Ankara, 06800, Turkey.
| | - Demet Kaçaroğlu
- Department of Medical Biology, Faculty of Medicine, Lokman Hekim University, Ankara, 06800, Turkey
| | - Özgür Hürkal
- Plastic Reconstructive and Aesthetic Surgery, Lokman Hekim Hospital, Ankara, 06800, Turkey
| | - Alper Murat Ulaşlı
- Physical Therapy and Rehabilitation, Faculty of Health Sciences, Lokman Hekim University, Ankara, 06800, Turkey
- Romatem Ankara Physical Therapy and Rehabilitation Center, Ankara, 06700, Turkey
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18
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Zhuo Y, Li X, He Z, Lu M. Pathological mechanisms of neuroimmune response and multitarget disease-modifying therapies of mesenchymal stem cells in Parkinson's disease. Stem Cell Res Ther 2023; 14:80. [PMID: 37041580 PMCID: PMC10091615 DOI: 10.1186/s13287-023-03280-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 03/13/2023] [Indexed: 04/13/2023] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN); the etiology and pathological mechanism of the disease are still unclear. Recent studies have shown that the activation of a neuroimmune response plays a key role in the development of PD. Alpha-synuclein (α-Syn), the primary pathological marker of PD, can gather in the SN and trigger a neuroinflammatory response by activating microglia which can further activate the dopaminergic neuron's neuroimmune response mediated by reactive T cells through antigen presentation. It has been shown that adaptive immunity and antigen presentation processes are involved in the process of PD and further research on the neuroimmune response mechanism may open new methods for its prevention and therapy. While current therapeutic regimens are still focused on controlling clinical symptoms, applications such as immunoregulatory strategies can delay the symptoms and the process of neurodegeneration. In this review, we summarized the progression of the neuroimmune response in PD based on recent studies and focused on the use of mesenchymal stem cell (MSC) therapy and challenges as a strategy of disease-modifying therapy with multiple targets.
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Affiliation(s)
- Yi Zhuo
- Department of Neurosurgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, 410000, Hunan, China
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410006, Hunan, China
| | - Xuan Li
- Department of Neurosurgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, 410000, Hunan, China
| | - Zhengwen He
- Department of Neurosurgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, 410000, Hunan, China.
| | - Ming Lu
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410006, Hunan, China.
- Hunan Provincial Key Laboratory of Neurorestoratology, The Second Affiliated Hospital (the 921st Hospital of PLA), Hunan Normal University, Changsha, 410003, Hunan, China.
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19
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Ross EA, Turner LA, Donnelly H, Saeed A, Tsimbouri MP, Burgess KV, Blackburn G, Jayawarna V, Xiao Y, Oliva MAG, Willis J, Bansal J, Reynolds P, Wells JA, Mountford J, Vassalli M, Gadegaard N, Oreffo ROC, Salmeron-Sanchez M, Dalby MJ. Nanotopography reveals metabolites that maintain the immunomodulatory phenotype of mesenchymal stromal cells. Nat Commun 2023; 14:753. [PMID: 36765065 PMCID: PMC9918539 DOI: 10.1038/s41467-023-36293-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 01/25/2023] [Indexed: 02/12/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are multipotent progenitor cells that are of considerable clinical potential in transplantation and anti-inflammatory therapies due to their capacity for tissue repair and immunomodulation. However, MSCs rapidly differentiate once in culture, making their large-scale expansion for use in immunomodulatory therapies challenging. Although the differentiation mechanisms of MSCs have been extensively investigated using materials, little is known about how materials can influence paracrine activities of MSCs. Here, we show that nanotopography can control the immunomodulatory capacity of MSCs through decreased intracellular tension and increasing oxidative glycolysis. We use nanotopography to identify bioactive metabolites that modulate intracellular tension, growth and immunomodulatory phenotype of MSCs in standard culture and during larger scale cell manufacture. Our findings demonstrate an effective route to support large-scale expansion of functional MSCs for therapeutic purposes.
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Affiliation(s)
- Ewan A Ross
- Centre for the Cellular Microenvironment, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, Mazumdar-Shaw Advanced Research Centre, University of Glasgow, Glasgow, G11 6EW, UK
- School of Biosciences, College of Health and Life Sciences, Aston University, Birmingham, B4 7ET, UK
| | - Lesley-Anne Turner
- Centre for the Cellular Microenvironment, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, Mazumdar-Shaw Advanced Research Centre, University of Glasgow, Glasgow, G11 6EW, UK
| | - Hannah Donnelly
- Centre for the Cellular Microenvironment, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, Mazumdar-Shaw Advanced Research Centre, University of Glasgow, Glasgow, G11 6EW, UK
| | - Anwer Saeed
- Division of Biomedical Engineering, James Watt School of Engineering, University of Glasgow, Glasgow, G12 8QQ, UK
| | - Monica P Tsimbouri
- Centre for the Cellular Microenvironment, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, Mazumdar-Shaw Advanced Research Centre, University of Glasgow, Glasgow, G11 6EW, UK
| | - Karl V Burgess
- Glasgow Polyomics, Wolfson Wohl Cancer Research Centre, Garscube Campus, Bearsden, Glasgow, G61 1QH, UK
| | - Gavin Blackburn
- Glasgow Polyomics, Wolfson Wohl Cancer Research Centre, Garscube Campus, Bearsden, Glasgow, G61 1QH, UK
| | - Vineetha Jayawarna
- Centre for the Cellular Microenvironment, Division of Biomedical Engineering, James Watt School of Engineering, Mazumdar-Shaw Advanced Research Centre, University of Glasgow, Glasgow, G11 6EW, UK
| | - Yinbo Xiao
- Centre for the Cellular Microenvironment, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, Mazumdar-Shaw Advanced Research Centre, University of Glasgow, Glasgow, G11 6EW, UK
| | - Mariana A G Oliva
- Centre for the Cellular Microenvironment, Division of Biomedical Engineering, James Watt School of Engineering, Mazumdar-Shaw Advanced Research Centre, University of Glasgow, Glasgow, G11 6EW, UK
| | - Jennifer Willis
- School of Biosciences, College of Health and Life Sciences, Aston University, Birmingham, B4 7ET, UK
| | - Jaspreet Bansal
- School of Biosciences, College of Health and Life Sciences, Aston University, Birmingham, B4 7ET, UK
| | - Paul Reynolds
- Division of Biomedical Engineering, James Watt School of Engineering, University of Glasgow, Glasgow, G12 8QQ, UK
| | - Julia A Wells
- Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, Southampton, SO16 6YD, UK
| | - Joanne Mountford
- Scottish National Blood Transfusion Service, Advanced Therapeutics, Jack Copland Centre, 52 Research Avenue North, Heriot Watt Research Park, Edinburgh, EH14 4BE, UK
| | - Massimo Vassalli
- Centre for the Cellular Microenvironment, Division of Biomedical Engineering, James Watt School of Engineering, Mazumdar-Shaw Advanced Research Centre, University of Glasgow, Glasgow, G11 6EW, UK
| | - Nikolaj Gadegaard
- Division of Biomedical Engineering, James Watt School of Engineering, University of Glasgow, Glasgow, G12 8QQ, UK
| | - Richard O C Oreffo
- Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, Southampton, SO16 6YD, UK
| | - Manuel Salmeron-Sanchez
- Centre for the Cellular Microenvironment, Division of Biomedical Engineering, James Watt School of Engineering, Mazumdar-Shaw Advanced Research Centre, University of Glasgow, Glasgow, G11 6EW, UK
| | - Matthew J Dalby
- Centre for the Cellular Microenvironment, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, Mazumdar-Shaw Advanced Research Centre, University of Glasgow, Glasgow, G11 6EW, UK.
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Pretreated Mesenchymal Stem Cells and Their Secretome: Enhanced Immunotherapeutic Strategies. Int J Mol Sci 2023; 24:ijms24021277. [PMID: 36674790 PMCID: PMC9864323 DOI: 10.3390/ijms24021277] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/24/2022] [Accepted: 12/28/2022] [Indexed: 01/11/2023] Open
Abstract
Mesenchymal stem cells (MSCs) with self-renewing, multilineage differentiation and immunomodulatory properties, have been extensively studied in the field of regenerative medicine and proved to have significant therapeutic potential in many different pathological conditions. The role of MSCs mainly depends on their paracrine components, namely secretome. However, the components of MSC-derived secretome are not constant and are affected by the stimulation MSCs are exposed to. Therefore, the content and composition of secretome can be regulated by the pretreatment of MSCs. We summarize the effects of different pretreatments on MSCs and their secretome, focusing on their immunomodulatory properties, in order to provide new insights for the therapeutic application of MSCs and their secretome in inflammatory immune diseases.
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21
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Zhu F, Wei C, Wu H, Shuai B, Yu T, Gao F, Yuan Y, Zuo D, Liu X, Zhang L, Fan H. Hypoxic mesenchymal stem cell-derived exosomes alleviate ulcerative colitis injury by limiting intestinal epithelial cells reactive oxygen species accumulation and DNA damage through HIF-1α. Int Immunopharmacol 2022; 113:109426. [DOI: 10.1016/j.intimp.2022.109426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 11/01/2022] [Accepted: 11/01/2022] [Indexed: 11/09/2022]
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22
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Huang Y, Yi Q, Feng J, Xie W, Sun W, Sun W. The role of lincRNA-p21 in regulating the biology of cancer cells. Hum Cell 2022; 35:1640-1649. [PMID: 35969349 DOI: 10.1007/s13577-022-00768-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 08/08/2022] [Indexed: 12/24/2022]
Abstract
Long non-coding RNAs (lncRNAs) are a type of multifunctional endogenous RNA transcript. The dysregulation of lncRNAs is considered to play a role in the initiation and progression of cancer. One such lncRNA, long intergenic non-coding RNA-p21 (lincRNA-p21), was identified in 2010 as a regulator in the p53 pathway and is gradually being identified to play crucial roles in diverse cellular processes. In this review, we have summarised the diverse regulatory functions of lincRNA-p21. For example, lincRNA-p21 has been reported to function as a protein decoy, act as a competitive endogenous RNA, regulate the transcription, regulate the translation processes and exist in the secreted exosomes. Furthermore, we highlight the emerging roles of lincRNA-p21 in cancer cell regulation. Various types of cancers, including colorectal carcinoma, hepatocellular carcinoma and non-small cell lung carcinoma, aberrantly express lincRNA-p21. However, the current understanding of the roles of lincRNA-p21 in cancer remains limited. Therefore, considering its potential as a valuable therapeutic target or biomarker for cancer, more research should be conducted to understand the role of lincRNA-p21 in cancer and other diseases.
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Affiliation(s)
- Yan Huang
- Department of Dermatology, Suining First People's Hospital, Suining, 629000, Sichuan, China
| | - Qian Yi
- The Central Laboratory, Affiliated Hospital of Putian University, Putian, China
- Department of Physiology, School of Basic Medical Science, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Jianguo Feng
- Laboratory of Anesthesiology, Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Wei Xie
- Department of Orthopedics, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, Guangdong, China
| | - Wei Sun
- Department of Orthopedics, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, Guangdong, China.
| | - Weichao Sun
- Department of Orthopedics, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, Guangdong, China.
- The Central Laboratory, Shenzhen Second People' Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, Guangdong, China.
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23
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Jiang XH, Li HF, Chen ML, Zhang YX, Chen HB, Chen RH, Xiao YC, Liu N. Treadmill exercise exerts a synergistic effect with bone marrow mesenchymal stem cell-derived exosomes on neuronal apoptosis and synaptic-axonal remodeling. Neural Regen Res 2022; 18:1293-1299. [PMID: 36453414 PMCID: PMC9838147 DOI: 10.4103/1673-5374.357900] [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] [Indexed: 11/27/2022] Open
Abstract
Treadmill exercise and mesenchymal stem cell transplantation are both practical and effective methods for the treatment of cerebral ischemia. However, whether there is a synergistic effect between the two remains unclear. In this study, we established rat models of ischemia/reperfusion injury by occlusion of the middle cerebral artery for 2 hours and reperfusion for 24 hours. Rat models were perfused with bone marrow mesenchymal stem cell-derived exosomes (MSC-exos) via the tail vein and underwent 14 successive days of treadmill exercise. Neurological assessment, histopathology, and immunohistochemistry results revealed decreased neuronal apoptosis and cerebral infarct volume, evident synaptic formation and axonal regeneration, and remarkably recovered neurological function in rats subjected to treadmill exercise and MSC-exos treatment. These effects were superior to those in rats subjected to treadmill exercise or MSC-exos treatment alone. Mechanistically, further investigation revealed that the activation of JNK1/c-Jun signaling pathways regulated neuronal apoptosis and synaptic-axonal remodeling. These findings suggest that treadmill exercise may exhibit a synergistic effect with MSC-exos treatment, which may be related to activation of the JNK1/c-Jun signaling pathway. This study provides novel theoretical evidence for the clinical application of treadmill exercise combined with MSC-exos treatment for ischemic cerebrovascular disease.
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Affiliation(s)
- Xin-Hong Jiang
- Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China,Fujian Institute of Cerebrovascular Disease, Fuzhou, Fujian Province, China,Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Hang-Feng Li
- Department of Neurology, Longyan First Hospital of Fujian Medical University, Longyan, Fujian Province, China
| | - Man-Li Chen
- Fujian Institute of Cerebrovascular Disease, Fuzhou, Fujian Province, China,Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China,Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Yi-Xian Zhang
- Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China,Fujian Institute of Cerebrovascular Disease, Fuzhou, Fujian Province, China,Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Hong-Bin Chen
- Fujian Institute of Cerebrovascular Disease, Fuzhou, Fujian Province, China,Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China,Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Rong-Hua Chen
- Fujian Institute of Cerebrovascular Disease, Fuzhou, Fujian Province, China,Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China,Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Ying-Chun Xiao
- Fujian Institute of Cerebrovascular Disease, Fuzhou, Fujian Province, China,Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China,Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Nan Liu
- Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China,Fujian Institute of Cerebrovascular Disease, Fuzhou, Fujian Province, China,Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China,Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China,Correspondence to: Nan Liu, .
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24
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Feng XD, Zhou JH, Chen JY, Feng B, Hu RT, Wu J, Pan QL, Yang JF, Yu J, Cao HC. Long non-coding RNA SNHG16 promotes human placenta-derived mesenchymal stem cell proliferation capacity through the PI3K/AKT pathway under hypoxia. World J Stem Cells 2022; 14:714-728. [PMID: 36188116 PMCID: PMC9516465 DOI: 10.4252/wjsc.v14.i9.714] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 06/24/2022] [Accepted: 08/15/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The effect of hypoxia on mesenchymal stem cells (MSCs) is an emerging topic in MSC biology. Although long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) are reported to play a critical role in regulating the biological characteristics of MSCs, their specific expression and co-expression profiles in human placenta-derived MSCs (hP-MSCs) under hypoxia and the underlying mech anisms of lncRNAs in hP-MSC biology are unknown. AIM To reveal the specific expression profiles of lncRNAs in hP-MSCs under hypoxia and initially explored the possible mechanism of lncRNAs on hP-MSC biology. METHODS Here, we used a multigas incubator (92.5% N2, 5% CO2, and 2.5% O2) to mimic the hypoxia condition and observed that hypoxic culture significantly promoted the proliferation potential of hP-MSCs. RNA sequencing technology was applied to identify the exact expression profiles of lncRNAs and mRNAs under hypoxia. RESULTS We identified 289 differentially expressed lncRNAs and 240 differentially expressed mRNAs between the hypoxia and normoxia groups. Among them, the lncRNA SNHG16 was upregulated under hypoxia, which was also validated by reverse transcription-polymerase chain reaction. SNHG16 was confirmed to affect hP-MSC proliferation rates using a SNHG16 knockdown model. SNHG16 overexpression could significantly enhance the proliferation capacity of hP-MSCs, activate the PI3K/AKT pathway, and upregulate the expression of cell cycle-related proteins. CONCLUSION Our results revealed the specific expression characteristics of lncRNAs and mRNAs in hypoxia-cultured hP-MSCs and that lncRNA SNHG16 can promote hP-MSC proliferation through the PI3K/AKT pathway.
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Affiliation(s)
- Xu-Dong Feng
- State Key Laboratory for The Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Jia-Hang Zhou
- State Key Laboratory for The Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Jun-Yao Chen
- State Key Laboratory for The Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Bing Feng
- State Key Laboratory for The Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Rui-Tian Hu
- Department of Chemistry, Duke University, Durham, NC 27708, United States
| | - Jian Wu
- State Key Laboratory for The Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250117, Shandong Province, China
| | - Qiao-Ling Pan
- State Key Laboratory for The Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Jin-Feng Yang
- State Key Laboratory for The Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Jiong Yu
- State Key Laboratory for The Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Hong-Cui Cao
- State Key Laboratory for The Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China.
- Key Laboratory of Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
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25
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Qin Q, Liu Y, Yang Z, Aimaijiang M, Ma R, Yang Y, Zhang Y, Zhou Y. Hypoxia-Inducible Factors Signaling in Osteogenesis and Skeletal Repair. Int J Mol Sci 2022; 23:ijms231911201. [PMID: 36232501 PMCID: PMC9569554 DOI: 10.3390/ijms231911201] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/10/2022] [Accepted: 09/14/2022] [Indexed: 11/23/2022] Open
Abstract
Sufficient oxygen is required to maintain normal cellular and physiological function, such as a creature’s development, breeding, and homeostasis. Lately, some researchers have reported that both pathological hypoxia and environmental hypoxia might affect bone health. Adaptation to hypoxia is a pivotal cellular event in normal cell development and differentiation and in pathological settings such as ischemia. As central mediators of homeostasis, hypoxia-inducible transcription factors (HIFs) can allow cells to survive in a low-oxygen environment and are essential for the regulation of osteogenesis and skeletal repair. From this perspective, we summarized the role of HIF-1 and HIF-2 in signaling pathways implicated in bone development and skeletal repair and outlined the molecular mechanism of regulation of downstream growth factors and protein molecules such as VEGF, EPO, and so on. All of these present an opportunity for developing therapies for bone regeneration.
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26
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Tian Y, Fang J, Zeng F, Chen Y, Pei Y, Gu F, Ding C, Niu G, Gu B. The role of hypoxic mesenchymal stem cells in tumor immunity. Int Immunopharmacol 2022; 112:109172. [PMID: 36087506 DOI: 10.1016/j.intimp.2022.109172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 08/06/2022] [Accepted: 08/14/2022] [Indexed: 11/09/2022]
Abstract
The emerging evidence has shown that mesenchymal stem cells (MSCs) not only exert a significant role in the occurrence and development of tumors, but also have immunosuppressive potential in tumor immunity. Hypoxia is a sign of solid tumors, but how functions of hypoxic MSCs alter in the tumor microenvironment (TME) remains less well and comprehensively described. Herein, we mostly describe and investigate recent advances in our comprehension of the emerging effects of different tissue derived MSCs in hypoxia condition on tumor progression and development, as well as bidirectional influence between hypoxic MSCs and immune cells of the TME. Furthermore, we also discuss the potential drug-resistant and therapeutic role of hypoxic MSCs. It can be envisaged that novel and profound insights into the functionality of hypoxic MSCs and the underlying mechanisms in tumor and tumor immunity will promote the meaningful and promising treatment strategies against tumor.
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Affiliation(s)
- Yiqing Tian
- Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, Jiangsu, PR China
| | - Jian Fang
- The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei 230022, Anhui, PR China
| | - Fanpeng Zeng
- Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, Jiangsu, PR China
| | - Yongqiang Chen
- Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, Jiangsu, PR China
| | - Yunfeng Pei
- Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, Jiangsu, PR China
| | - Feng Gu
- Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, Jiangsu, PR China
| | - Chen Ding
- Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, Jiangsu, PR China.
| | - Guoping Niu
- Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, Jiangsu, PR China.
| | - Bing Gu
- Laboratory Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510000, PR China.
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27
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Lozano Navarro LV, Chen X, Giratá Viviescas LT, Ardila-Roa AK, Luna-Gonzalez ML, Sossa CL, Arango-Rodríguez ML. Mesenchymal stem cells for critical limb ischemia: their function, mechanism, and therapeutic potential. Stem Cell Res Ther 2022; 13:345. [PMID: 35883198 PMCID: PMC9327195 DOI: 10.1186/s13287-022-03043-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/07/2022] [Indexed: 11/21/2022] Open
Abstract
Peripheral arterial disease is atherosclerotic occlusive disease of the lower extremity arteries and afflicts hundreds of millions of individuals worldwide. Its most severe manifestation is chronic limb-threatening ischemia (Petersen et al. (Science 300(5622):1140–2, 2003)), which is associated with severe pain at rest in the limbs, which progresses to necrosis, limb amputation, and/or death of the patient. Consequently, the care of these patients is considered a financial burden for both patients and health systems. Multidisciplinary endeavors are required to address this refractory disease and to find definitive solutions that lead to improved living conditions. Revascularization is the cornerstone of therapy for preventing limb amputation, and both open vascular surgery and endovascular therapy play a key role in the treatment of patients with CLI. Around one-third of these patients are not candidates for conventional surgical treatment, however, leading to higher amputation rates (approaching 20–25% at one year) with high morbidity and lower quality of life. Advances in regenerative medicine have enabled the development of cell-based therapies that promote the formation of new blood vessels. Particularly, mesenchymal stem cells (MSCs) have emerged as an attractive therapeutic agent in various diseases, including CLI, due to their role in tissue regeneration and immunomodulation. This review discusses the characteristics of MSCs, as well as their regenerative properties and their action mechanisms on CLI.
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Affiliation(s)
- Laura V Lozano Navarro
- Faculty of Health Sciences, Universidad Autónoma de Bucaramanga (UNAB), 681004153, Bucaramanga, Colombia
| | - Xueyi Chen
- Faculty of Health Sciences, Universidad Autónoma de Bucaramanga (UNAB), 681004153, Bucaramanga, Colombia
| | - Lady Tatiana Giratá Viviescas
- Banco Multitejidos y Centro de Terapias Avanzadas, Fundación Oftalmológica de Santander-FOSCAL, 681004153, Floridablanca, Colombia
| | - Andrea K Ardila-Roa
- Banco Multitejidos y Centro de Terapias Avanzadas, Fundación Oftalmológica de Santander-FOSCAL, 681004153, Floridablanca, Colombia
| | - Maria L Luna-Gonzalez
- Faculty of Health Sciences, Universidad Autónoma de Bucaramanga (UNAB), 681004153, Bucaramanga, Colombia.,Programa Para el Tratamiento y Estudio de Enfermedades Hematológicas y Oncológicas de Santander (PROTEHOS), 681004153, Floridablanca, Colombia
| | - Claudia L Sossa
- Faculty of Health Sciences, Universidad Autónoma de Bucaramanga (UNAB), 681004153, Bucaramanga, Colombia.,Banco Multitejidos y Centro de Terapias Avanzadas, Fundación Oftalmológica de Santander-FOSCAL, 681004153, Floridablanca, Colombia.,Programa Para el Tratamiento y Estudio de Enfermedades Hematológicas y Oncológicas de Santander (PROTEHOS), 681004153, Floridablanca, Colombia.,Universidad de Valencia, Valencia, Spain
| | - Martha L Arango-Rodríguez
- Banco Multitejidos y Centro de Terapias Avanzadas, Fundación Oftalmológica de Santander-FOSCAL, 681004153, Floridablanca, Colombia.
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28
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Jiang DT, Tuo L, Bai X, Bing WD, Qu QX, Zhao X, Song GM, Bi YW, Sun WY. Prostaglandin E1 reduces apoptosis and improves the homing of mesenchymal stem cells in pulmonary arterial hypertension by regulating hypoxia-inducible factor 1 alpha. Stem Cell Res Ther 2022; 13:316. [PMID: 35842683 PMCID: PMC9288720 DOI: 10.1186/s13287-022-03011-x] [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: 10/07/2021] [Accepted: 05/14/2022] [Indexed: 11/17/2022] Open
Abstract
Background Pulmonary arterial hypertension (PAH) is associated with oxidative stress and affects the survival and homing of transplanted mesenchymal stem cells (MSCs) as well as cytokine secretion by the MSCs, thereby altering their therapeutic potential. In this study, we preconditioned the MSCs with prostaglandin E1 (PGE1) and performed in vitro and in vivo cell experiments to evaluate the therapeutic effects of MSCs in rats with PAH. Methods We studied the relationship between PGE1 and vascular endothelial growth factor (VEGF) secretion, B-cell lymphoma 2 (Bcl-2) expression, and C-X-C chemokine receptor 4 (CXCR4) expression in MSCs and MSC apoptosis as well as migration through the hypoxia-inducible factor (HIF) pathway in vitro. The experimental rats were randomly divided into five groups: (I) control group, (II) monocrotaline (MCT) group, (III) MCT + non-preconditioned (Non-PC) MSC group, (IV) MCT + PGE1-preconditioned (PGE1-PC) MSC group, and (V) MCT+PGE1+YC-1-PCMSC group. We studied methane dicarboxylic aldehyde (MDA) levels, MSC homing to rat lungs, mean pulmonary artery pressure, pulmonary artery systolic pressure, right ventricular hypertrophy index, wall thickness index (%WT), and relative wall area index (%WA) of rat pulmonary arterioles. Results Preconditioning with PGE1 increased the protein levels of HIF-1 alpha (HIF-1α) in MSCs, which can reduce MSC apoptosis and increase the protein levels of CXCR4, MSC migration, and vascular endothelial growth factor secretion. Upon injection with PGE1-PCMSCs, the pulmonary artery systolic pressure, mean pulmonary artery pressure, right ventricular hypertrophy index, %WT, and %WA decreased in rats with PAH. PGE1-PCMSCs exhibited better therapeutic effects than non-PCMSCs. Interestingly, lificiguat (YC-1), an inhibitor of the HIF pathway, blocked the effects of PGE1 preconditioning. Conclusions Our findings indicate that PGE1 modulates the properties of MSCs by regulating the HIF pathway, providing insights into the mechanism by which PGE1 preconditioning can be used to improve the therapeutic potential of MSCs in PAH. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03011-x.
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Affiliation(s)
- De-Tian Jiang
- Department of Cardiovascular Surgery, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, 266035, Shandong, China
| | - Lei Tuo
- Department of Cardiovascular Surgery, Weifang Yidu Central Hospital, Qingzhou, Weifang, 262500, Shandong, China
| | - Xiao Bai
- Department of Cardiovascular Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250062, Shandong, China
| | - Wei-Dong Bing
- Department of Cardiovascular Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250062, Shandong, China
| | - Qing-Xi Qu
- Department of Cardiovascular Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250062, Shandong, China
| | - Xin Zhao
- Department of Cardiovascular Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250062, Shandong, China
| | - Guang-Min Song
- Department of Cardiovascular Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250062, Shandong, China
| | - Yan-Wen Bi
- Department of Cardiovascular Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250062, Shandong, China.
| | - Wen-Yu Sun
- Department of Cardiovascular Surgery, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, 266035, Shandong, China.
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29
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Zeng J, Chen M, Yang Y, Wu B. A novel hypoxic lncRNA, HRL-SC, promotes the proliferation and migration of human dental pulp stem cells through the PI3K/AKT signaling pathway. Stem Cell Res Ther 2022; 13:286. [PMID: 35765088 PMCID: PMC9241257 DOI: 10.1186/s13287-022-02970-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 04/09/2022] [Indexed: 11/10/2022] Open
Abstract
Background Human dental pulp stem cells (hDPSCs) are critical for pulp generation. hDPSCs proliferate faster under hypoxia, but the mechanism by which long noncoding RNA (lncRNA) regulates this process is not fully understood. Methods Novel lncRNAs were obtained by reanalysis of transcriptome datasets from RNA-Seq under hypoxia compared with normoxia, and a differential expression analysis of target genes was performed. Bioinformatics analyses, including gene ontology analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis and gene set enrichment analysis, were used to understand the function of key novel lncRNAs. hDPSCs were isolated from dental pulp tissue. EdU and scratch wound healing assays were used to detect the proliferation and migration of hDPSCs. qRT-PCR was used to detect changes in the RNA expression of selected genes. RNA fluorescence in situ hybridization, small interfering RNA, qRT-PCR and Western blot analysis were used to explore the function of key novel lncRNAs. Results We identified 496 novel lncRNAs in hDPSCs under hypoxia, including 45 differentially expressed novel lncRNAs. Of these, we focused on a key novel lncRNA, which we designated HRL-SC (hypoxia-responsive lncRNA in stem cells). Functional annotation revealed that HRL-SC was associated with hypoxic conditions and the PI3K/AKT signaling pathway. HRL-SC was mainly located in the cytoplasm of hDPSCs and had stable high expression under hypoxia. Knockdown of HRL-SC inhibited the proliferation and migration of hDPSCs and the expression levels of PI3K/AKT-related marker proteins. Furthermore, the AKT activator SC79 partially offset the inhibitory effect caused by the knockdown, indicating that HRL-SC promoted hDPSCs through the PI3K/AKT signaling pathway. Conclusions Hypoxia-responsive lncRNA HRL-SC promotes the proliferation and migration of hDPSCs through the PI3K/AKT signaling pathway, and this understanding may facilitate the regenerative application of hDPSCs. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02970-5.
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Affiliation(s)
- Junkai Zeng
- Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.,School of Stomatology, Southern Medical University, Guangzhou, People's Republic of China
| | - Ming Chen
- Stomatological Hospital, Southern Medical University, Guangzhou, People's Republic of China.,School of Stomatology, Southern Medical University, Guangzhou, People's Republic of China
| | - Yeqing Yang
- Stomatological Hospital, Southern Medical University, Guangzhou, People's Republic of China.,School of Stomatology, Southern Medical University, Guangzhou, People's Republic of China
| | - Buling Wu
- Shenzhen Stomatology Hospital (Pingshan), Southern Medical University, Shenzhen, 510515, Guangdong, People's Republic of China. .,School of Stomatology, Southern Medical University, Guangzhou, People's Republic of China.
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30
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Mesenchymal stem cells: A living carrier for active tumor-targeted delivery. Adv Drug Deliv Rev 2022; 185:114300. [PMID: 35447165 DOI: 10.1016/j.addr.2022.114300] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 03/22/2022] [Accepted: 04/12/2022] [Indexed: 12/16/2022]
Abstract
The strategy of using mesenchymal stem cells (MSCs) as a living carrier for active delivery of therapeutic agents targeting tumor sites has been attempted in a wide range of studies to validate the feasibility and efficacy for tumor treatment. This approach reveals powerful tumor targeting and tumor penetration. In addition, MSCs have been confirmed to actively participate in immunomodulation of the tumor microenvironment. Thus, MSCs are not inert delivery vehicles but have a strong impact on the fate of tumor cells. In this review, these active properties of MSCs are addressed to highlight the advantages and challenges of using MSCs for tumor-targeted delivery. In addition, some of the latest examples of using MSCs to carry a variety of anti-tumor agents for tumor-targeted therapy are summarized. Recent technologies to improve the performance and safety of this delivery strategy will be introduced. The advances, applications, and challenges summarized in this review will provide a general understanding of this promising strategy for actively delivering drugs to tumor tissues.
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Zheng J, Mao X, Wang D, Xia S. Preconditioned MSCs Alleviate Cerebral Ischemia-Reperfusion Injury in Rats by Improving the Neurological Function and the Inhibition of Apoptosis. Brain Sci 2022; 12:631. [PMID: 35625017 PMCID: PMC9140028 DOI: 10.3390/brainsci12050631] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/27/2022] [Accepted: 05/01/2022] [Indexed: 02/01/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have great application prospects in the treatment of ischemic injury. However, their long-time cultivation before transplantation and poor survival after transplantation greatly limit the therapeutic effect and applications. This study aimed to investigate whether MSCs under the ischemic microenvironment could improve their survival and better alleviate cerebral ischemic injury. Firstly, we used ischemic brain tissue to culture MSCs and evaluated the functional changes of MSCs. Then a middle cerebral artery occlusion (MCAO) model was induced in rats, and the pretreated MSCs were injected via the tail vein. The adhesive removal test, rotarod test, modified neurological severity score, and pathological analyses were applied to assess the rats' neurological function. Then the expression of neuron and apoptosis related markers was detected. The results indicated that ischemic brain tissue pretreated MSCs promoted the proliferation and the release of the growth factors of MSCs. Meanwhile, in MCAO model rats, transplantation of pretreated MSCs enhanced the neurogenesis, attenuated behavioral changes, reduced infarct size, and inhibited apoptosis. The expression of B-cell lymphoma-2 (Bcl-2), brain-derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), NF-L, and NeuN were increased, while BCL2-Associated X (Bax) and Caspase-3 decreased. Our results suggest that MSCs pretreatment with stroke brain tissue could be an effective strategy in treating cerebral ischemic injury.
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Affiliation(s)
- Jin Zheng
- Department of Neurology, Tongde Hospital of Zhejiang Province, Hangzhou 310012, China
| | - Xueyu Mao
- Department of Neurology, Minhang Hospital, Fudan University, Shanghai 201199, China; (X.M.); (D.W.); (S.X.)
| | - Delong Wang
- Department of Neurology, Minhang Hospital, Fudan University, Shanghai 201199, China; (X.M.); (D.W.); (S.X.)
| | - Shiliang Xia
- Department of Neurology, Minhang Hospital, Fudan University, Shanghai 201199, China; (X.M.); (D.W.); (S.X.)
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Hao C, You J, Qiu H, Zhou O, Liu J, Zou W, Yang K, Fu Z, Zou L. Hypoxic preconditioning improves the survival and pro-angiogenic capacity of transplanted human umbilical cord mesenchymal stem cells via HIF-1α signaling in a rat model of bronchopulmonary dysplasia. Biochem Biophys Res Commun 2022; 605:111-118. [DOI: 10.1016/j.bbrc.2022.03.044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/08/2022] [Accepted: 03/08/2022] [Indexed: 11/02/2022]
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Xu Y, Jiang Y, Wang Y, Jia B, Gao S, Yu H, Zhang H, Lv C, Li H, Li T. LINC00473-modified bone marrow mesenchymal stem cells incorporated thermosensitive PLGA hydrogel transplantation for steroid-induced osteonecrosis of femoral head: A detailed mechanistic study and validity evaluation. Bioeng Transl Med 2022; 7:e10275. [PMID: 35600648 PMCID: PMC9115691 DOI: 10.1002/btm2.10275] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 11/25/2021] [Accepted: 11/26/2021] [Indexed: 11/23/2022] Open
Abstract
The pathogenesis of steroid-induced osteonecrosis of the femoral head (SONFH) involves a glucocorticoid-induced imbalance of osteogenic and adipogenic differentiation, and apoptosis of bone marrow mesenchymal stem cells (BMSCs). An increasing number of genes, especially noncoding RNAs, have been implicated in the function of BMSCs. Our previous studies have confirmed the key role of LINC00473 and miR-23a-3p on the osteogenic, adipogenic differentiation, and apoptosis of BMSCs. However, the underlying mechanism of this process is still unclear. Based on bioinformatics analysis, here we investigated the effects of LINC00473 on the LRP5/Wnt/β-catenin signaling pathway in the osteogenesis and adipogenesis of BMSCs, as well as the PEBP1/Akt/Bad/Bcl-2 signaling pathway in dexamethasone- (Dex-) induced apoptosis of BMSCs. Our data showed that LINC00473 could promote osteogenesis and suppress the adipogenesis of BMSCs through the activation of the miR-23a-3p/LRP5/Wnt/β-catenin signaling pathway axis, while rescuing BMSCs from Dex-induced apoptosis by activating the miR-23a-3p/PEBP1/Akt/Bad/Bcl-2 signaling pathway axis. Notably, we observed that LINC00473 interacted with miR-23a-3p in an Argonaute 2 (AGO2)-dependent manner based on dual-luciferase reporter assay, AGO2-related RNA immunoprecipitation, and RNA antisense purification assay. Furthermore, injectable thermosensitive polylactic-co-glycolic acid (PLGA) hydrogel loaded with rat-derived BMSCs (rBMSCs) modified by LINC00473 were used for the treatment of SONFH in a rat model. Our results demonstrated that PLGA hydrogels provided a suitable environment for harboring rBMSCs. Besides, transplantation of PLGA hydrogels loaded with rBMSCs modified by LINC00473 could significantly promote the bone repair and reconstruction of the necrotic area at the femoral head in our SONFH rat model. Surprisingly, compared with the transplantation of BMSCs alone, the transplanted rBMSCs encapsulated within the PLGA hydrogel could migrate from the medullary cavity to the femoral head. In summary, LINC00473 promoted osteogenesis, inhibited adipogenesis, and antagonized Dex-induced apoptosis of BMSCs. Therefore, LINC00473 could provide a new strategy for the treatment of SONFH.
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Affiliation(s)
- Yingxing Xu
- Department of Joint SurgeryThe Affiliated Hospital of Qingdao UniversityQingdaoChina
- Department of MedicineQingdao UniversityQingdaoChina
| | - Yaping Jiang
- Department of MedicineQingdao UniversityQingdaoChina
- Department of Oral ImplantologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Yingzhen Wang
- Department of Joint SurgeryThe Affiliated Hospital of Qingdao UniversityQingdaoChina
- Department of MedicineQingdao UniversityQingdaoChina
| | - Bin Jia
- Department of Joint SurgeryThe Affiliated Hospital of Qingdao UniversityQingdaoChina
- Department of MedicineQingdao UniversityQingdaoChina
| | - Song Gao
- Department of RadiologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Haiyang Yu
- Department of RadiologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Haining Zhang
- Department of Joint SurgeryThe Affiliated Hospital of Qingdao UniversityQingdaoChina
- Department of MedicineQingdao UniversityQingdaoChina
| | - Chengyu Lv
- Department of Joint SurgeryThe Affiliated Hospital of Qingdao UniversityQingdaoChina
- Department of MedicineQingdao UniversityQingdaoChina
| | - Haiyan Li
- Department of Joint SurgeryThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Tao Li
- Department of Joint SurgeryThe Affiliated Hospital of Qingdao UniversityQingdaoChina
- Department of MedicineQingdao UniversityQingdaoChina
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Xu Z, Lin L, Fan Y, Huselstein C, De Isla N, He X, Chen Y, Li Y. Secretome of Mesenchymal Stem Cells from Consecutive Hypoxic Cultures Promotes Resolution of Lung Inflammation by Reprogramming Anti-Inflammatory Macrophages. Int J Mol Sci 2022; 23:ijms23084333. [PMID: 35457151 PMCID: PMC9032661 DOI: 10.3390/ijms23084333] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/08/2022] [Accepted: 04/11/2022] [Indexed: 02/06/2023] Open
Abstract
The secretome from hypoxia-preconditioned mesenchymal stem cells (MSCs) has been shown to promote resolution of inflammation and alleviate acute lung injury (ALI) through its immunomodulatory function. However, the effects of consecutive hypoxic culture on immunomodulatory function of the MSCs secretome are largely unclarified. Here, we intend to investigate the effects of consecutive hypoxia on therapeutic efficacy of conditioned medium derived from MSCs (MSCs-CM) in alleviating ALI. Human umbilical cord-derived MSCs (UC-MSCs) were consecutively cultured in 21% O2 (Nor-MSCs) or in 1% O2 (Hypo-MSCs) from passage 0. Their conditioned medium (Nor-CM and Hypo-CM respectively) was collected and administered into ALI models. Our findings confirmed that Hypo-MSCs exhibited increased proliferation ability and decreased cell senescence compared with Nor-MSCs. Consecutive hypoxia promoted UC-MSCs to secrete immunomodulatory cytokines, such as insulin-like growth factor 1(IGF1), IL10, TNFα-stimulated gene 6(TSG6), TGFβ, and prostaglandin E2 (PGE2). Both Nor-CM and Hypo-CM could effectively limit lung inflammation, promote efferocytosis and modulate anti-inflammatory polarization of lung macrophages in ALI models. Moreover, the effects of Hypo-CM were more potent than Nor-CM. Taken together, our findings indicate that consecutive hypoxic cultures could not only promote both proliferation and quality of UC-MSCs, but also enhance the therapeutic efficacy of their secretome in mitigating lung inflammation by promoting efferocytosis and anti-inflammatory polarization of macrophages.
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Affiliation(s)
- Zhihong Xu
- Department of Pathophysiology, Hubei Province Key Laboratory of Allergy and Immunology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China; (Z.X.); (L.L.); (Y.F.); (X.H.); (Y.C.)
| | - Lulu Lin
- Department of Pathophysiology, Hubei Province Key Laboratory of Allergy and Immunology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China; (Z.X.); (L.L.); (Y.F.); (X.H.); (Y.C.)
| | - Yuxuan Fan
- Department of Pathophysiology, Hubei Province Key Laboratory of Allergy and Immunology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China; (Z.X.); (L.L.); (Y.F.); (X.H.); (Y.C.)
| | - Céline Huselstein
- UMR 7365 CNRS, Medical School, University of Lorraine, 54505 Nancy, France; (C.H.); (N.D.I.)
| | - Natalia De Isla
- UMR 7365 CNRS, Medical School, University of Lorraine, 54505 Nancy, France; (C.H.); (N.D.I.)
| | - Xiaohua He
- Department of Pathophysiology, Hubei Province Key Laboratory of Allergy and Immunology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China; (Z.X.); (L.L.); (Y.F.); (X.H.); (Y.C.)
| | - Yun Chen
- Department of Pathophysiology, Hubei Province Key Laboratory of Allergy and Immunology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China; (Z.X.); (L.L.); (Y.F.); (X.H.); (Y.C.)
| | - Yinping Li
- Department of Pathophysiology, Hubei Province Key Laboratory of Allergy and Immunology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China; (Z.X.); (L.L.); (Y.F.); (X.H.); (Y.C.)
- Correspondence: ; Tel.: +86-27-6875-8727; Fax: +86-27-6875-9222
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Babajani A, Moeinabadi-Bidgoli K, Niknejad F, Rismanchi H, Shafiee S, Shariatzadeh S, Jamshidi E, Farjoo MH, Niknejad H. Human placenta-derived amniotic epithelial cells as a new therapeutic hope for COVID-19-associated acute respiratory distress syndrome (ARDS) and systemic inflammation. Stem Cell Res Ther 2022; 13:126. [PMID: 35337387 PMCID: PMC8949831 DOI: 10.1186/s13287-022-02794-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 02/25/2022] [Indexed: 02/07/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has become in the spotlight regarding the serious early and late complications, including acute respiratory distress syndrome (ARDS), systemic inflammation, multi-organ failure and death. Although many preventive and therapeutic approaches have been suggested for ameliorating complications of COVID-19, emerging new resistant viral variants has called the efficacy of current therapeutic approaches into question. Besides, recent reports on the late and chronic complications of COVID-19, including organ fibrosis, emphasize a need for a multi-aspect therapeutic method that could control various COVID-19 consequences. Human amniotic epithelial cells (hAECs), a group of placenta-derived amniotic membrane resident stem cells, possess considerable therapeutic features that bring them up as a proposed therapeutic option for COVID-19. These cells display immunomodulatory effects in different organs that could reduce the adverse consequences of immune system hyper-reaction against SARS-CoV-2. Besides, hAECs would participate in alveolar fluid clearance, renin-angiotensin-aldosterone system regulation, and regeneration of damaged organs. hAECs could also prevent thrombotic events, which is a serious complication of COVID-19. This review focuses on the proposed early and late therapeutic mechanisms of hAECs and their exosomes to the injured organs. It also discusses the possible application of preconditioned and genetically modified hAECs as well as their promising role as a drug delivery system in COVID-19. Moreover, the recent advances in the pre-clinical and clinical application of hAECs and their exosomes as an optimistic therapeutic hope in COVID-19 have been reviewed.
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Affiliation(s)
- Amirhesam Babajani
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kasra Moeinabadi-Bidgoli
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farnaz Niknejad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamidreza Rismanchi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sepehr Shafiee
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Siavash Shariatzadeh
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Elham Jamshidi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Hadi Farjoo
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hassan Niknejad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Yu Q, Qiao GH, Wang M, Yu L, Sun Y, Shi H, Ma TL. Stem Cell-Based Therapy for Diabetic Foot Ulcers. Front Cell Dev Biol 2022; 10:812262. [PMID: 35178389 PMCID: PMC8844366 DOI: 10.3389/fcell.2022.812262] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 01/04/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetic foot ulcer has become a worldwide clinical medical challenge as traditional treatments are not effective enough to reduce the amputation rate. Therefore, it is of great social significance to deeply study the pathogenesis and biological characteristics of the diabetic foot, explore new treatment strategies and promote their application. Stem cell-based therapy holds tremendous promise in the field of regenerative medicine, and its mechanisms include promoting angiogenesis, ameliorating neuroischemia and inflammation, and promoting collagen deposition. Studying the specific molecular mechanisms of stem cell therapy for diabetic foot has an important role and practical clinical significance in maximizing the repair properties of stem cells. In addition, effective application modalities are also crucial in order to improve the survival and viability of stem cells at the wound site. In this paper, we reviewed the specific molecular mechanisms of stem cell therapy for diabetic foot and the extended applications of stem cells in recent years, with the aim of contributing to the development of stem cell-based therapy in the repair of diabetic foot ulcers.
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Affiliation(s)
- Qian Yu
- Department of Hepatology, Songjiang Hospital Affiliated to Nanjing Medical University, Shanghai, China
| | - Guo-Hong Qiao
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Min Wang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Li Yu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yaoxiang Sun
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Hui Shi
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China.,Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Tie-Liang Ma
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
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Huang X, Meng L, Wang S, Man Q, Jiang Y, Zhu G. Transcriptional dynamics of the circulating chicken primordial germ cells revealing key genes in cell adhesion and proliferation prior to gonad colonization. Mol Reprod Dev 2022; 89:214-226. [PMID: 35118723 DOI: 10.1002/mrd.23558] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 11/14/2021] [Accepted: 12/14/2021] [Indexed: 11/07/2022]
Abstract
Primordial germ cells (PGCs), precursors to sperms and oocytes, are responsible for the transfer of genetic information to the next generation. The PGCs arise far away from the developing gonad and thus have to migrate across the embryo to reach their site of function. The migration of PGCs from extraembryonic regions to the genital ridges is accomplished through distinct routes among different species. In particular, the birds PGCs utilized the developing circulation system to travel long distance before settling within the gonad. This study screened the transcriptome profile of chicken PGCs isolated from the bloodstream and the genital ridges to identify the cell intrinsic signals that could guide the unique migration path through circulation. We found cell adhesion and extracellular matrix (ECM) associated pathways were highly enriched in the PGCs from blood but not gonads. The platelet-derived growth factor receptors (PDGFRA and PDGFRB) were downregulated during gonad colonization and knockdown of either PDGFRA or PDGFRB inhibit the proliferation of blood PGCs. Furthermore, the migration of blood PGCs was impaired by the suppression of PDGFRA but not PDGFRB. Hence, the chicken PGCs show dynamic transcriptional remodeling during the blood-to-gonad migration and colonization. The free-floating PGCs in the circulation already express genes associated with cell-cell and cell-ECM interactions and therefore prepare for gonadal colonization.
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Affiliation(s)
- Xiaochen Huang
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of the Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Lu Meng
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of the Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Sheng Wang
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of the Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Qiu Man
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of the Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Yunqi Jiang
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of the Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Guiyu Zhu
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of the Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
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Vitale E, Rossin D, Perveen S, Miletto I, Lo Iacono M, Rastaldo R, Giachino C. Silica Nanoparticle Internalization Improves Chemotactic Behaviour of Human Mesenchymal Stem Cells Acting on the SDF1α/CXCR4 Axis. Biomedicines 2022; 10:biomedicines10020336. [PMID: 35203545 PMCID: PMC8961775 DOI: 10.3390/biomedicines10020336] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/20/2022] [Accepted: 01/27/2022] [Indexed: 02/05/2023] Open
Abstract
Human mesenchymal stem cell (hMSC)-based therapy is an emerging resource in regenerative medicine. Despite the innate ability of hMSCs to migrate to sites of injury, homing of infused hMSCs to the target tissue is inefficient. It was shown that silica nanoparticles (SiO2-NPs), previously developed to track the stem cells after transplantation, accumulated in lysosomes leading to a transient blockage of the autophagic flux. Since CXCR4 turnover is mainly regulated by autophagy, we tested the effect of SiO2-NPs on chemotactic migration of hMSCs along the SDF1α/CXCR4 axis that plays a pivotal role in directing MSC homing to sites of injury. Our results showed that SiO2-NP internalization augmented CXCR4 surface levels. We demonstrated that SiO2-NP-dependent CXCR4 increase was transient, and it reversed at the same time as lysosomal compartment normalization. Furthermore, the autophagy inhibitor Bafilomycin-A1 reproduced CXCR4 overexpression in control hMSCs confirming the direct effect of the autophagic degradation blockage on CXCR4 expression. Chemotaxis assays showed that SiO2-NPs increased hMSC migration toward SDF1α. In contrast, migration improvement was not observed in TNFα/TNFR axis, due to the proteasome-dependent TNFR regulation. Overall, our findings demonstrated that SiO2-NP internalization increases the chemotactic behaviour of hMSCs acting on the SDF1α/CXCR4 axis, unmasking a high potential to improve hMSC migration to sites of injury and therapeutic efficacy upon cell injection in vivo.
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Affiliation(s)
- Emanuela Vitale
- Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy; (E.V.); (D.R.); (S.P.); (M.L.I.); (C.G.)
| | - Daniela Rossin
- Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy; (E.V.); (D.R.); (S.P.); (M.L.I.); (C.G.)
| | - Sadia Perveen
- Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy; (E.V.); (D.R.); (S.P.); (M.L.I.); (C.G.)
| | - Ivana Miletto
- Department of Science and Technological Innovation, University of Eastern Piedmont, 15121 Alessandria, Italy;
| | - Marco Lo Iacono
- Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy; (E.V.); (D.R.); (S.P.); (M.L.I.); (C.G.)
| | - Raffaella Rastaldo
- Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy; (E.V.); (D.R.); (S.P.); (M.L.I.); (C.G.)
- Correspondence:
| | - Claudia Giachino
- Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy; (E.V.); (D.R.); (S.P.); (M.L.I.); (C.G.)
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Fan X, Wei H, Du J, Lu X, Wang L. Hypoxic preconditioning neural stem cell transplantation promotes spinal cord injury in rats by affecting transmembrane immunoglobulin domain-containing. Hum Exp Toxicol 2022; 41:9603271211066587. [PMID: 35243930 DOI: 10.1177/09603271211066587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE To explore the effects of hypoxic preconditioning neural stem cell (P-NSC) transplantation on rats with spinal cord injury (SCI). METHODS After identification, the NSCs were treated with hypoxic preconditioning. The NSCs migration was detected by Transwell method. RT-qPCR was used to detect the mRNA levels of HIF-1α, CXCR4 in NSC. The secretion of representative neurotrophic factors (VEGF, HGF, and BDNF) was checked by Western blot. Forty-six SCI rats were randomly divided into three experimental groups: SCI group (PBS injection, n = 10); N-NSC group (NSC atmospheric normoxic pretreatment injection, n = 18); and P-NSC group (NSC 's hypoxic preconditioning injection, n = 18). The sham operation group was also included (rats underwent laminectomy but not SCI, n = 10). The recovery of hindlimb motor function was evaluated by BBB score. The level of spinal cord inflammation (IL-1β, TNF-α, and IL-6) was determined by ELISA. Western blot was used to detect the content of TMIGD1 and TMIGD3 in spinal cord. RESULTS Compared with the N-NSC group, the number of NSC-passing membranes in the P-NSC group increased with the increase of the culture time (p < 0.05). Compared with N-NSC, P-NSC had higher levels of VEGF, HGF, and BDNF after 1 week of culture (p < 0.05). The BBB score of the P-NSC group was significantly higher than that of the N-NSC group at 7 and 28 days (p < 0.05). Compared with the SCI group, the levels of TNF-α, IL-1β, and IL-6 were significantly reduced after NSC treatment, and the P-NSC group was lower than the N-NSC group (p < 0.05). Compared with the SCI group, the levels of TMIGD1 and TMIGD3 increased. Compared with the N-NSC group, and the levels of TMIGD1 and TMIGD3 increased in the P-NSC group (p < 0.05). CONCLUSION P-NSC administration could improve SCI injury, and the levels of TMIGD1 and TMIGD3.
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Affiliation(s)
- Xiaoguang Fan
- The Second Department of Spine Surgery, 519688Yantaishan Hospital, Yantai, China
| | - Hongchun Wei
- Department of Neurology, 117747the Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Juan Du
- Department of Neurology, 519688Yantaishan Hospital, Yantai, China
| | - Xiuguo Lu
- Department of spine surgery, Yantai Yeda Hospital, Yantai, China
| | - Leisheng Wang
- The Second Department of Spine Surgery, 519688Yantaishan Hospital, Yantai, China
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Liu H, Huang Y, Yang Y, Han Y, Jia L, Li W. Compressive force-induced LincRNA-p21 inhibits mineralization of cementoblasts by impeding autophagy. FASEB J 2021; 36:e22120. [PMID: 34958157 DOI: 10.1096/fj.202101589r] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 11/30/2021] [Accepted: 12/13/2021] [Indexed: 12/13/2022]
Abstract
The mineralization capability of cementoblasts is the foundation for repairing orthodontic treatment-induced root resorption. It is essential to investigate the regulatory mechanism of mineralization in cementoblasts under mechanical compression to improve orthodontic therapy. Autophagy has a protective role in maintaining cell homeostasis under environmental stress and was reported to be involved in the mineralization process. Long noncoding RNAs are important regulators of biological processes, but their functions in compressed cementoblasts during orthodontic tooth movement remain unclear. In this study, we showed that compressive force downregulated the expression of mineralization-related markers. LincRNA-p21 was strongly enhanced by compressive force. Overexpression of lincRNA-p21 downregulated the expression of mineralization-related markers, while knockdown of lincRNA-p21 reversed the compressive force-induced decrease in mineralization. Furthermore, we found that autophagy was impeded in compressed cementoblasts. Then, overexpression of lincRNA-p21 decreased autophagic activity, while knockdown of lincRNA-p21 reversed the autophagic process decreased by mechanical compression. However, the autophagy inhibitor 3-methyladenine abolished the lincRNA-p21 knockdown-promoted mineralization, and the autophagy activator rapamycin rescued the mineralization inhibited by lincRNA-p21 overexpression. Mechanistically, the direct binding between lincRNA-p21 and FoxO3 blocked the expression of autophagy-related genes. In a mouse orthodontic tooth movement model, knockdown of lincRNA-p21 rescued the impeded autophagic process in cementoblasts, enhanced cementogenesis, and alleviated orthodontic force-induced root resorption. Overall, compressive force-induced lincRNA-p21 inhibits the mineralization capability of cementoblasts by impeding the autophagic process.
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Affiliation(s)
- Hao Liu
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China
| | - Yiping Huang
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China
| | - Yuhui Yang
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China
| | - Yineng Han
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China
| | - Lingfei Jia
- Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, China.,Department of Oral and Maxillofacial Surgery, Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, China
| | - Weiran Li
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China.,National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China
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41
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Ye Y, Zhao X, Xu Y, Yu J. Hypoxia-Inducible Non-coding RNAs in Mesenchymal Stem Cell Fate and Regeneration. FRONTIERS IN DENTAL MEDICINE 2021. [DOI: 10.3389/fdmed.2021.799716] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem cells (MSCs) can differentiate into multiple cell lines, which makes them an important source of cells for tissue engineering applications. They are defined by the capability to renew themselves and maintain pluripotency. This ability is modulated by the balance between complex cues from cellular microenvironment. Self-renewal and differentiation abilities are regulated by particular microenvironmental signals. Oxygen is considered to be an important part of cell microenvironment, which not only acts as a metabolic substrate but also a signal molecule. It has been proved that MSCs are hypoxic in the physiological environment. Signals from MSCs' microenvironment or niche which means the anatomical location of the MSCs, maintain the final properties of MSCs. Physiological conditions like oxygen tension are deemed to be a significant part of the mesenchymal stem cell niche, and have been proved to be involved in modulating embryonic and adult MSCs. Non-coding RNAs (ncRNAs), which play a key role in cell signal transduction, transcription and translation of genes, have been widely concerned as epigenetic regulators in a great deal of tissues. With the rapid development of bioinformatics analysis tools and high-throughput RNA sequencing technology, more and more evidences show that ncRNAs play a key role in tissue regeneration. It shows potential as a biomarker of MSC differentiation. In this paper, we reviewed the physiological correlation of hypoxia as a unique environmental parameter which is conducive to MSC expansion and maintenance, discussed the correlation of tissue engineering, and summarized the influence of hypoxia related ncRNAs on MSCs' fate and regeneration. This review will provide reference for future research of MSCs' regeneration.
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Abstract
Cerebral ischemic injury may lead to a series of serious brain diseases, death or different degrees of disability. Hypoxia-inducible factor-1α (HIF-1α) is an oxygen-sensitive transcription factor, which mediates the adaptive metabolic response to hypoxia and serves a key role in cerebral ischemia. HIF-1α is the main molecule that responds to hypoxia. HIF-1α serves an important role in the development of cerebral ischemia by participating in numerous processes, including metabolism, proliferation and angiogenesis. The present review focuses on the endogenous protective mechanism of cerebral ischemia and elaborates on the role of HIF-1α in cerebral ischemia. In addition, it focuses on cerebral ischemia interventions that act on the HIF-1α target, including biological factors, non-coding RNA, hypoxic-ischemic preconditioning and drugs, and expands upon the measures to strengthen the endogenous compensatory response to support HIF-1α as a therapeutic target, thus providing novel suggestions for the treatment of cerebral ischemia.
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Affiliation(s)
- Peiliang Dong
- Institute of Traditional Chinese Medicine, Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
| | - Qingna Li
- College of Pharmacy, Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
| | - Hua Han
- College of Pharmacy, Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
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43
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Li C, Zhao H, Cheng L, Wang B. Allogeneic vs. autologous mesenchymal stem/stromal cells in their medication practice. Cell Biosci 2021; 11:187. [PMID: 34727974 PMCID: PMC8561357 DOI: 10.1186/s13578-021-00698-y] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 10/12/2021] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem/stromal cell (MSC)-based therapeutics is already available for treatment of a range of diseases or medical conditions. Autologous or allogeneic MSCs obtained from self or donors have their own advantages and disadvantages in their medical practice. Therapeutic benefits of using autologous vs. allogeneic MSCs are inconclusive. Transplanted MSCs within the body interact with their physical microenvironment or niche, physiologically or pathologically, and such cells in a newly established tissue microenvironment may be impacted by the pathological harmful environmental factors to alter their unique biological behaviors. Meanwhile, a temporary microenvironment/niche may be also altered by the resident or niche-surrounding MSCs. Therefore, the functional plasticity and heterogeneity of MSCs caused by different donors and subpopulations of MSCs may result in potential uncertainty in their safe and efficacious medical practice. Acknowledging a connection between MSCs' biology and their existing microenvironment, donor-controlled clinical practice for the long-term therapeutic benefit is suggested to further consider minimizing MSCs potential harm for MSC-based individual therapies. In this review, we summarize the advantages and disadvantages of autologous vs. allogeneic MSCs in their therapeutic applications. Among other issues, we highlight the importance of better understanding of the various microenvironments that may affect the properties of niche-surrounding MSCs and discuss the clinical applications of MSCs within different contexts for treatment of different diseases including cardiomyopathy, lupus and lupus nephritis, diabetes and diabetic complications, bone and cartilage repair, cancer and tissue fibrosis.
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Affiliation(s)
- Chenghai Li
- Stem Cell Program of Clinical Research Center, People's Hospital of Zhengzhou University, 7 Weiwu Road, Zhengzhou, 450003, China.
| | - Hua Zhao
- Institute of Reproductive Medicine, People's Hospital of Zhengzhou University, 7 Weiwu Road, Zhengzhou, 450003, China
| | - Linna Cheng
- Institute of Hematology, People's Hospital of Zhengzhou University, 7 Weiwu Road, Zhengzhou, 450003, China
| | - Bin Wang
- Department of Neurosurgery, People's Hospital of Zhengzhou University, 7 Weiwu Road, Zhengzhou, 450003, China.
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Cell-Based Transplantation versus Cell Homing Approaches for Pulp-Dentin Complex Regeneration. Stem Cells Int 2021; 2021:8483668. [PMID: 34646323 PMCID: PMC8505125 DOI: 10.1155/2021/8483668] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 08/01/2021] [Accepted: 08/19/2021] [Indexed: 12/19/2022] Open
Abstract
Regenerative dentistry has paved the way for a new era for the replacement of damaged dental tissues. Whether the causative factor is dental caries, trauma, or chemical insult, the loss of the pulp vitality constitutes one of the major health problems worldwide. Two regenerative therapies were introduced for a fully functional pulp-dentin complex regeneration, namely, cell-based (cell transplantation) and cell homing (through revascularization or homing by injection of stem cells in situ or intravenously) therapies, with each demonstrating advantages as well as drawbacks, especially in clinical application. The present review is aimed at elaborating on these two techniques in the treatment of irreversibly inflamed or necrotic pulp, which is aimed at regenerating a fully functional pulp-dentin complex.
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45
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Moeinabadi-Bidgoli K, Babajani A, Yazdanpanah G, Farhadihosseinabadi B, Jamshidi E, Bahrami S, Niknejad H. Translational insights into stem cell preconditioning: From molecular mechanisms to preclinical applications. Biomed Pharmacother 2021; 142:112026. [PMID: 34411911 DOI: 10.1016/j.biopha.2021.112026] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 08/05/2021] [Accepted: 08/07/2021] [Indexed: 02/06/2023] Open
Abstract
Cell-based therapy (CBT) is a revolutionary approach for curing a variety of degenerative diseases. Stem cell-based regenerative medicine is a novel strategy for treating tissue damages regarding stem cells unique properties such as differentiation potential, paracrine impacts, and self-renewal ability. However, the current cell-based treatments encounter considerable challenges to be translated into clinical practice, including low cell survival, migration, and differentiation rate of transplanted stem cells. The poor stem cell therapy outcomes mainly originate from the unfavorable condition of damaged tissues for transplanted stem cells. The promising method of preconditioning improves cell resistance against the host environment's stress by imposing certain conditions similar to the harsh microenvironment of the damaged tissues on the transplanted stem cells. Various pharmacological, biological, and physical inducers are able to establish preconditioning. In addition to their known pharmacological effects on tissues and cells, these preconditioning agents improve cell biological aspects such as cell survival, proliferation, differentiation, migration, immunomodulation, paracrine impacts, and angiogenesis. This review focuses on different protocols and inducers of preconditioning along with underlying molecular mechanisms of their effects on stem cell behavior. Moreover, preclinical applications of preconditioned stem cells in various damaged organs such as heart, lung, brain, bone, cartilage, liver, and kidney are discussed with prospects of their translation into the clinic.
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Affiliation(s)
- Kasra Moeinabadi-Bidgoli
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amirhesam Babajani
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ghasem Yazdanpanah
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, IL, USA
| | | | - Elham Jamshidi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soheyl Bahrami
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in AUVA Research Center, Vienna, Austria
| | - Hassan Niknejad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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46
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He X, An W, Liu J. Effects of hypoxia on stemness, survival and angiogenic capacity of muscle-derived stem/progenitor cells. ALL LIFE 2021. [DOI: 10.1080/26895293.2021.1977725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Affiliation(s)
- Xiao He
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Weizheng An
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Jianyu Liu
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
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47
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Modifying strategies for SDF-1/CXCR4 interaction during mesenchymal stem cell transplantation. Gen Thorac Cardiovasc Surg 2021; 70:1-10. [PMID: 34510332 PMCID: PMC8732940 DOI: 10.1007/s11748-021-01696-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 09/04/2021] [Indexed: 12/14/2022]
Abstract
Mesenchymal stem cell (MSC) transplantation is regarded as a promising candidate for the treatment of ischaemic heart disease. The major hurdles for successful clinical translation of MSC therapy are poor survival, retention, and engraftment in the infarcted heart. Stromal cell-derived factor-1/chemokine receptor 4 (SDF-1/CXCR4) constitutes one of the most efficient chemokine/chemokine receptor pairs regarding cell homing. In this review, we mainly focused on previous studies on how to regulate the SDF-1/CXCR4 interaction through various priming strategies to maximize the efficacy of mesenchymal stem cell transplantation on ischaemic hearts or to facilitate the required effects. The strengthened measures for enhancing the therapeutic efficacy of the SDF-1/CXCR4 interaction for mesenchymal stem cell transplantation included the combination of chemokines and cytokines, hormones and drugs, biomaterials, gene engineering, and hypoxia. The priming strategies on recipients for stem cell transplantation included ischaemic conditioning and device techniques.
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48
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Sharma A, Chakraborty A, Jaganathan BG. Review of the potential of mesenchymal stem cells for the treatment of infectious diseases. World J Stem Cells 2021; 13:568-593. [PMID: 34249228 PMCID: PMC8246252 DOI: 10.4252/wjsc.v13.i6.568] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/07/2021] [Accepted: 06/03/2021] [Indexed: 02/06/2023] Open
Abstract
The therapeutic value of mesenchymal stem cells (MSCs) for the treatment of infectious diseases and the repair of disease-induced tissue damage has been explored extensively. MSCs inhibit inflammation, reduce pathogen load and tissue damage encountered during infectious diseases through the secretion of antimicrobial factors for pathogen clearance and they phagocytose certain bacteria themselves. MSCs dampen tissue damage during infection by downregulating the levels of pro-inflammatory cytokines, and inhibiting the excessive recruitment of neutrophils and proliferation of T cells at the site of injury. MSCs aid in the regeneration of damaged tissue by differentiating into the damaged cell types or by releasing paracrine factors that direct tissue regeneration, differentiation, and wound healing. In this review, we discuss in detail the various mechanisms by which MSCs help combat pathogens, tissue damage associated with infectious diseases, and challenges in utilizing MSCs for therapy.
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Affiliation(s)
- Amit Sharma
- Stem Cell and Cancer Biology Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, India
| | - Anuja Chakraborty
- Stem Cell and Cancer Biology Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, India
| | - Bithiah Grace Jaganathan
- Stem Cell and Cancer Biology Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, India
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49
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Hu XM, Zhang Q, Zhou RX, Wu YL, Li ZX, Zhang DY, Yang YC, Yang RH, Hu YJ, Xiong K. Programmed cell death in stem cell-based therapy: Mechanisms and clinical applications. World J Stem Cells 2021; 13:386-415. [PMID: 34136072 PMCID: PMC8176847 DOI: 10.4252/wjsc.v13.i5.386] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/26/2021] [Accepted: 05/07/2021] [Indexed: 02/06/2023] Open
Abstract
Stem cell-based therapy raises hopes for a better approach to promoting tissue repair and functional recovery. However, transplanted stem cells show a high death percentage, creating challenges to successful transplantation and prognosis. Thus, it is necessary to investigate the mechanisms underlying stem cell death, such as apoptotic cascade activation, excessive autophagy, inflammatory response, reactive oxygen species, excitotoxicity, and ischemia/hypoxia. Targeting the molecular pathways involved may be an efficient strategy to enhance stem cell viability and maximize transplantation success. Notably, a more complex network of cell death receives more attention than one crucial pathway in determining stem cell fate, highlighting the challenges in exploring mechanisms and therapeutic targets. In this review, we focus on programmed cell death in transplanted stem cells. We also discuss some promising strategies and challenges in promoting survival for further study.
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Affiliation(s)
- Xi-Min Hu
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China
| | - Qi Zhang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China
| | - Rui-Xin Zhou
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China
| | - Yan-Lin Wu
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China
| | - Zhi-Xin Li
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China
| | - Dan-Yi Zhang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China
| | - Yi-Chao Yang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China
| | - Rong-Hua Yang
- Department of Burns, Fo Shan Hospital of Sun Yat-Sen University, Foshan 528000, Guangdong Province, China
| | - Yong-Jun Hu
- Department of Cardiovascular Medicine, Hunan People's Hospital (the First Affiliated Hospital of Hunan Normal University, Changsha 410005, Hunan Province, China
| | - Kun Xiong
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China.
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50
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Egea V, Kessenbrock K, Lawson D, Bartelt A, Weber C, Ries C. Let-7f miRNA regulates SDF-1α- and hypoxia-promoted migration of mesenchymal stem cells and attenuates mammary tumor growth upon exosomal release. Cell Death Dis 2021; 12:516. [PMID: 34016957 PMCID: PMC8137693 DOI: 10.1038/s41419-021-03789-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 05/03/2021] [Accepted: 05/03/2021] [Indexed: 12/13/2022]
Abstract
Bone marrow-derived human mesenchymal stem cells (hMSCs) are recruited to damaged or inflamed tissues where they contribute to tissue repair. This multi-step process involves chemokine-directed invasion of hMSCs and on-site release of factors that influence target cells or tumor tissues. However, the underlying molecular mechanisms are largely unclear. Previously, we described that microRNA let-7f controls hMSC differentiation. Here, we investigated the role of let-7f in chemotactic invasion and paracrine anti-tumor effects. Incubation with stromal cell-derived factor-1α (SDF-1α) or inflammatory cytokines upregulated let-7f expression in hMSCs. Transfection of hMSCs with let-7f mimics enhanced CXCR4-dependent invasion by augmentation of pericellular proteolysis and release of matrix metalloproteinase-9. Hypoxia-induced stabilization of the hypoxia-inducible factor 1 alpha in hMSCs promoted cell invasion via let-7f and activation of autophagy. Dependent on its endogenous level, let-7f facilitated hMSC motility and invasion through regulation of the autophagic flux in these cells. In addition, secreted let-7f encapsulated in exosomes was increased upon upregulation of endogenous let-7f by treatment of the cells with SDF-1α, hypoxia, or induction of autophagy. In recipient 4T1 tumor cells, hMSC-derived exosomal let-7f attenuated proliferation and invasion. Moreover, implantation of 3D spheroids composed of hMSCs and 4T1 cells into a breast cancer mouse model demonstrated that hMSCs overexpressing let-7f inhibited tumor growth in vivo. Our findings provide evidence that let-7f is pivotal in the regulation of hMSC invasion in response to inflammation and hypoxia, suggesting that exosomal let-7f exhibits paracrine anti-tumor effects.
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Affiliation(s)
- Virginia Egea
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University of Munich, Munich, Germany.
| | - Kai Kessenbrock
- Department of Anatomy, University of California, San Francisco, CA, USA
| | - Devon Lawson
- Department of Anatomy, University of California, San Francisco, CA, USA
| | - Alexander Bartelt
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University of Munich, Munich, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.,Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.,Department of Molecular Metabolism, 665 Huntington Avenue, Harvard T.H. Chan School of Public Health, 02115, Boston, MA, USA
| | - Christian Weber
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University of Munich, Munich, Germany.,Dept. Biochemistry, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands.,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Christian Ries
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University of Munich, Munich, Germany.
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