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Wu CY, Vadhan A, Wei WY, Yu HS, Hsieh YC, Chen WC, Hsu CC, Liu YH, Hsu WL. Luteinizing Hormone Induces Murine Hair Loss through Transient Receptor Potential Canonical Channel-Mediated Cell Aging Responses: Implications for Female Pattern Hair Loss Pathogenesis. J Invest Dermatol 2025:S0022-202X(25)00453-1. [PMID: 40311867 DOI: 10.1016/j.jid.2025.03.044] [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: 04/28/2024] [Revised: 03/08/2025] [Accepted: 03/31/2025] [Indexed: 05/03/2025]
Abstract
Menopause-related hormonal imbalances, particularly the decline in estrogen and the rise in luteinizing hormone (LH), are implicated in female-pattern hair loss (FPHL). This study investigated the role of LH in FPHL, because its precise function has remained unclear. Our results found a significant association between elevated LH levels and FPHL. The binding of LH to LH receptor activates downstream transient receptor potential canonical channels (TRPCs), which potentially mediate excess calcium ion signals to initiate cell-aging responses. We revealed that LH causes ROS accumulation, calcium ion elevation and senescence in vibrissa follicles, and cell damage through DNA damage response, senescence, and senescence-associated secretory phenotype activation in dermal papilla cells. Hair loss in mice was due to LH-induced hair follicle damage and aging. The involvement of TRPCs in LH-induced pathogenesis was examined by treatment with TRPC inhibitors. Similarly, the balding area of FPHL showed higher levels of LH receptor than the nonbalding area, whereas expressions of DNA damage response-related genes, senescence-associated secretory phenotype-related genes, and TRPCs were upregulated in scalp biopsies. Overall, we identified the impacts of LH/LH receptor signaling on the pathogenesis of FPHL, including TRPC-mediated cell-aging responses in hair follicles.
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Affiliation(s)
- Ching-Ying Wu
- Department of Dermatology, Chung-Ho Memorial Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Anupama Vadhan
- National Center for Geriatrics and Welfare Research, National Health Research Institutes, Yunlin, Taiwan
| | - Wei-Yen Wei
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hsin-Su Yu
- Graduate Institute of Clinical Medicine, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Chun Hsieh
- National Center for Geriatrics and Welfare Research, National Health Research Institutes, Yunlin, Taiwan
| | - Wei-Chiao Chen
- Department of Dermatology, Chung-Ho Memorial Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chin-Chia Hsu
- National Center for Geriatrics and Welfare Research, National Health Research Institutes, Yunlin, Taiwan
| | - Yi-Hsuan Liu
- National Center for Geriatrics and Welfare Research, National Health Research Institutes, Yunlin, Taiwan
| | - Wen-Li Hsu
- National Center for Geriatrics and Welfare Research, National Health Research Institutes, Yunlin, Taiwan; Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Environmental Science and Engineering, National Pingtung University of Science and Technology, Pingtung, Taiwan.
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2
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Li X, Li Y, Yu H, Men LL, Deng G, Liu Z, Du JL. Oxidized Low-Density Lipoprotein Decreases the Survival of Bone Marrow Stem Cells via Inhibition of Bcl-2 Expression. Tissue Eng Part A 2025; 31:325-333. [PMID: 38818810 DOI: 10.1089/ten.tea.2024.0025] [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] [Indexed: 06/01/2024] Open
Abstract
Therapy with mesenchymal stem cells (MSCs) is considered an attractive strategy for the repair or regeneration of damaged tissues. However, low survival of MSCs limits their applications clinically. Oxidized low-density lipoprotein (ox-LDL) is significantly increased in patients with hyperlipidemia and decreases the survival of MSCs. Bcl-2 is critically involved in important cell functions, including cell membrane integrity and cell survival. The present study was designed to test the hypothesis that ox-LDL attenuates the survival of MSCs through suppression of Bcl-2 expression. Bone marrow MSCs from C57BL/6 mice were cultured with ox-LDL at different concentrations (0-140 μg/mL) for 24 h with native LDL as control. Ox-LDL treatment substantially decreased the survival of MSCs dose-dependently and enhanced the release of intracellular lactate dehydrogenase (LDH) in association with a significant decrease in Bcl-2 protein level without change in BAX protein expression in MSCs. Bcl-2 overexpression effectively protected MSCs against ox-LDL-induced damages with preserved cell numbers without significant increase in LDH release. Treatment with N-acetylcysteine (NAC) (1 mM) effectively preserved Bcl-2 protein expression in MSCs and significantly attenuated ox-LDL-induced decrease of cell number and increase in the release of intracellular LDH. These data indicated that ox-LDL treatment resulted in a significant damage of cell membrane and dramatically decreased the survival of MSCs dose-dependently through inhibition of Bcl-2 expression. NAC treatment significantly protected MSCs against the damage of cell membrane by ox-LDL and promoted the survival of MSCs in association with preserved Bcl-2 expression.
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Affiliation(s)
- Xin Li
- Department of Endocrinology, The First Affiliated Hospital, Dalian Medical University, Dalian, China
- Department of Endocrinology, Ningbo No 2 Hospital, Ningbo, China
| | - Yu Li
- Department of Endocrinology, The First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Hao Yu
- Department of Endocrinology, The First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Li-Li Men
- Department of Endocrinology, The First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Glenn Deng
- Research Center for Single-Cell Omics and Personalized Medicine, Ningbo No 2 Hospital, Ningbo, China
| | - Zhenguo Liu
- Center for Precision Medicine and Division of Cardiovascular Medicine, Department of Medicine, University of Missouri School of Medicine, Columbia, Missouri, USA
| | - Jian-Ling Du
- Department of Endocrinology, The First Affiliated Hospital, Dalian Medical University, Dalian, China
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Zhong X, Luo L, Wu J, Li W, Liu X, Ye T, Li Z, Shi P. Adhesion-Assisted Antioxidant-Engineered Mesenchymal Stromal Cells for Enhanced Cardiac Repair in Myocardial Infarction. ACS NANO 2025; 19:11412-11426. [PMID: 40073336 DOI: 10.1021/acsnano.5c00820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/14/2025]
Abstract
Mesenchymal stromal cell (MSC) therapy holds great promise for treating myocardial infarction (MI). However, the inflammatory and reactive oxygen species (ROS)-rich environment in infarcted myocardium challenges MSC survival, limiting its therapeutic impact. In this study, we demonstrate that chemical modification of MSCs with anti-VCAM1 and polydopamine (PD) significantly enhances MSC survival and promotes cardiac repair. Anti-VCAM1 modification facilitates MSC adhesion to inflamed tissue, ensuring MSC retention in the injured myocardium, while PD scavenges ROS surrounding MSCs, creating a conducive environment for cell transplantation. Our data indicate that chemically engineered MSCs effectively disrupt the inflammation-ROS cycle and modulate inflammation-related immune responses, thus improving MI microenvironments. Single-cell RNA sequencing of rat hearts reveals that treatment with engineered MSCs inhibits cardiac fibrosis by suppressing HB-EGF-EGFR signaling between anti-inflammatory macrophages and activated fibrillates. Ultimately, engineered MSCs demonstrate superior therapeutic efficacy in a rat model of MI. This study presents a straightforward, safe, and efficient chemical method for enhancing MSC therapy.
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Affiliation(s)
- Xianghua Zhong
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, P. R. China
| | - Li Luo
- The Tenth Affiliated Hospital of Southern Medical University, Dongguan 523059, P. R. China
| | - Jiyuan Wu
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, P. R. China
| | - Weirun Li
- The Tenth Affiliated Hospital of Southern Medical University, Dongguan 523059, P. R. China
| | - Xinyang Liu
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, P. R. China
| | - Tenghui Ye
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, P. R. China
| | - Zhenhua Li
- The Tenth Affiliated Hospital of Southern Medical University, Dongguan 523059, P. R. China
| | - Peng Shi
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, P. R. China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, P. R. China
- Guangdong Provincial Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou 510006, P. R. China
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4
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Hang C, Guo H, Moawad MS, Sayes CM, Chen YH, Yang J. Application of Cerium Oxide Nanozymes (CeONZs) in Human Pluripotent Stem Cell-Derived Cardiomyocytes. Methods Mol Biol 2025. [PMID: 40106142 DOI: 10.1007/7651_2025_606] [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: 03/22/2025]
Abstract
Cardiovascular diseases (CVDs) are a leading cause of death globally. Excessive production of reactive oxygen species (ROS) is detrimental to cardiomyocytes (CMs), triggering inflammation, inducing cell death, disrupting calcium homeostasis, and leading to arrhythmia. Thus, ROS is considered a common pathological factor in CVDs. Although the efficacy of antioxidants targeting ROS is currently limited, nanotechnology offers opportunities to develop antioxidants with improved selectivity and bioavailability, which can effectively prevent or treat oxidative stress-related CVDs. Cerium oxide nanozymes (CeONZs) can efficiently scavenge excessive ROS by mimicking the activity of endogenous antioxidant enzymes. However, their nanosafety and efficacy in human CMs remain unclear, posing a critical issue to be addressed before clinical applications. Due to the scarcity of primary human CMs, human pluripotent stem cells (hPSCs) and their derived cardiomyocytes (hPSC-CMs) provide a valuable source for modeling CVDs and their therapeutic interventions. This chapter presents a preparation method for CeONZs and outlines the assessment of their biosafety and antioxidant efficacy in hPSC-CMs.
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Affiliation(s)
- Chengwen Hang
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Huixin Guo
- Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Mohamed S Moawad
- Department of Toxicology and Forensic Medicine, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt.
| | - Christie M Sayes
- Department of Environmental Science, Baylor University, Waco, TX, USA
| | - Yi-Han Chen
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jian Yang
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
- Department of Cell Biology and Genetics, Tongji University School of Medicine, Shanghai, China.
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Cha E, Hong SH, La V, Madabhushi P, Teramoto D, Fung C, Thankam FG. Ischemia-induced expression status of cofilin 1, CRSP2, HSP90, HSP27, and IL8 in epicardial adipose tissue and single cell transcriptomic profiling of stromal cells. Biochem Cell Biol 2025; 103:1-15. [PMID: 39689294 DOI: 10.1139/bcb-2024-0210] [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] [Indexed: 12/19/2024] Open
Abstract
Epicardial adipose tissue (EAT) is a rich source of EAT-derived stromal cells (EATDS), which possess regenerative potential. CRSP2, HSP27, IL8, HSP90, and Cofilin 1 were detected in the secretome of left ventricular stromal cells under ischemia challenge. However, the association of these genes in the EAT and EATDS remain understudied. We aim to assess the status of cofilin 1, CRSP2, HSP27, IL8, and HSP90 in the EAT of myocardial infarction (MI) and coronary artery bypass graft (CABG) swine models and in vitro stimulated ischemic EATDS. Expression status of these proteins in EAT were assessed by immunostaining, and in EATDS using qRT-PCR, immunostaining, and Western blot. EATDS phenotyping was performed using sc-RNAseq analysis. Cofilin 1 was increased while the other four genes were decreased in the CABG. IL8 and HSP90 were increased, while CRSP2, HSP27, and cofilin 1 were decreased in the MI group. Similar trend was displayed in the expression of these genes in EATDS. Additionally, EATDS displayed versatile phenotypes at single cell resolution based on the differential expression of various gene signatures. The findings revealed novel insights into EAT/EATDS biology and further understanding regarding the EATDS sub-phenotypes would open novel avenues in translational cardiology.
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Affiliation(s)
- Ed Cha
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Sung Ho Hong
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Vy La
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Pranav Madabhushi
- Department of Biology, University of California San Diego, San Diego, CA 92093, USA
| | - Darren Teramoto
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Cameron Fung
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Finosh G Thankam
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
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6
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Li Z, Zhang M, Wang Y, Li Y, Zhu YZ. A Novel Human Amniotic Membrane Suspension Improves the Therapeutic Effect of Mesenchymal Stem Cells on Myocardial Infarction in Rats. ADVANCED NANOBIOMED RESEARCH 2024; 4. [DOI: 10.1002/anbr.202400084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025] Open
Abstract
Mesenchymal stem cell (MSC) therapy aids cardiac repair and regeneration, but the low rate of MSC survival and engulfment in the infarcted heart remains a major obstacle for routine clinical application. Here, an injectable suspension of human acellular amniotic membrane (HAAM) that may serve as synergistic cell delivery vehicle for the treatment of myocardial infarction (MI) by improving MSC homing and survival is developed. The results demonstrate that compared with MSC transplantation alone, HAAM‐loaded MSCs have higher survival and engraftment rates in infarcted tissue, alleviated hypoxia‐induced myocardial damage, achieved higher improvements in cardiac function, promoted angiogenesis, and reduced myocardial fibrosis. In addition, HAAM‐loaded MSCs increase N‐cadherin levels and thereby enhance the efficacy of MSCs in treating MI. This study provides a new approach for MSC‐based cardiac repair and regeneration.
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Affiliation(s)
- Zhaoyi Li
- Pharmacy, Faculty of Medicine & State Key Laboratory of Quality Research in Chinese Medicine Macau University of Science and Technology Macau 999078 China
| | - Meirong Zhang
- Huaxia (Qingdao) Biotech Co., Ltd. Qingdao 266000 China
- Huaxia Regenerative Medicine Institute for Human Materials Langfang 065000 China
| | - Yi Wang
- Huaxia (Qingdao) Biotech Co., Ltd. Qingdao 266000 China
- Huaxia Regenerative Medicine Institute for Human Materials Langfang 065000 China
| | - Yijia Li
- Huaxia (Qingdao) Biotech Co., Ltd. Qingdao 266000 China
- Huaxia Regenerative Medicine Institute for Human Materials Langfang 065000 China
| | - Yi Zhun Zhu
- Pharmacy, Faculty of Medicine & State Key Laboratory of Quality Research in Chinese Medicine Macau University of Science and Technology Macau 999078 China
- Laboratory of Drug Discovery from Natural Resources and Industrialization, School of Pharmacy Macau University of Science and Technology Macau 999078 China
- Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy Fudan University Shanghai 201203 China
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Huang S, Li J, Li Q, Wang Q, Zhou X, Chen J, Chen X, Bellou A, Zhuang J, Lei L. Cardiomyopathy: pathogenesis and therapeutic interventions. MedComm (Beijing) 2024; 5:e772. [PMID: 39465141 PMCID: PMC11502724 DOI: 10.1002/mco2.772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 09/12/2024] [Accepted: 09/16/2024] [Indexed: 10/29/2024] Open
Abstract
Cardiomyopathy is a group of disease characterized by structural and functional damage to the myocardium. The etiologies of cardiomyopathies are diverse, spanning from genetic mutations impacting fundamental myocardial functions to systemic disorders that result in widespread cardiac damage. Many specific gene mutations cause primary cardiomyopathy. Environmental factors and metabolic disorders may also lead to the occurrence of cardiomyopathy. This review provides an in-depth analysis of the current understanding of the pathogenesis of various cardiomyopathies, highlighting the molecular and cellular mechanisms that contribute to their development and progression. The current therapeutic interventions for cardiomyopathies range from pharmacological interventions to mechanical support and heart transplantation. Gene therapy and cell therapy, propelled by ongoing advancements in overarching strategies and methodologies, has also emerged as a pivotal clinical intervention for a variety of diseases. The increasing number of causal gene of cardiomyopathies have been identified in recent studies. Therefore, gene therapy targeting causal genes holds promise in offering therapeutic advantages to individuals diagnosed with cardiomyopathies. Acting as a more precise approach to gene therapy, they are gradually emerging as a substitute for traditional gene therapy. This article reviews pathogenesis and therapeutic interventions for different cardiomyopathies.
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Affiliation(s)
- Shitong Huang
- Department of Cardiac Surgical Intensive Care UnitGuangdong Cardiovascular InstituteGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
| | - Jiaxin Li
- Department of Cardiac Surgical Intensive Care UnitGuangdong Cardiovascular InstituteGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
| | - Qiuying Li
- Department of Cardiac Surgical Intensive Care UnitGuangdong Cardiovascular InstituteGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
| | - Qiuyu Wang
- Department of Cardiac Surgical Intensive Care UnitGuangdong Cardiovascular InstituteGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
| | - Xianwu Zhou
- Department of Cardiovascular SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Jimei Chen
- Department of Cardiovascular SurgeryGuangdong Cardiovascular InstituteGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
- Department of Cardiovascular SurgeryGuangdong Provincial Key Laboratory of South China Structural Heart DiseaseGuangzhouChina
| | - Xuanhui Chen
- Department of Medical Big Data CenterGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
| | - Abdelouahab Bellou
- Department of Emergency Medicine, Institute of Sciences in Emergency MedicineGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
- Department of Emergency MedicineWayne State University School of MedicineDetroitMichiganUSA
| | - Jian Zhuang
- Department of Cardiovascular SurgeryGuangdong Cardiovascular InstituteGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
- Department of Cardiovascular SurgeryGuangdong Provincial Key Laboratory of South China Structural Heart DiseaseGuangzhouChina
| | - Liming Lei
- Department of Cardiac Surgical Intensive Care UnitGuangdong Cardiovascular InstituteGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
- Department of Cardiovascular SurgeryGuangdong Provincial Key Laboratory of South China Structural Heart DiseaseGuangzhouChina
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Xu C, Xie Y, Wang B. Genetically modified mesenchymal stromal cells: a cell-based therapy offering more efficient repair after myocardial infarction. Stem Cell Res Ther 2024; 15:323. [PMID: 39334266 PMCID: PMC11438184 DOI: 10.1186/s13287-024-03942-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 09/16/2024] [Indexed: 09/30/2024] Open
Abstract
Myocardial infarction (MI) is a serious complication of coronary artery disease. This condition is common worldwide and has a profound impact on patients' lives and quality of life. Despite significant advances in the treatment of heart disease in modern medicine, the efficient treatment of MI still faces a number of challenges. Problems such as scar formation and loss of myocardial function after a heart attack still limit patients' recovery. Therefore, the search for a new therapeutic tool that can promote repair and regeneration of myocardial tissue has become crucial. In this context, mesenchymal stromal cells (MSCs) have attracted much attention as a potential therapeutic tool. MSCs are a class of adult stem cells with multidirectional differentiation potential, derived from bone marrow, fat, placenta and other tissues, and possessing properties such as self-renewal and immunomodulation. The application of MSCs may provide a new direction for the treatment of MI. These stem cells have the potential to differentiate into cardiomyocytes and vascular endothelial cells in damaged tissue and to repair and protect myocardial tissue through anti-inflammatory, anti-fibrotic and pro-neovascularization mechanisms. However, the clinical results of MSCs transplantation for the treatment of MI are less satisfactory due to the limitations of the native function of MSCs. Genetic modification has overcome problems such as the low survival rate of transplanted MSCs in vivo and enhanced their functions of promoting neovascularization and differentiation into cardiomyocytes, paving the way for them to become an effective tool for repair therapy after MI. In previous studies, MSCs have shown some therapeutic potential in experimental animals and preliminary clinical trials. This review aims to provide readers with a comprehensive and in-depth understanding to promote the wider application of engineering MSCs in the field of MI therapy, offering new hope for recovery and improved survival of cardiac patients.
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Affiliation(s)
- Congwang Xu
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese, Medicine321 Zhongshan Road, Nanjing, 210008, People's Republic of China
| | - Yuanyuan Xie
- Clinical Stem Cell Center, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210000, People's Republic of China
| | - Bin Wang
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese, Medicine321 Zhongshan Road, Nanjing, 210008, People's Republic of China.
- Clinical Stem Cell Center, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210000, People's Republic of China.
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Olatunji G, Kokori E, Yusuf I, Ayanleke E, Damilare O, Afolabi S, Adetunji B, Mohammed S, Akinmoju O, Aboderin G, Aderinto N. Stem cell-based therapies for heart failure management: a narrative review of current evidence and future perspectives. Heart Fail Rev 2024; 29:573-598. [PMID: 37733137 DOI: 10.1007/s10741-023-10351-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/13/2023] [Indexed: 09/22/2023]
Abstract
Heart failure (HF) is a prevalent and debilitating global cardiovascular condition affecting around 64 million individuals, placing significant strain on healthcare systems and diminishing patients' quality of life. The escalating prevalence of HF underscores the urgent need for innovative therapeutic approaches that target the root causes and aim to restore normal cardiac function. Stem cell-based therapies have emerged as promising candidates, representing a fundamental departure from conventional treatments focused primarily on symptom management. This review explores the evolving landscape of stem cell-based therapies for HF management. It delves into the mechanisms of action, clinical evidence from both positive and negative outcomes, ethical considerations, and regulatory challenges. Key findings include the potential for improved cardiac function, enhanced quality of life, and long-term benefits associated with stem cell therapies. However, adverse events and patient vulnerabilities necessitate stringent safety assessments. Future directions in stem cell-based HF therapies include enhancing efficacy and safety through optimized stem cell types, delivery techniques, dosing strategies, and long-term safety assessments. Personalized medicine, combining therapies, addressing ethical and regulatory challenges, and expanding access while reducing costs are crucial aspects of the evolving landscape.
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Affiliation(s)
- Gbolahan Olatunji
- Department of Medicine and Surgery, University of Ilorin, Ilorin, Nigeria
| | - Emmanuel Kokori
- Department of Medicine and Surgery, University of Ilorin, Ilorin, Nigeria
| | - Ismaila Yusuf
- Department of Medicine and Surgery, Obafemi Awolowo University, Osun, Nigeria
| | - Emmanuel Ayanleke
- Department of Medicine and Surgery, University of Ilorin, Ilorin, Nigeria
| | - Olakanmi Damilare
- Department of Medicine and Surgery, Ladoke Akintola University Teaching Hospital, Ogbomoso, Nigeria
| | - Samson Afolabi
- Department of Medicine and Surgery, Ladoke Akintola University Teaching Hospital, Ogbomoso, Nigeria
| | - Busayo Adetunji
- Department of Medicine and Surgery, Ladoke Akintola University Teaching Hospital, Ogbomoso, Nigeria
| | - Saad Mohammed
- Al-Kindy College of Medicine, University of Baghdad, Baghdad, Iraq
| | | | - Gbolahan Aboderin
- Department of Medicine and Surgery, Ladoke Akintola University Teaching Hospital, Ogbomoso, Nigeria
| | - Nicholas Aderinto
- Department of Medicine and Surgery, Ladoke Akintola University Teaching Hospital, Ogbomoso, Nigeria.
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10
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Zhang C. Exosomes Derived from Mesenchymal Stem Cells: Therapeutic Opportunities for Spinal Cord Injury. Bull Exp Biol Med 2024; 176:716-721. [PMID: 38888648 DOI: 10.1007/s10517-024-06095-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Indexed: 06/20/2024]
Abstract
Spinal cord injury (SCI) is a serious neurological condition comprising primary and secondary injury and causing severe neurological impairments. The effect of the conventional treatment is limited, including supportive therapy and emergency surgery. Exosomes derived from mesenchymal stem cells (MSCs-Exos) were previously reported to exert its potential therapeutic effects on SCI. Compared with mesenchymal stem cells (MSCs) transplantation for SCI, MSC-Exos showed several superiorities. In the present review, we summarized the revealed data of mechanisms underlying MSC-Exos repairing of SCI and discussed the issues of MSC-Exos use. Thus, in this review we summarized the latest studies on MSCs-Exos in the therapy of SCI and discussed whether MSCs-Exos can be applied to SCI and the prospects of transformation application.
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Affiliation(s)
- C Zhang
- Department of Medical Nanobiotechnology, Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation, Moscow, Russia.
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11
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Gill JK, Rehsia SK, Verma E, Sareen N, Dhingra S. Stem cell therapy for cardiac regeneration: past, present, and future. Can J Physiol Pharmacol 2024; 102:161-179. [PMID: 38226807 DOI: 10.1139/cjpp-2023-0202] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2024]
Abstract
Cardiac disorders remain the leading cause of mortality worldwide. Current clinical strategies, including drug therapy, surgical interventions, and organ transplantation offer limited benefits to patients without regenerating the damaged myocardium. Over the past decade, stem cell therapy has generated a keen interest owing to its unique self-renewal and immune privileged characteristics. Furthermore, the ability of stem cells to differentiate into specialized cell types, has made them a popular therapeutic tool against various diseases. This comprehensive review provides an overview of therapeutic potential of different types of stem cells in reference to cardiovascular diseases. Furthermore, it sheds light on the advantages and limitations associated with each cell type. An in-depth analysis of the challenges associated with stem cell research and the hurdles for its clinical translation and their possible solutions have also been elaborated upon. It examines the controversies surrounding embryonic stem cells and the emergence of alternative approaches, such as the use of induced pluripotent stem cells for cardiac therapeutic applications. Overall, this review serves as a valuable resource for researchers, clinicians, and policymakers involved in the field of regenerative medicine, guiding the development of safe and effective stem cell-based therapies to revolutionize patient care.
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Affiliation(s)
- Jaideep Kaur Gill
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre Regenerative Medicine Program, Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, Biomedical Engineering Program, University of Manitoba, Winnipeg MB, R2H2A6, Canada
| | - Sargun Kaur Rehsia
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre Regenerative Medicine Program, Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, Biomedical Engineering Program, University of Manitoba, Winnipeg MB, R2H2A6, Canada
| | - Elika Verma
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre Regenerative Medicine Program, Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, Biomedical Engineering Program, University of Manitoba, Winnipeg MB, R2H2A6, Canada
| | - Niketa Sareen
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre Regenerative Medicine Program, Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, Biomedical Engineering Program, University of Manitoba, Winnipeg MB, R2H2A6, Canada
| | - Sanjiv Dhingra
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre Regenerative Medicine Program, Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, Biomedical Engineering Program, University of Manitoba, Winnipeg MB, R2H2A6, Canada
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Zineldeen DH, Mushtaq M, Haider KH. Cellular preconditioning and mesenchymal stem cell ferroptosis. World J Stem Cells 2024; 16:64-69. [PMID: 38455100 PMCID: PMC10915960 DOI: 10.4252/wjsc.v16.i2.64] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/04/2024] [Accepted: 01/19/2024] [Indexed: 02/26/2024] Open
Abstract
In this editorial, we comment on the article published in the recent issue of the World Journal of Stem Cells. They focus on stem cell preconditioning to prevent ferroptosis by modulating the cystathionine γ-lyase/hydrogen sulfide (H2S) pathway as a novel approach to treat vascular disorders, particularly pulmonary hypertension. Preconditioned stem cells are gaining popularity in regenerative medicine due to their unique ability to survive by resisting the harsh, unfavorable microenvironment of the injured tissue. They also secrete various paracrine factors against apoptosis, necrosis, and ferroptosis to enhance cell survival. Ferroptosis, a regulated form of cell death characterized by iron accumulation and oxidative stress, has been implicated in various pathologies encompassing degenerative disorders to cancer. The lipid peroxidation cascade initiates and sustains ferroptosis, generating many reactive oxygen species that attack and damage multiple cellular structures. Understanding these intertwined mechanisms provides significant insights into developing therapeutic modalities for ferroptosis-related diseases. This editorial primarily discusses stem cell preconditioning in modulating ferroptosis, focusing on the cystathionase gamma/H2S ferroptosis pathway. Ferroptosis presents a significant challenge in mesenchymal stem cell (MSC)-based therapies; hence, the emerging role of H2S/cystathionase gamma/H2S signaling in abrogating ferroptosis provides a novel option for therapeutic intervention. Further research into understanding the precise mechanisms of H2S-mediated cytoprotection against ferroptosis is warranted to enhance the therapeutic potential of MSCs in clinical settings, particularly vascular disorders.
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Affiliation(s)
- Doaa Hussein Zineldeen
- Basic Sciences, Sulaiman AlRajhi University, Albukairiyah 52736, AlQaseem, Saudi Arabia
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Tanta University, Tanta 6632110, Egypt
| | - Mazhar Mushtaq
- Basic Sciences, Sulaiman AlRajhi University, Albukairiyah 52736, AlQaseem, Saudi Arabia
| | - Khawaja Husnain Haider
- Basic Sciences, Sulaiman AlRajhi University, Albukairiyah 52736, AlQaseem, Saudi Arabia.
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Nithesh Kumar H, Jeevanandham S, Shankar Ganesh M, Ashmi Sabana M, Manivasakam P. Emerging Strategies and Effective Prevention Measures for Investigating the Association Between Stroke and Sudden Cardiac Fatality. Curr Cardiol Rev 2024; 20:35-44. [PMID: 38310557 PMCID: PMC11284691 DOI: 10.2174/011573403x259676231222053709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 10/19/2023] [Accepted: 11/17/2023] [Indexed: 02/06/2024] Open
Abstract
Stroke-related cardiac death is a significant concern for patients with stroke and their healthcare providers. It is a complex and multifaceted condition that requires careful management of both modifiable and non-modifiable risk factors. This review provides an overview of the pathophysiology, risk factors, and prevention strategies for stroke-related cardiac death. The review highlights the importance of identifying and managing modifiable risk factors such as hypertension, diabetes, and lifestyle factors, as well as non-modifiable risk factors such as age and genetics. Additionally, the review explores emerging strategies for prevention, including the use of wearable devices and genetic testing to identify patients at risk, stem cell therapy and gene therapy for cardiac dysfunction, and precision medicine for personalized treatment plans. Despite some limitations to this review, it provides valuable insights into the current understanding of stroke-related cardiac death and identifies important areas for future research. Ultimately, the implementation of evidence-based prevention strategies and personalized treatment plans has the potential to improve outcomes for patients with stroke and reduce the burden of stroke-related cardiac death in the population.
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Affiliation(s)
| | - S. Jeevanandham
- Pharmacy Practice, JKKN College of Pharmacy, Namakkal, India
| | | | - M. Ashmi Sabana
- Pharmacy Practice, JKKN College of Pharmacy, Namakkal, India
| | - P. Manivasakam
- Pharmacy Practice, JKKN College of Pharmacy, Namakkal, India
- Department of Pharmaceutics, Vellalar College of Pharmacy, Erode, India
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14
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Abdelwahid E, de Carvalho KAT. Molecular Research on Heart Protection. Int J Mol Sci 2023; 25:11. [PMID: 38203180 PMCID: PMC10779149 DOI: 10.3390/ijms25010011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 10/30/2023] [Indexed: 01/12/2024] Open
Abstract
Recently, various molecular bases of heart protection have been discovered and used in many experimental and clinical investigations [...].
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Affiliation(s)
- Eltyeb Abdelwahid
- Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
- Department of Medicine, University of Illinois at Chicago, 909 South Wolcott Avenue, Chicago, IL 60612, USA
| | - Katherine Athayde Teixeira de Carvalho
- Advanced Therapy and Cellular Biotechnology in Regenerative Medicine Department, Pelé Pequeno Príncipe Institute, Child and Adolescent Health Research & Pequeno Príncipe Faculties, Ave. Silva Jardim, n°1632, Curitiba 80240-020, Paraná, Brazil;
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15
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He H, Yuan Y, Wu Y, Lu J, Yang X, Lu K, Liu A, Cao Z, Sun M, Yu M, Wang H. Exoskeleton Partial-Coated Stem Cells for Infarcted Myocardium Restoring. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2023; 35:e2307169. [PMID: 37962473 DOI: 10.1002/adma.202307169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 10/30/2023] [Indexed: 11/15/2023]
Abstract
The integration of abiotic materials with live cells has emerged as an exciting strategy for the control of cellular functions. Exoskeletons consisting ofmetal-organic frameworks are generated to produce partial-coated bone marrow stem cells (BMSCs) to overcome low cell survival leading to disappointing effects for cell-based cardiac therapy. Partially coated exoskeletons can promote the survival of suspended BMSCs by integrating the support of exoskeletons and unimpaired cellular properties. In addition, partial exoskeletons exhibit protective effects against detrimental environmental conditions, including reactive oxygen species, pH changes, and osmotic pressure. The partial-coated cells exhibit increased intercellular adhesion forces to aggregate and adhere, promoting cell survival and preventing cell escape during cell therapy. The exoskeletons interact with cell surface receptors integrin α5β1, leading to augmented biological functions with profitable gene expression alteration, such as Vegfa, Cxcl12, and Adm. The partial-coated BMSCs display enhanced cell retention in infarcted myocardium through non-invasive intravenous injections. The repair of myocardial infarction has been achieved with improved cardiac function, myocardial angiogenesis, proliferation, and inhibition of cell apoptosis. This discovery advances the elucidation of potential molecular and cellular mechanisms for cell-exoskeleton interactions and benefits the rational design and manufacture of next-generation nanobiohybrids.
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Affiliation(s)
- Huihui He
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
| | - Yuan Yuan
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Hangzhou, Zhejiang Province, 310058, China
| | - Yunhong Wu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
| | - Jingyi Lu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
| | - Xiaofu Yang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
| | - Kejie Lu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
| | - An Liu
- Department of Orthopaedic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310009, China
| | - Zelin Cao
- The First Clinical Medical College, Wenzhou Medical University, Wenzhou, Zhejiang Province, 325035, China
| | - Miao Sun
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
| | - Mengfei Yu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
| | - Huiming Wang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
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16
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Vetter VC, Bouten CVC, van der Pol A. Hydrogels for Cardiac Restorative Support: Relevance of Gelation Mechanisms for Prospective Clinical Use. Curr Heart Fail Rep 2023; 20:519-529. [PMID: 37812347 PMCID: PMC10746579 DOI: 10.1007/s11897-023-00630-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/20/2023] [Indexed: 10/10/2023]
Abstract
PURPOSE OF REVIEW Cardiac tissue regenerative strategies have gained much traction over the years, in particular those utilizing hydrogels. With our review, and with special focus on supporting post-myocardial infarcted tissue, we aim to provide insights in determining crucial design considerations of a hydrogel and the implications these could have for future clinical use. RECENT FINDINGS To date, two hydrogel delivery strategies are being explored, cardiac injection or patch, to treat myocardial infarction. Recent advances have demonstrated that the mechanism by which a hydrogel is gelated (i.e., physically or chemically cross-linked) not only impacts the biocompatibility, mechanical properties, and chemical structure, but also the route of delivery of the hydrogel and thus its effect on cardiac repair. With regard to cardiac regeneration, various hydrogels have been developed with the ability to function as a delivery system for therapeutic strategies (e.g., drug and stem cells treatments), as well as a scaffold to guide cardiac tissue regeneration following myocardial infarction. However, these developments remain within the experimental and pre-clinical realm and have yet to transition towards the clinical setting.
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Affiliation(s)
- Valentine C Vetter
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
- Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Carlijn V C Bouten
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
- Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Atze van der Pol
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.
- Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands.
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17
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Zhang G, Wang D, Ren J, Li J, Guo Q, Shi L, Li C. Antler stem cell-derived exosomes promote regenerative wound healing via fibroblast-to-myofibroblast transition inhibition. J Biol Eng 2023; 17:67. [PMID: 37940994 PMCID: PMC10633995 DOI: 10.1186/s13036-023-00386-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 10/23/2023] [Indexed: 11/10/2023] Open
Abstract
INTRODUCTION The typical outcome of mammalian wound healing is scarring, a fibrotic process mediated by myofibroblast aggregation. Perfect healing in a clinical setting is relatively unexplored. Surprisingly, our previous studies have shown that the large wound (10 cm diameter or more) of the pedicle of deer naturally achieves regenerative restoration, realized through a paracrine pathway from adjacent antler stem cells (AnSCs). METHODS AnSC-derived exosomes (AnSC-exos) were topically injected around the full-thickness wounds in a rat model. The effects on the rate of wound healing and the quality of healing were evaluated via morphological, histological, and molecular biological techniques on days 14 and 28 after surgery. RESULTS The results showed that AnSC-exos significantly accelerated the rate of wound healing and improved healing quality, including regeneration of cutaneous appendages (hair follicles and sebaceous glands) and the distribution pattern of collagen (basket-weave-like) in the healed skin. These effects of AnSC-exos were comparable to those of AnSCs but were significantly more potent than those of exosomes derived from bone marrow mesenchymal stem cells (bMSC-exos). Furthermore, AnSC-exos treatment effectively inhibited fibroblast-to-myofibroblast transition (FMT), as evidenced by the reduction of full-thickness skin injury-induced FMT in vivo and TGF-β1-induced FMT in vitro. CONCLUSION AnSC-exos could effectively promote regenerative cutaneous wound healing, highly likely through FMT inhibition. This suggests that AnSC-exos treatment could provide the potential for a novel approach to induce regenerative wound healing in the clinical setting.
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Affiliation(s)
- Guokun Zhang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, No. 1345 of Pudong Rd., Changchun, Jilin, 130600, China
| | - Dongxu Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, No. 1345 of Pudong Rd., Changchun, Jilin, 130600, China
| | - Jing Ren
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, No. 1345 of Pudong Rd., Changchun, Jilin, 130600, China
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China
| | - Jiping Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, No. 1345 of Pudong Rd., Changchun, Jilin, 130600, China
| | - Qianqian Guo
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, No. 1345 of Pudong Rd., Changchun, Jilin, 130600, China
| | - Liyan Shi
- China-Japan Union Hospital, Jilin University, Changchun, 130033, China
| | - Chunyi Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, No. 1345 of Pudong Rd., Changchun, Jilin, 130600, China.
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China.
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18
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Abdelwahid E, Athayde Teixeira de Carvalho K. Editorial: Examining genetic and epigenetic regulation in cardiovascular development, regeneration and disease. Front Cardiovasc Med 2023; 10:1306263. [PMID: 37920181 PMCID: PMC10619739 DOI: 10.3389/fcvm.2023.1306263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 10/10/2023] [Indexed: 11/04/2023] Open
Affiliation(s)
- Eltyeb Abdelwahid
- Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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19
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Zhang G, Shi L, Li J, Wang S, Ren J, Wang D, Hu P, Wang Y, Li C. Antler stem cell exosomes alleviate pulmonary fibrosis via inhibiting recruitment of monocyte macrophage, rather than polarization of M2 macrophages in mice. Cell Death Discov 2023; 9:359. [PMID: 37770458 PMCID: PMC10539297 DOI: 10.1038/s41420-023-01659-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 09/11/2023] [Accepted: 09/19/2023] [Indexed: 09/30/2023] Open
Abstract
Pulmonary fibrosis (PF), a chronic interstitial lung disease, is characterized by over-abundant deposition of extracellular matrix consisting mainly of collagen I. In previous studies, we demonstrated that deer antler stem cells (AnSCs), a novel type of adult stem cell, are capable of significantly down-regulating collagen formation in different organs and tissues and speculated that they could effectively treat PF via reducing collagen deposition in the lung tissue. In the present study, we found that administration of AnSCs improved the survival rate of PF mice and reduced lung fibrosis, collagen deposition and myofibroblast differentiation. The effects of AnSC treatment were significantly better than the positive control (adipose-derived stem cells). Interestingly, AnSC-Exos were almost equally effective as AnSCs in treating PF, suggesting that the effects of AnSCs on reduction of PF may be mainly through a paracrine mechanism. Further, AnSC-Exos reduced the number of M2 macrophages, a type of macrophage that secrets pro-fibrotic factors to accelerate fibrotic progression, in the lung tissues. In vitro experiments showed that the effects of AnSC-Exos on macrophage modulation were likely achieved via inhibition of the recruitment of circulating monocyte-derived macrophages (reducing the number of macrophages), rather than via inhibition of M2 polarization of macrophages. Inhibition of macrophage recruitment by AnSCs may be achieved indirectly via inhibiting CCL7 expression in fibroblasts; both let-7b and let-7a were highly enriched in AnSC-Exos and may play a critical role in the inhibition of CCL7 expression of fibroblasts. Collectively, the use of antler stem cells or their exosomes opens up a novel strategy for PF treatment in the clinical setting.
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Affiliation(s)
- Guokun Zhang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, 130600, Changchun, China
| | - Liyan Shi
- China-Japan Union Hospital, Jilin University, 130033, Changchun, China
| | - Jiping Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, 130600, Changchun, China
| | - Shengnan Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, 130600, Changchun, China
| | - Jing Ren
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, 130600, Changchun, China
- College of Chinese Medicinal Materials, Jilin Agricultural University, 130118, Changchun, China
| | - Dongxu Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, 130600, Changchun, China
| | - Pengfei Hu
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, 130600, Changchun, China
| | - Yimin Wang
- China-Japan Union Hospital, Jilin University, 130033, Changchun, China
| | - Chunyi Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, 130600, Changchun, China.
- College of Chinese Medicinal Materials, Jilin Agricultural University, 130118, Changchun, China.
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Jhunjhunwala A, Kim J, Kubelick KP, Ethier CR, Emelianov SY. In Vivo Photoacoustic Monitoring of Stem Cell Location and Apoptosis with Caspase-3-Responsive Nanosensors. ACS NANO 2023; 17:17931-17945. [PMID: 37703202 PMCID: PMC10540261 DOI: 10.1021/acsnano.3c04161] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 09/06/2023] [Indexed: 09/15/2023]
Abstract
Stem cell therapy has immense potential in a variety of regenerative medicine applications. However, clinical stem cell therapy is severely limited by challenges in assessing the location and functional status of implanted cells in vivo. Thus, there is a great need for longitudinal, noninvasive stem cell monitoring. Here we introduce a multidisciplinary approach combining nanosensor-augmented stem cell labeling with ultrasound guided photoacoustic (US/PA) imaging for the spatial tracking and functional assessment of transplanted stem cell fate. Specifically, our nanosensor incorporates a peptide sequence that is selectively cleaved by caspase-3, the primary effector enzyme in mammalian cell apoptosis; this cleavage event causes labeled cells to show enhanced optical absorption in the first near-infrared (NIR) window. Optimization of labeling protocols and spectral characterization of the nanosensor in vitro showed a 2.4-fold increase in PA signal from labeled cells during apoptosis while simultaneously permitting cell localization. We then successfully tracked the location and apoptotic status of mesenchymal stem cells in a mouse hindlimb ischemia model for 2 weeks in vivo, demonstrating a 4.8-fold increase in PA signal and spectral slope changes in the first NIR window under proapoptotic (ischemic) conditions. We conclude that our nanosensor allows longitudinal, noninvasive, and nonionizing monitoring of stem cell location and apoptosis, which is a significant improvement over current end-point monitoring methods such as biopsies and histological staining of excised tissue.
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Affiliation(s)
- Anamik Jhunjhunwala
- Wallace
H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, Georgia 30332, United States
| | - Jinhwan Kim
- Wallace
H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, Georgia 30332, United States
- School
of Electrical & Computer Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Kelsey P. Kubelick
- Wallace
H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, Georgia 30332, United States
- School
of Electrical & Computer Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - C. Ross Ethier
- Wallace
H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, Georgia 30332, United States
| | - Stanislav Y. Emelianov
- Wallace
H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, Georgia 30332, United States
- School
of Electrical & Computer Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
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Malektaj H, Nour S, Imani R, Siadati MH. Angiogenesis induction as a key step in cardiac tissue Regeneration: From angiogenic agents to biomaterials. Int J Pharm 2023; 643:123233. [PMID: 37460050 DOI: 10.1016/j.ijpharm.2023.123233] [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: 01/25/2023] [Revised: 07/02/2023] [Accepted: 07/14/2023] [Indexed: 07/23/2023]
Abstract
Cardiovascular diseases are the leading cause of death worldwide. After myocardial infarction, the vascular supply of the heart is damaged or blocked, leading to the formation of scar tissue, followed by several cardiac dysfunctions or even death. In this regard, induction of angiogenesis is considered as a vital process for supplying nutrients and oxygen to the cells in cardiac tissue engineering. The current review aims to summarize different approaches of angiogenesis induction for effective cardiac tissue repair. Accordingly, a comprehensive classification of induction of pro-angiogenic signaling pathways through using engineered biomaterials, drugs, angiogenic factors, as well as combinatorial approaches is introduced as a potential platform for cardiac regeneration application. The angiogenic induction for cardiac repair can enhance patient treatment outcomes and generate economic prospects for the biomedical industry. The development and commercialization of angiogenesis methods often involves collaboration between academic institutions, research organizations, and biomedical companies.
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Affiliation(s)
- Haniyeh Malektaj
- Department of Materials and Production, Aalborg University, Fibigerstraede 16, Aalborg 9220, Denmark
| | - Shirin Nour
- Department of Biomedical Engineering, Graeme Clark Institute, The University of Melbourne, VIC 3010, Australia; Department of Chemical Engineering, The University of Melbourne, VIC 3010, Australia
| | - Rana Imani
- Department of Biomedical Engineering, Amirkabir University of Technology, Tehran, Iran.
| | - Mohammad H Siadati
- Materials Science and Engineering Faculty, K. N. Toosi University of Technology, Tehran, Iran
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22
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Lai P, Sheng M, Ye JH, Tang ZX, Hu S, Wang B, Yuan JL, Yang YH, Zhong YM, Liao YL. Research trends in cardiovascular tissue engineering from 1992 to 2022: a bibliometric analysis. Front Cardiovasc Med 2023; 10:1208227. [PMID: 37593146 PMCID: PMC10427867 DOI: 10.3389/fcvm.2023.1208227] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 07/18/2023] [Indexed: 08/19/2023] Open
Abstract
Background Cardiovascular tissue engineering (CTE) is a promising technique to treat incurable cardiovascular diseases, such as myocardial infarction and ischemic cardiomyopathy. Plenty of studies related to CTE have been published in the last 30 years. However, an analysis of the research status, trends, and potential directions in this field is still lacking. The present study applies a bibliometric analysis to reveal CTE research trends and potential directions. Methods On 5 August 2022, research articles and review papers on CTE were searched from the Web of Science Core Collection with inclusion and exclusion criteria. Publication trends, research directions, and visual maps in this field were obtained using Excel (Microsoft 2009), VOSviewer, and Citespace software. Results A total of 2,273 documents from 1992 to 2022 were included in the final analysis. Publications on CTE showed an upward trend from 1992 [number of publications (Np):1] to 2021 (Np:165). The United States (Np: 916, number of citations: 152,377, H-index: 124) contributed the most publications and citations in this field. Research on CTE has a wide distribution of disciplines, led by engineering (Np: 788, number of citations: 40,563, H-index: 105). "Functional maturation" [red cluster, average published year (APY): 2018.63, 30 times], "cell-derived cardiomyocytes" (red cluster, APY: 2018.43, 46 times), "composite scaffolds" (green cluster, APY: 2018.54, 41 times), and "maturation" (red cluster, APY: 2018.17, 84 times) are the main emerging keywords in this area. Conclusion Research on CTE is a hot research topic. The United States is a dominant player in CTE research. Interdisciplinary collaboration has played a critical role in the progress of CTE. Studies on functional maturation and the development of novel biologically relevant materials and related applications will be the potential research directions in this field.
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Affiliation(s)
- Ping Lai
- Department of Cardiology, First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, China
| | - Ming Sheng
- Department of Library, Gannan Medical University, Ganzhou, China
| | - Jin-hua Ye
- Department of Physiology, School of Basic Medical Sciences, Gannan Medical University, Ganzhou, China
| | - Zhi-xian Tang
- Department of Thoracic Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Shuo Hu
- Department of Heart Medical Centre, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Bei Wang
- Department of Cardiology, First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, China
| | - Jing-lin Yuan
- Department of Cardiology, First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, China
| | - Yi-hong Yang
- Department of Cardiology, First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, China
| | - Yi-ming Zhong
- Department of Cardiology, First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, China
| | - Yong-ling Liao
- Department of Cardiology, First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, China
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Abubakar M, Masood MF, Javed I, Adil H, Faraz MA, Bhat RR, Fatima M, Abdelkhalek AM, Buccilli B, Raza S, Hajjaj M. Unlocking the Mysteries, Bridging the Gap, and Unveiling the Multifaceted Potential of Stem Cell Therapy for Cardiac Tissue Regeneration: A Narrative Review of Current Literature, Ethical Challenges, and Future Perspectives. Cureus 2023; 15:e41533. [PMID: 37551212 PMCID: PMC10404462 DOI: 10.7759/cureus.41533] [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] [Accepted: 07/06/2023] [Indexed: 08/09/2023] Open
Abstract
Revolutionary advancements in regenerative medicine have brought stem cell therapy to the forefront, offering promising prospects for the regeneration of ischemic cardiac tissue. Yet, its full efficacy, safety, and role in treating ischemic heart disease (IHD) remain limited. This literature review explores the intricate mechanisms underlying stem cell therapy. Furthermore, we unravel the innovative approaches employed to bolster stem cell survival, enhance differentiation, and seamlessly integrate them within the ischemic cardiac tissue microenvironment. Our comprehensive analysis uncovers how stem cells enhance cell survival, promote angiogenesis, and modulate the immune response. Stem cell therapy harnesses a multifaceted mode of action, encompassing paracrine effects and direct cell replacement. As our review progresses, we underscore the imperative for standardized protocols, comprehensive preclinical and clinical studies, and careful regulatory considerations. Lastly, we explore the integration of tissue engineering and genetic modifications, envisioning a future where stem cell therapy reigns supreme in regenerative medicine.
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Affiliation(s)
- Muhammad Abubakar
- Department of Internal Medicine, Ameer-Ud-Din Medical College, Lahore General Hospital, Lahore, PAK
- Department of Internal Medicine, Siddique Sadiq Memorial Trust Hospital, Gujranwala, PAK
| | | | - Izzah Javed
- Department of Internal Medicine, Ameer-Ud-Din Medical College, Lahore General Hospital, Lahore, PAK
| | - Hira Adil
- Department of Community Medicine, Khyber Girls Medical College, Hayatabad, PAK
| | - Muhammad Ahmad Faraz
- Department of Forensic Medicine, Post Graduate Medical Institute, Lahore General Hospital, Lahore, PAK
| | - Rakshita Ramesh Bhat
- Department of Medical Oncology, Mangalore Institute of Oncology, Mangalore, IND
- Department of Internal Medicine, Bangalore Medical College and Research Institute, Bangalore, IND
| | - Mahek Fatima
- Department of Internal Medicine, Osmania Medical College, Hyderabad, IND
| | | | - Barbara Buccilli
- Department of Human Neuroscience, Sapienza University of Rome, Rome, ITA
| | - Saud Raza
- Department of Internal Medicine, Ameer-Ud-Din Medical College, Lahore General Hospital, Lahore, PAK
| | - Mohsin Hajjaj
- Department of Internal Medicine, Jinnah Hospital Lahore, Lahore, PAK
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24
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Ai X, Yan B, Witman N, Gong Y, Yang L, Tan Y, Chen Y, Liu M, Lu T, Luo R, Wang H, Chien KR, Wang W, Fu W. Transient secretion of VEGF protein from transplanted hiPSC-CMs enhances engraftment and improves rat heart function post MI. Mol Ther 2023; 31:211-229. [PMID: 35982619 PMCID: PMC9840120 DOI: 10.1016/j.ymthe.2022.08.012] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 07/15/2022] [Accepted: 08/12/2022] [Indexed: 01/28/2023] Open
Abstract
Cell-based therapies offer an exciting and novel treatment for heart repair following myocardial infarction (MI). However, these therapies often suffer from poor cell viability and engraftment rates, which involve many factors, including the hypoxic conditions of the infarct environment. Meanwhile, vascular endothelial growth factor (VEGF) has previously been employed as a therapeutic agent to limit myocardial damage and simultaneously induce neovascularization. This study took an approach to transiently overexpress VEGF protein, in a controlled manner, by transfecting human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with VEGF mRNA prior to transplantation. The conditioning of iPSC-CMs with VEGF mRNA ultimately led to greater survival rates of the transplanted cells, which promoted a stable vascular network in the grafted region. Furthermore, bulk RNA transcriptomics data and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt) and AGE-RAGE signaling pathways were significantly upregulated in the VEGF-treated iPSC-CMs group. The over-expression of VEGF from iPSC-CMs stimulated cell proliferation and partially attenuated the hypoxic environment in the infarcted area, resulting in reduced ventricular remodeling. This study provides a valuable solution for the survival of transplanted cells in tissue-engineered heart regeneration and may further promote the application of modified mRNA (modRNA) in the field of tissue engineering.
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Affiliation(s)
- Xuefeng Ai
- Department of Pediatric Cardiothoracic Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Bingqian Yan
- Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Nevin Witman
- Department of Cell and Molecular Biology, Karolinska Institutet, 17165 Stockholm, Sweden; Department of Clinical Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Yiqi Gong
- Department of Pediatric Cardiothoracic Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Li Yang
- Department of Anesthesiology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Yao Tan
- Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Ying Chen
- Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Minglu Liu
- Department of Pediatric Cardiothoracic Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Tingting Lu
- Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Runjiao Luo
- Department of Pediatric Cardiothoracic Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Huijing Wang
- Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Kenneth R Chien
- Department of Cell and Molecular Biology, Karolinska Institutet, 17165 Stockholm, Sweden
| | - Wei Wang
- Department of Pediatric Cardiothoracic Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
| | - Wei Fu
- Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China; Shanghai Key Laboratory of Tissue Engineering, Shanghai 9th People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China.
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25
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Zhang Y, Shi L, Li X, Liu Y, Zhang G, Wang Y. Placental stem cells-derived exosomes stimulate cutaneous wound regeneration via engrailed-1 inhibition. Front Bioeng Biotechnol 2022; 10:1044773. [PMID: 36568306 PMCID: PMC9780460 DOI: 10.3389/fbioe.2022.1044773] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 11/28/2022] [Indexed: 12/13/2022] Open
Abstract
Introduction: Skin wounds generally heal by scarring, a fibrotic process mediated by the Engrailed-1 (EN1) fibroblast lineage. Scar is detrimental to tissue structure and function, but perfect healing in clinical settings remains to be explored. Recent studies have shown that mesenchymal stem cell (MSC) transplantation can reduce scarring Methods: Here, we investigated the effects of placental MSCs (pMSCs) and exosomes derived from pMSCs (pMSC-exos) on wound healing using a full-thickness rat model. Results: The results showed that placental MSCs significantly accelerated the wound healing rate. Moreover, placental MSCs improved the quality of wound healing, including regenerating cutaneous appendages (hair follicles and sebaceous glands), decreasing collagen I and increasing collagen III, and improving collagen pattern (basket-wave-like) in the healed skin. placental MSCs treatment also increased the regeneration of blood vessels. Importantly, all these listed effects of placental MSCs were comparable to those of exosomes derived from pMSCs, but significantly stronger than those of adipose MSC-derived exosomes (aMSC-exos). Further studies showed that the effects of placental MSCs and exosomes derived from pMSCs on wound regeneration may be mainly achieved via the down-regulation of the Yes-associated protein signaling pathway, thus inhibiting the activation of EN1. Discussion: In summary, placental MSCs could effectively stimulate wound regeneration, and their effect could be achieved through their exosomes. This suggests that exosomes derived from pMSCs treatment could be used as a novel cell-free approach to induce wound regeneration in clinical settings.
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Affiliation(s)
- Yan Zhang
- China-Japan Union Hospital of Jilin University, Changchun, China
| | - Liyan Shi
- China-Japan Union Hospital of Jilin University, Changchun, China
| | - Xiuying Li
- China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yang Liu
- Jilin Province People’s Hospital, Changchun, China
| | - Guokun Zhang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
| | - Yimin Wang
- China-Japan Union Hospital of Jilin University, Changchun, China
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26
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Razzaq SS, Khan I, Naeem N, Salim A, Begum S, Haneef K. Overexpression of GATA binding protein 4 and myocyte enhancer factor 2C induces differentiation of mesenchymal stem cells into cardiac-like cells. World J Stem Cells 2022; 14:700-713. [PMID: 36188117 PMCID: PMC9516467 DOI: 10.4252/wjsc.v14.i9.700] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 06/20/2022] [Accepted: 08/30/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Heart diseases are the primary cause of death all over the world. Following myocardial infarction, billions of cells die, resulting in a huge loss of cardiac function. Stem cell-based therapies have appeared as a new area to support heart regeneration. The transcription factors GATA binding protein 4 (GATA-4) and myocyte enhancer factor 2C (MEF2C) are considered prominent factors in the development of the cardiovascular system. AIM To explore the potential of GATA-4 and MEF2C for the cardiac differentiation of human umbilical cord mesenchymal stem cells (hUC-MSCs). METHODS hUC-MSCs were characterized morphologically and immunologically by the presence of specific markers of MSCs via immunocytochemistry and flow cytometry, and by their potential to differentiate into osteocytes and adipocytes. hUC-MSCs were transfected with GATA-4, MEF2C, and their combination to direct the differentiation. Cardiac differentiation was confirmed by semiquantitative real-time polymerase chain reaction and immunocytochemistry. RESULTS hUC-MSCs expressed specific cell surface markers CD105, CD90, CD44, and vimentin but lack the expression of CD45. The transcription factors GATA-4 and MEF2C, and their combination induced differentiation in hUC-MSCs with significant expression of cardiac genes i.e., GATA-4, MEF2C, NK2 homeobox 5 (NKX2.5), MHC, and connexin-43, and cardiac proteins GATA-4, NKX2.5, cardiac troponin T, and connexin-43. CONCLUSION Transfection with GATA-4, MEF2C, and their combination effectively induces cardiac differentiation in hUC-MSCs. These genetically modified MSCs could be a promising treatment option for heart diseases in the future.
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Affiliation(s)
- Syeda Saima Razzaq
- Dr. Zafar H. Zaidi Center for Proteomics, University of Karachi, Karachi 75270, Pakistan
| | - Irfan Khan
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
| | - Nadia Naeem
- Dow Research Institute of Biotechnology & Biomedical Sciences (DRIBBS), Dow University of Health Sciences (DUHS), Ojha Campus, Karachi 75200, Pakistan
| | - Asmat Salim
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
| | - Sumreen Begum
- Stem Cells Research Laboratory (SCRL), Sindh Institute of Urology and Transplantation (SIUT), Karachi 74200, Pakistan
| | - Kanwal Haneef
- Dr. Zafar H. Zaidi Center for Proteomics, University of Karachi, Karachi 75270, Pakistan.
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27
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Liu X, Lu F, Chen X. Examination of the role of necroptotic damage-associated molecular patterns in tissue fibrosis. Front Immunol 2022; 13:886374. [PMID: 36110858 PMCID: PMC9468929 DOI: 10.3389/fimmu.2022.886374] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 08/08/2022] [Indexed: 11/29/2022] Open
Abstract
Fibrosis is defined as the abnormal and excessive deposition of extracellular matrix (ECM) components, which leads to tissue or organ dysfunction and failure. However, the pathological mechanisms underlying fibrosis remain unclear. The inflammatory response induced by tissue injury is closely associated with tissue fibrosis. Recently, an increasing number of studies have linked necroptosis to inflammation and fibrosis. Necroptosis is a type of preprogrammed death caused by death receptors, interferons, Toll-like receptors, intracellular RNA and DNA sensors, and other mediators. These activate receptor-interacting protein kinase (RIPK) 1, which recruits and phosphorylates RIPK3. RIPK3 then phosphorylates a mixed lineage kinase domain-like protein and causes its oligomerization, leading to rapid plasma membrane permeabilization, the release of cellular contents, and exposure of damage-associated molecular patterns (DAMPs). DAMPs, as inflammatory mediators, are involved in the loss of balance between extensive inflammation and tissue regeneration, leading to remodeling, the hallmark of fibrosis. In this review, we discuss the role of necroptotic DAMPs in tissue fibrosis and highlight the inflammatory responses induced by DAMPs in tissue ECM remodeling. By summarizing the existing literature on this topic, we underscore the gaps in the current research, providing a framework for future investigations into the relationship among necroptosis, DAMPs, and fibrosis, as well as a reference for later transformation into clinical treatment.
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Affiliation(s)
| | - Feng Lu
- *Correspondence: Feng Lu, ; Xihang Chen,
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28
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Basir HRG, Karbasi A, Ravan AP, Abbasalipourkabir R, Bahmani M. Is human umbilical cord mesenchymal stem cell-derived conditioned medium effective against oxidative and inflammatory status in CCl 4- induced acute liver injury? Life Sci 2022; 305:120730. [PMID: 35753436 DOI: 10.1016/j.lfs.2022.120730] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 06/11/2022] [Accepted: 06/20/2022] [Indexed: 11/27/2022]
Abstract
INTRODUCTION Acute liver injury (ALI) is diagnosed by detection of elevated liver enzymes within six months after liver damage. Mesenchymal stem cells (MSCs) have recently been considered a beneficial strategy for treating various diseases due to holding secretory factors. Therapeutic effects of human umbilical cord MSCs-derived conditioned medium (hMSC-CM) were evaluated on CCl4-induced ALI. MATERIALS AND METHODS Twenty-four male Wistar rats were divided into groups including N (received saline), ALI (received CCl4), RPMI (received CCl4 and RPMI medium), and ALI-CM (received CCl4 and hMSC-CM) groups. The expression of TNF-α and TGFβ-1 genes was evaluated with qPCR. Hepatic levels of TNF-α and TGF-β were measured by ELISA. Total antioxidant capacity (TAC), total oxidant status (TOS), malondialdehyde (MDA), glutathione peroxidase (GPx) activity, and catalase (CAT) activity were also assayed. Hematoxylin-eosin (H&E), Masson's trichrome, reticulin, and Periodic Acid-Schiff (PAS) stainings were conducted to evaluate tissue lesions. RESULTS CCl4 increased expression of TNF-α and TGF-1β at both mRNA and protein levels, while hMSC-CM decreased these parameters in the ALI-CM group. TAC levels significantly decreased in the ALI group, and CCl4 increased TOS and MDA levels compared with the N group. hMSC-CM treatment led to the return of these parameters to their baseline levels. GPx and CAT activity in the ALI group were significantly lower than in the N group and hMSC-CM reduced these parameters to the baseline in the ALI-CM group. hMSC-CM modulated CCl4-induced tissue lesions. CONCLUSION The present study suggests hMSC-CM probably improves CCl4-induced ALI through its antioxidant and anti-inflammatory effects.
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Affiliation(s)
- Hamid Reza Ghasemi Basir
- Department of Pathology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ashkan Karbasi
- Department of Clinical Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Alireza Pouyandeh Ravan
- Department of Medical Laboratory Sciences, School of Paramedicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Roghayeh Abbasalipourkabir
- Department of Clinical Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mahdi Bahmani
- Department of Clinical Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
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29
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Avalos PN, Forsthoefel DJ. An Emerging Frontier in Intercellular Communication: Extracellular Vesicles in Regeneration. Front Cell Dev Biol 2022; 10:849905. [PMID: 35646926 PMCID: PMC9130466 DOI: 10.3389/fcell.2022.849905] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 03/28/2022] [Indexed: 12/12/2022] Open
Abstract
Regeneration requires cellular proliferation, differentiation, and other processes that are regulated by secreted cues originating from cells in the local environment. Recent studies suggest that signaling by extracellular vesicles (EVs), another mode of paracrine communication, may also play a significant role in coordinating cellular behaviors during regeneration. EVs are nanoparticles composed of a lipid bilayer enclosing proteins, nucleic acids, lipids, and other metabolites, and are secreted by most cell types. Upon EV uptake by target cells, EV cargo can influence diverse cellular behaviors during regeneration, including cell survival, immune responses, extracellular matrix remodeling, proliferation, migration, and differentiation. In this review, we briefly introduce the history of EV research and EV biogenesis. Then, we review current understanding of how EVs regulate cellular behaviors during regeneration derived from numerous studies of stem cell-derived EVs in mammalian injury models. Finally, we discuss the potential of other established and emerging research organisms to expand our mechanistic knowledge of basic EV biology, how injury modulates EV biogenesis, cellular sources of EVs in vivo, and the roles of EVs in organisms with greater regenerative capacity.
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Affiliation(s)
- Priscilla N. Avalos
- Department of Cell Biology, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
| | - David J. Forsthoefel
- Department of Cell Biology, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
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30
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Park YS, Park BW, Choi H, Lee SH, Kim M, Park HJ, Kim IB. Chorion-derived perinatal mesenchymal stem cells improve cardiac function and vascular regeneration: preferential treatment for ischemic heart disease. Hellenic J Cardiol 2022; 66:52-58. [DOI: 10.1016/j.hjc.2022.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 05/24/2022] [Accepted: 05/24/2022] [Indexed: 11/04/2022] Open
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Yang L, Patel KD, Rathnam C, Thangam R, Hou Y, Kang H, Lee KB. Harnessing the Therapeutic Potential of Extracellular Vesicles for Biomedical Applications Using Multifunctional Magnetic Nanomaterials. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2104783. [PMID: 35132796 PMCID: PMC9344859 DOI: 10.1002/smll.202104783] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 01/12/2022] [Indexed: 04/14/2023]
Abstract
Extracellular vesicles (e.g., exosomes) carrying various biomolecules (e.g., proteins, lipids, and nucleic acids) have rapidly emerged as promising platforms for many biomedical applications. Despite their enormous potential, their heterogeneity in surfaces and sizes, the high complexity of cargo biomolecules, and the inefficient uptake by recipient cells remain critical barriers for their theranostic applications. To address these critical issues, multifunctional nanomaterials, such as magnetic nanomaterials, with their tunable physical, chemical, and biological properties, may play crucial roles in next-generation extracellular vesicles (EV)-based disease diagnosis, drug delivery, tissue engineering, and regenerative medicine. As such, one aims to provide cutting-edge knowledge pertaining to magnetic nanomaterials-facilitated isolation, detection, and delivery of extracellular vesicles and their associated biomolecules. By engaging the fields of extracellular vesicles and magnetic nanomaterials, it is envisioned that their properties can be effectively combined for optimal outcomes in biomedical applications.
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Affiliation(s)
- Letao Yang
- Department of Chemistry and Chemical Biology, Rutgers-the State University of New Jersey, 123 Bevier Road, Piscataway, NJ 08854, USA
| | - Kapil D. Patel
- Department of Materials Science and Engineering, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Christopher Rathnam
- Department of Chemistry and Chemical Biology, Rutgers-the State University of New Jersey, 123 Bevier Road, Piscataway, NJ 08854, USA
| | - Ramar Thangam
- Department of Materials Science and Engineering, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Yannan Hou
- Department of Chemistry and Chemical Biology, Rutgers-the State University of New Jersey, 123 Bevier Road, Piscataway, NJ 08854, USA
| | - Heemin Kang
- Department of Materials Science and Engineering, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Ki-Bum Lee
- Department of Chemistry and Chemical Biology, Rutgers-the State University of New Jersey, 123 Bevier Road, Pis cataway, NJ 08854, USA
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32
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Narang P, Shah M, Beljanski V. Exosomal RNAs in diagnosis and therapies. Noncoding RNA Res 2022; 7:7-15. [PMID: 35087990 PMCID: PMC8777382 DOI: 10.1016/j.ncrna.2022.01.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 01/11/2022] [Accepted: 01/12/2022] [Indexed: 12/17/2022] Open
Abstract
The field of extracellular vesicles has been rapidly developing after it became evident that a defined subset of vesicles, called exosomes, can modulate several biological functions in distant cells and tissues. Exosomes range in a size from 40 to 160 nm in diameter, are released by majority of cells in our body, and carry molecules which reflect the cell of origin. The types of biomolecules packed, their respective purpose, and their impact on the physiological state of distinct cells and tissues should be understood to advance the using of exosomes as biomarkers of health and disease. Many of such physiological effects can be linked to exosomal RNA molecules which include both coding and non-coding RNAs. The biological role(s) of various exosomal RNAs have started being recognized after RNA sequencing methods became widely available which led to discovery of a variety of RNA molecules in exosomes and their roles in regulating of many biological processes are beginning to be unraveled. In present review, we outline and discuss recent progress in the elucidation of the various biological processes driven by exosomal RNA and their relevance for several major conditions including disorders of central nervous system, cardiovascular system, metabolism, cancer, and immune system. Furthermore, we also discuss potential use of exosomes as valuable therapeutics for tissue regeneration and for conditions resulting from excessive inflammation. While exosome research is still in its infancy, in-depth understanding of exosome formation, their biological effects, and specific cell-targeting will uncover how they can be used as disease biomarkers and therapeutics.
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Affiliation(s)
- Pranay Narang
- Department of Biological Sciences, Halmos College of Natural Sciences and Oceanography, Nova Southeastern University, Fort Lauderdale, Davie, Florida, United States
| | - Morish Shah
- Department of Public Health, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Davie, Florida, United States
| | - Vladimir Beljanski
- Department of Biological Sciences, Halmos College of Natural Sciences and Oceanography, Nova Southeastern University, Fort Lauderdale, Davie, Florida, United States
- Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Davie, Florida, United States
- Cell Therapy Institute, Dr Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Davie, Florida, United States
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Abdelwahid E, de Carvalho KAT. Editorial: MicroRNAs in Heart Regeneration: Regulatory Mechanisms and Therapeutic Applications. Front Cardiovasc Med 2022; 9:863332. [PMID: 35295258 PMCID: PMC8920091 DOI: 10.3389/fcvm.2022.863332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 02/04/2022] [Indexed: 11/13/2022] Open
Affiliation(s)
- Eltyeb Abdelwahid
- Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- *Correspondence: Eltyeb Abdelwahid
| | - Katherine Athayde Teixeira de Carvalho
- Advanced Therapy and Cellular Biotechnology in Regenerative Medicine Department, The Pelé Pequeno Príncipe Research Institute, Child and Adolescent Health Research and Pequeno Príncipe Faculties, Curitiba, Brazil
- Katherine Athayde Teixeira de Carvalho
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Gao X, Ma S, Xing X, Yang J, Xu X, Liang C, Yu Y, Liu L, Liao L, Tian W. Microvessels derived from hiPSCs are a novel source for angiogenesis and tissue regeneration. J Tissue Eng 2022; 13:20417314221143240. [PMID: 36600998 PMCID: PMC9806436 DOI: 10.1177/20417314221143240] [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: 07/12/2022] [Accepted: 11/18/2022] [Indexed: 12/28/2022] Open
Abstract
The establishment of effective vascularization represents a key challenge in regenerative medicine. Adequate sources of vascular cells and intact vessel fragments have not yet been explored. We herein examined the potential application of microvessels induced from hiPSCs for rapid angiogenesis and tissue regeneration. Microvessels were generated from human pluripotent stem cells (iMVs) under a defined induction protocol and compared with human adipose tissue-derived microvessels (ad-MVs) to illustrate the similarity and differences of the alternative source. Then, the therapeutic effect of iMVs was detected by transplantation in vivo. The renal ischemia-reperfusion model and skin damage model were applied to explore the potential effect of vascular cells derived from iMVs (iMVs-VCs). Besides, the subcutaneous transplantation model and muscle injury model were established to explore the ability of iMVs for angiogenesis and tissue regeneration. The results revealed that iMVs had remarkable similarities to natural blood vessels in structure and cellular composition, and were potent for vascular formation and self-organization. The infusion of iMVs-VCs promoted tissue repair in the renal and skin damage model through direct contribution to the reconstruction of blood vessels and modulation of the immune microenvironment. Moreover, the transplantation of intact iMVs could form a massive perfused blood vessel and promote muscle regeneration at the early stage. The infusion of iMVs-VCs could facilitate the reconstruction and regeneration of blood vessels and modulation of the immune microenvironment to restore structures and functions of damaged tissues. Meanwhile, the intact iMVs could rapidly form perfused vessels and promote muscle regeneration. With the advantages of abundant sources and high angiogenesis potency, iMVs could be a candidate source for vascularization units for regenerative medicine.
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Affiliation(s)
| | | | | | - Jian Yang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xun Xu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Cheng Liang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yejia Yu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Lei Liu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Li Liao
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Weidong Tian
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Schena GJ, Murray EK, Hildebrand AN, Headrick AL, Yang Y, Koch KA, Kubo H, Eaton D, Johnson J, Berretta R, Mohsin S, Kishore R, McKinsey TA, Elrod JW, Houser SR. Cortical bone stem cell-derived exosomes' therapeutic effect on myocardial ischemia-reperfusion and cardiac remodeling. Am J Physiol Heart Circ Physiol 2021; 321:H1014-H1029. [PMID: 34623184 PMCID: PMC8793944 DOI: 10.1152/ajpheart.00197.2021] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 09/27/2021] [Accepted: 09/27/2021] [Indexed: 12/20/2022]
Abstract
Heart failure is the one of the leading causes of death in the United States. Heart failure is a complex syndrome caused by numerous diseases, including severe myocardial infarction (MI). MI occurs after an occlusion of a cardiac artery causing downstream ischemia. MI is followed by cardiac remodeling involving extensive remodeling and fibrosis, which, if the original insult is severe or prolonged, can ultimately progress into heart failure. There is no "cure" for heart failure because therapies to regenerate dead tissue are not yet available. Previous studies have shown that in both post-MI and post-ischemia-reperfusion (I/R) models of heart failure, administration of cortical bone stem cell (CBSC) treatment leads to a reduction in scar size and improved cardiac function. Our first study investigated the ability of mouse CBSC-derived exosomes (mCBSC-dEXO) to recapitulate mouse CBSCs (mCBSC) therapeutic effects in a 24-h post-I/R model. This study showed that injection of mCBSCs and mCBSC-dEXOs into the ischemic region of an infarct had a protective effect against I/R injury. mCBSC-dEXOs recapitulated the effects of CBSC treatment post-I/R, indicating exosomes are partly responsible for CBSC's beneficial effects. To examine if exosomes decrease fibrotic activation, adult rat ventricular fibroblasts (ARVFs) and adult human cardiac fibroblasts (NHCFs) were treated with transforming growth factor β (TGFβ) to activate fibrotic signaling before treatment with mCBSC- and human CBSC (hCBSC)-dEXOs. hCBSC-dEXOs caused a 100-fold decrease in human fibroblast activation. To further understand the signaling mechanisms regulating the protective decrease in fibrosis, we performed RNA sequencing on the NHCFs after hCBSC-dEXO treatment. The group treated with both TGFβ and exosomes showed a decrease in small nucleolar RNA (snoRNA), known to be involved with ribosome stability.NEW & NOTEWORTHY Our work is noteworthy due to the identification of factors within stem cell-derived exosomes (dEXOs) that alter fibroblast activation through the hereto-unknown mechanism of decreasing small nucleolar RNA (snoRNA) signaling within cardiac fibroblasts. The study also shows that the injection of stem cells or a stem-cell-derived exosome therapy at the onset of reperfusion elicits cardioprotection, emphasizing the importance of early treatment in the post-ischemia-reperfusion (I/R) wounded heart.
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Affiliation(s)
- Giana J Schena
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Emma K Murray
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Alycia N Hildebrand
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Alaina L Headrick
- Division of Cardiology & Consortium for Fibrosis Research and Translation, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Yijun Yang
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Keith A Koch
- Division of Cardiology & Consortium for Fibrosis Research and Translation, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Hajime Kubo
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Deborah Eaton
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Jaslyn Johnson
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Remus Berretta
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Sadia Mohsin
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Raj Kishore
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Timothy A McKinsey
- Division of Cardiology & Consortium for Fibrosis Research and Translation, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - John W Elrod
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Steven R Houser
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
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36
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Zhu Q, Hao H, Xu H, Fichman Y, Cui Y, Yang C, Wang M, Mittler R, Hill MA, Cowan PJ, Zhang G, He X, Zhou S, Liu Z. Combination of Antioxidant Enzyme Overexpression and N-Acetylcysteine Treatment Enhances the Survival of Bone Marrow Mesenchymal Stromal Cells in Ischemic Limb in Mice With Type 2 Diabetes. J Am Heart Assoc 2021; 10:e023491. [PMID: 34569277 PMCID: PMC8649154 DOI: 10.1161/jaha.121.023491] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Background Therapy with mesenchymal stem cells remains a promising but challenging approach to critical limb ischemia in diabetes because of the dismal cell survival. Methods and Results Critical limb ischemia in type 2 diabetes mouse model was used to explore the impact of diabetic limb ischemia on the survival of bone marrow mesenchymal stromal cells (bMSCs). Inhibition of intracellular reactive oxygen species was achieved with concomitant overexpression of superoxide dismutase (SOD)‐1 and glutathione peroxidase‐1 in the transplanted bMSCs, and extracellular reactive oxygen species was attenuated using SOD‐3 overexpression and N‐acetylcysteine treatment. In vivo optical fluorescence imaging and laser Doppler perfusion imaging were used to track cell retention and determine blood flow in diabetic ischemic limb, respectively. Survival of the transplanted bMSCs was significantly decreased in diabetic ischemic limb compared with the control. In vitro study indicated that advanced glycation end products, not high glucose, significantly decreased the proliferation of bMSCs and increased their apoptosis associated with increased reactive oxygen species production and selective reduction of SOD‐1 and SOD‐3. In vivo study demonstrated that concomitant overexpression of SOD‐1, SOD‐3, and glutathione peroxidase‐1, or host treatment with N‐acetylcysteine, significantly enhanced in vivo survival of transplanted bMSCs, and improved critical limb ischemia in diabetic mice. Combination of triple antioxidant enzyme overexpression in bMSCs with host N‐acetylcysteine treatment further improved bMSC survival with enhanced circulatory and functional recovery from diabetic critical limb ischemia. Conclusions Simultaneous suppression of reactive oxygen species from transplanted bMSCs and host tissue could additively enhance bMSC survival in diabetic ischemic limb with increased therapeutic efficacy in diabetes.
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Affiliation(s)
- Qiang Zhu
- Center for Precision Medicine and Division of Cardiovascular Medicine Department of Medicine University of Missouri School of Medicine Columbia MO.,Department of Cardiology Second Xiangya Hospital Central South University Changsha City Hunan Province China
| | - Hong Hao
- Center for Precision Medicine and Division of Cardiovascular Medicine Department of Medicine University of Missouri School of Medicine Columbia MO
| | - Huifang Xu
- Center for Precision Medicine and Division of Cardiovascular Medicine Department of Medicine University of Missouri School of Medicine Columbia MO
| | - Yosef Fichman
- College of Agriculture, Food and Natural Resources University of Missouri Columbia MO.,Dalton Cardiovascular Research Center University of Missouri Columbia MO
| | - Yuqi Cui
- Center for Precision Medicine and Division of Cardiovascular Medicine Department of Medicine University of Missouri School of Medicine Columbia MO
| | - Chunlin Yang
- Center for Precision Medicine and Division of Cardiovascular Medicine Department of Medicine University of Missouri School of Medicine Columbia MO
| | - Meifang Wang
- Center for Precision Medicine and Division of Cardiovascular Medicine Department of Medicine University of Missouri School of Medicine Columbia MO
| | - Ron Mittler
- College of Agriculture, Food and Natural Resources University of Missouri Columbia MO.,Dalton Cardiovascular Research Center University of Missouri Columbia MO
| | - Michael A Hill
- Dalton Cardiovascular Research Center University of Missouri Columbia MO.,Department of Surgery University of Missouri School of MedicineChristopher S. Bond Life Sciences CenterUniversity of Missouri Columbia MO
| | - Peter J Cowan
- Department of Medicine University of Melbourne Australia.,Immunology Research Centre St. Vincent's Hospital Melbourne Australia
| | - Guangsen Zhang
- Institute of Molecular Hematopathy Second Xiangya Hospital Central South University Changsha City Hunan Province China
| | - Xiaoming He
- Fischell Department of Bioengineering University of Maryland College Park MD
| | - Shenghua Zhou
- Department of Cardiology Second Xiangya Hospital Central South University Changsha City Hunan Province China
| | - Zhenguo Liu
- Center for Precision Medicine and Division of Cardiovascular Medicine Department of Medicine University of Missouri School of Medicine Columbia MO
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Zhang Y, Pan Y, Liu Y, Li X, Tang L, Duan M, Li J, Zhang G. Exosomes derived from human umbilical cord blood mesenchymal stem cells stimulate regenerative wound healing via transforming growth factor-β receptor inhibition. Stem Cell Res Ther 2021; 12:434. [PMID: 34344478 PMCID: PMC8336384 DOI: 10.1186/s13287-021-02517-0] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 04/28/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Scar formation is a common consequence of skin wound healing, and no effective treatment exists. Umbilical cord blood mesenchymal stem cells (UCB-MSCs) can improve wound healing; however, the role of UCB-MSCs remains unclear and whether they can ameliorate scar formation has not been fully elucidated. METHODS To determine the function of UCB-MSCs, we examined and compared the therapeutic effects of UCB-MSCs and UCB-MSC-derived exosomes (UCB-MSC-exo) on skin healing in rats. Moreover, UCB-MSC-exo-specific miRNAs were identified and their effects in inhibiting the human dermal fibroblast (HDF) differentiation into myofibroblasts were investigated. RESULTS Both UCB-MSCs and UCB-MSC-exo accelerated wound closure; reduced scar formation; improved the regeneration of skin appendages, nerves, and vessels; and regulated the natural distribution of collagen fibers in wound healing. Additionally, UCB-MSC-exo suppressed the excessive formation of myofibroblasts and collagen I and increased the proliferation and migration of skin cells in vivo and in vitro. Functional analysis showed that UCB-MSC-derived miRNAs were closely related to the transforming growth factor-β (TGF-β) signaling pathway, which could induce myofibroblast differentiation. We identified abundant miRNAs that were highly expressed in UCB-MSC-exo. miR-21-5p and miR-125b-5p were predicted to contribute to TGF-β receptor type II (TGFBR2) and TGF-β receptor type I (TGFBR1) inhibition, respectively. Using miRNA mimics, we found that miR-21-5p and miR-125b-5p were critical for anti-myofibroblast differentiation in the TGF-β1-induced HDF. CONCLUSION The effect of UCB-MSCs in stimulating regenerative wound healing might be achieved through exosomes, which can be, in part, through miR-21-5p- and miR-125b-5p-mediated TGF-β receptor inhibition, suggesting that UCB-MSC-exo might represent a novel strategy to prevent scar formation during wound healing.
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Affiliation(s)
- Yan Zhang
- Hospital of Stomatology, Jilin University, 1500 Qinghua Rd., Changchun, Jilin, 130021, China
- Jilin Provincial Laboratory of Biomedical Engineering, Jilin University, Changchun, China
| | - Yingjin Pan
- Center of Prosthodontics and Oral Implantology, Foshan Stomatology Hospital, School of Stomatology and Medicine, Foshan University, Foshan, 528000, China
| | - Yanhong Liu
- Center for Reproductive Medicine, Center for Prenatal Diagnosis, First Hospital, Jilin University, Changchun, China
| | - Xiheng Li
- Hospital of Stomatology, Jilin University, 1500 Qinghua Rd., Changchun, Jilin, 130021, China
- Jilin Provincial Laboratory of Biomedical Engineering, Jilin University, Changchun, China
| | - Liang Tang
- Hospital of Stomatology, Jilin University, 1500 Qinghua Rd., Changchun, Jilin, 130021, China
- Jilin Provincial Laboratory of Biomedical Engineering, Jilin University, Changchun, China
| | - Mengna Duan
- Hospital of Stomatology, Jilin University, 1500 Qinghua Rd., Changchun, Jilin, 130021, China.
| | - Jiang Li
- Hospital of Stomatology, Jilin University, 1500 Qinghua Rd., Changchun, Jilin, 130021, China.
- Affiliated Stomatology Hospital of Guangzhou Medical University, 39 Huangsha Ave., Guangzhou, 510080, Guangdong, China.
| | - Guokun Zhang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, 1345 Pudong Rd., Changchun, Jilin, 130600, China.
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences (CAAS), 4899 Juye St., Changchun, Jilin, 130112, China.
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Sun T, Wei L, Tian H, Zhan W, Ma H, Nie D, Wang S, Chen X, Tang G. Novel PET/CT tracers for targeted imaging of membrane receptors to evaluate cardiomyocyte apoptosis and tissue repair process in a rat model of myocardial infarction. Apoptosis 2021; 26:460-473. [PMID: 34185202 DOI: 10.1007/s10495-021-01681-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/19/2021] [Indexed: 12/12/2022]
Abstract
The purpose of this study was to employ novel tracers PET imaging approach to define the time course and intensity of myocardial repair after apoptosis and to correlate the imaging signal to immunohistochemical staining in myocardial infarction (MI). We designed novel αVβ3-targeted and radio-functionalized tracers for detection of apoptosis in H9C2 cells and myocardial tissue. MI rats were imaged with [18F]FDG, [18F]ANP-Cin or [18F]ANP-RGD2 using a small-animal PET/CT device. Rats were sacrificed, and tissue samples from viable and injured myocardial areas were sectioned for TUNEL assay and histology. The uncorrected radiochemical yield of [18F]ANP-Cin and [18F]ANP-RGD2 were 41.3 ± 5.4% and 21.17 ± 4.7%, respectively. Two tracers meet many criteria for cardiac imaging, including high stability, high binding, no toxicity, fast renal clearance and excellent biodistribution in rat models. The uptake of [18F]ANP-Cin was significantly higher on the 1st and 3rd day than the 7th or 28th day after MI induction, a timeframe associated with increased cardiomyocyte apoptosis. Higher uptake of [18F]ANP-Cin was observed in MI rats than in N-acetylcysteine (NAC)-treated rats on the 3rd days. In contrast with [18F]ANP-Cin, no hot-spots was observed with [18F]ANP-RGD2 on the 1st day and more hot-spots was observed from the 3rd day to the 7th day, then less on the 28th days in the high apoptotic site. There was no uptake of [18F]FDG in or around the apoptotic region. On the 7th day the uptake of [18F]ANP-RGD2 was higher in NAC-treated rats than MI rats. [18F]ANP-Cin and [18F]ANP-RGD2 are superior to [18F]FDG for PET/CT imaging for evaluation of cardiomyocyte apoptosis and tissue repair processes in the MI rats.
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Affiliation(s)
- Ting Sun
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
| | - Lijiang Wei
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
- Nanfang PET Center and Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Hua Tian
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China.
| | - Wanlin Zhan
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Hui Ma
- Department of Radiotherapy and Medical Imaging, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Dahong Nie
- Department of Radiotherapy and Medical Imaging, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Shilin Wang
- Department of Radiotherapy and Medical Imaging, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xin Chen
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Ganghua Tang
- Nanfang PET Center and Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
- Department of Radiotherapy and Medical Imaging, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China.
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Markides H, Foster NC, McLaren JS, Hopkins T, Black C, Oreffo ROC, Scammell BE, Echevarria I, White LJ, El Haj AJ. Short-Term Evaluation of Cellular Fate in an Ovine Bone Formation Model. Cells 2021; 10:1776. [PMID: 34359945 PMCID: PMC8305225 DOI: 10.3390/cells10071776] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/08/2021] [Accepted: 07/09/2021] [Indexed: 02/07/2023] Open
Abstract
The ovine critical-sized defect model provides a robust preclinical model for testing tissue-engineered constructs for use in the treatment of non-union bone fractures and severe trauma. A critical question in cell-based therapies is understanding the optimal therapeutic cell dose. Key to defining the dose and ensuring successful outcomes is understanding the fate of implanted cells, e.g., viability, bio-distribution and exogenous infiltration post-implantation. This study evaluates such parameters in an ovine critical-sized defect model 2 and 7 days post-implantation. The fate of cell dose and behaviour post-implantation when combined with nanomedicine approaches for multi-model tracking and remote control using external magnetic fields is also addressed. Autologous STRO-4 selected mesenchymal stromal cells (MSCs) were labelled with a fluorescent lipophilic dye (CM-Dil), functionalised magnetic nanoparticles (MNPs) and delivered to the site within a naturally derived bone extracellular matrix (ECM) gel. Encapsulated cells were implanted within a critical-sized defect in an ovine medial femoral condyle and exposed to dynamic gradients of external magnetic fields for 1 h per day. Sheep were sacrificed at 2 and 7 days post-initial surgery where ECM was harvested. STRO-4-positive (STRO-4+) stromal cells expressed osteocalcin and survived within the harvested gels at day 2 and day 7 with a 50% loss at day 2 and a further 45% loss at 7 days. CD45-positive leucocytes were also observed in addition to endogenous stromal cells. No elevation in serum C-reactive protein (CRP) or non-haem iron levels was observed following implantation in groups containing MNPs with or without magnetic field gradients. The current study demonstrates how numbers of therapeutic cells reduce substantially after implantation in the repair site. Cell death is accompanied by enhanced leucocyte invasion, but not by inflammatory blood marker levels. Crucially, a proportion of implanted STRO-4+ stromal cells expressed osteocalcin, which is indicative of osteogenic differentiation. Furthermore, MNP labelling did not alter cell number or result in a further deleterious impact on stromal cells following implantation.
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Affiliation(s)
- Hareklea Markides
- Guy Hilton Research Centre, Institute of Science and Technology in Medicine, Keele University, Thornburrow Drive, Stoke-on-Trent ST4 7QB, UK; (H.M.); (T.H.); (I.E.)
- Healthcare Technologies Institute, Institute of Translational Medicine, School of Chemical Engineering, University of Birmingham, Birmingham B15 2TT, UK;
| | - Nicola C. Foster
- Healthcare Technologies Institute, Institute of Translational Medicine, School of Chemical Engineering, University of Birmingham, Birmingham B15 2TT, UK;
| | - Jane S. McLaren
- Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (J.S.M.); (L.J.W.)
| | - Timothy Hopkins
- Guy Hilton Research Centre, Institute of Science and Technology in Medicine, Keele University, Thornburrow Drive, Stoke-on-Trent ST4 7QB, UK; (H.M.); (T.H.); (I.E.)
| | - Cameron Black
- Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK; (C.B.); (R.O.C.O.)
| | - Richard O. C. Oreffo
- Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK; (C.B.); (R.O.C.O.)
| | - Brigitte E. Scammell
- Academic Orthopaedics, Trauma and Sports Medicine, Queen’s Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK;
| | - Iria Echevarria
- Guy Hilton Research Centre, Institute of Science and Technology in Medicine, Keele University, Thornburrow Drive, Stoke-on-Trent ST4 7QB, UK; (H.M.); (T.H.); (I.E.)
| | - Lisa J. White
- Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (J.S.M.); (L.J.W.)
| | - Alicia J. El Haj
- Guy Hilton Research Centre, Institute of Science and Technology in Medicine, Keele University, Thornburrow Drive, Stoke-on-Trent ST4 7QB, UK; (H.M.); (T.H.); (I.E.)
- Healthcare Technologies Institute, Institute of Translational Medicine, School of Chemical Engineering, University of Birmingham, Birmingham B15 2TT, UK;
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Zhang Y, Yan J, Liu Y, Chen Z, Li X, Tang L, Li J, Duan M, Zhang G. Human Amniotic Fluid Stem Cell-Derived Exosomes as a Novel Cell-Free Therapy for Cutaneous Regeneration. Front Cell Dev Biol 2021; 9:685873. [PMID: 34235150 PMCID: PMC8255501 DOI: 10.3389/fcell.2021.685873] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 05/27/2021] [Indexed: 12/12/2022] Open
Abstract
Adult wound healing often results in fibrotic scarring that is caused by myofibroblast aggregation. Human amniotic fluid stem cells (hAFSCs) exhibit significantly anti-fibrotic scarring properties during wound healing. However, it is little known whether hAFSCs directly or indirectly (paracrine) contribute to this process. Using the full-thickness skin-wounded rats, we investigated the therapeutic potential of hAFSC-derived exosomes (hAFSC-exo). Our results showed that hAFSC-exo accelerated the wound healing rate and improved the regeneration of hair follicles, nerves, and vessels, as well as increased proliferation of cutaneous cells and the natural distribution of collagen during wound healing. Additionally, hAFSC-exo suppressed the excessive aggregation of myofibroblasts and the extracellular matrix. We identified several miRNAs, including let-7-5p, miR-22-3p, miR-27a-3p, miR-21-5p, and miR-23a-3p, that were presented in hAFSC-exo. The functional analysis demonstrated that these hAFSC-exo-miRNAs contribute to the inhibition of the transforming growth factor-β (TGF-β) signaling pathway by targeting the TGF-β receptor type I (TGF-βR1) and TGF-β receptor type II (TGF-βR2). The reduction of TGF-βR1 and TGF-βR2 expression induced by hAFSC-exo was also confirmed in the healing tissue. Finally, using mimics of miRNAs, we found that hAFSC-exo-miRNAs were essential for myofibroblast suppression during the TGF-β1-induced human dermal fibroblast-to-myofibroblast transition in vitro. In summary, this study is the first to show that exosomal miRNAs used in hAFSC-based therapy inhibit myofibroblast differentiation. Our study suggests that hAFSC-exo may represent a strategic tool for suppressing fibrotic scarring during wound healing.
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Affiliation(s)
- Yan Zhang
- Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Laboratory of Biomedical Engineering, Jilin University, Changchun, China
| | - Jiaqing Yan
- Hospital of Stomatology, Jilin University, Changchun, China
| | - Yanhong Liu
- Center for Reproductive Medicine, Center for Prenatal Diagnosis, The First Hospital of Jilin University, Changchun, China
| | - Zhenyu Chen
- Chengnan Branch, Foshan Stomatology Hospital, School of Stomatology and Medicine, Foshan University, Foshan, China
| | - Xiheng Li
- Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Laboratory of Biomedical Engineering, Jilin University, Changchun, China
| | - Liang Tang
- Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Laboratory of Biomedical Engineering, Jilin University, Changchun, China
| | - Jiang Li
- Affiliated Stomatology Hospital, Guangzhou Medical University, Guangzhou, China
| | - Mengna Duan
- Hospital of Stomatology, Jilin University, Changchun, China
| | - Guokun Zhang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
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Photo-Polymerization Damage Protection by Hydrogen Sulfide Donors for 3D-Cell Culture Systems Optimization. Int J Mol Sci 2021; 22:ijms22116095. [PMID: 34198821 PMCID: PMC8201135 DOI: 10.3390/ijms22116095] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 05/26/2021] [Accepted: 05/31/2021] [Indexed: 01/04/2023] Open
Abstract
Photo-polymerized hydrogels are ideally suited for stem-cell based tissue regeneration and three dimensional (3D) bioprinting because they can be highly biocompatible, injectable, easy to use, and their mechanical and physical properties can be controlled. However, photo-polymerization involves the use of potentially toxic photo-initiators, exposure to ultraviolet light radiation, formation of free radicals that trigger the cross-linking reaction, and other events whose effects on cells are not yet fully understood. The purpose of this study was to examine the effects of hydrogen sulfide (H2S) in mitigating cellular toxicity of photo-polymerization caused to resident cells during the process of hydrogel formation. H2S, which is the latest discovered member of the gasotransmitter family of gaseous signalling molecules, has a number of established beneficial properties, including cell protection from oxidative damage both directly (by acting as a scavenger molecule) and indirectly (by inducing the expression of anti-oxidant proteins in the cell). Cells were exposed to slow release H2S treatment using pre-conditioning with glutathione-conjugated-garlic extract in order to mitigate toxicity during the photo-polymerization process of hydrogel formation. The protective effects of the H2S treatment were evaluated in both an enzymatic model and a 3D cell culture system using cell viability as a quantitative indicator. The protective effect of H2S treatment of cells is a promising approach to enhance cell survival in tissue engineering applications requiring photo-polymerized hydrogel scaffolds.
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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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Stulpinas A, Uzusienis T, Imbrasaite A, Krestnikova N, Unguryte A, Kalvelyte AV. Cell-cell and cell-substratum contacts in the regulation of MAPK and Akt signalling: Importance in therapy, biopharmacy and bioproduction. Cell Signal 2021; 84:110034. [PMID: 33933583 DOI: 10.1016/j.cellsig.2021.110034] [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: 12/04/2020] [Revised: 04/23/2021] [Accepted: 04/27/2021] [Indexed: 11/17/2022]
Abstract
The use of cultured cells as a tool for research, precision medicine, biopharmacy, and biomanufacturing is constantly increasing. In parallel, the role of cell-cell and cell-substratum contacts in cell functioning is increasingly validated. Adhesion signalling plays a key role here. The activity of cell fate-regulating signalling molecules is an important factor in determining cell behaviour, as well as their response to treatment, depending on cell phenotypic status and location in the body. Three cellular state models (adherent, single cells in suspension, and aggregated cells) were compared for cell signalling, including focal adhesion (FAK), mitogen-activated (MAPK), as well as Akt protein kinases, and transcription factor cJun, by using lung adenocarcinoma A549, muscle-derived stem Myo, as well as primary lung cancer cell lines. Survival of both A549 and Myo cells was dependent on kinases Akt and ERK in detached conditions. Intercellular contacts in aggregates promoted activation of Akt and ERK, and cell survival. Loss of contacts with the substrate increased phosphorylation of MAP kinases JNK and p38, while decreased Akt phosphorylation by processes involving FAK. Unexpectedly, detachment increased phosphorylation of antiapoptotic kinase ERK in A549, while in Myo stem cells ERK phosphorylation was downregulated. JNK target transcription factor cJun protein level was markedly diminished by contacts between cells possibly involving mechanism of proteasomal degradation. Furthermore, studies revealed the opposite dependence of molecules of the same signalling pathway - phospho-cJun and phospho-JNK - on cell culture density. Differences in ERK activation under detachment conditions indicate that targeting of prosurvival kinases during anoikis should be different in different cells. Moreover, the outcome of JNK activation in cells may depend on the amount of cJun, which is determined by cell-cell contacts.
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Affiliation(s)
- Aurimas Stulpinas
- Dept. of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Centre, Vilnius University, Saulėtekio al. 7, LT-10257, Lithuania
| | - Tomas Uzusienis
- Dept. of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Centre, Vilnius University, Saulėtekio al. 7, LT-10257, Lithuania
| | - Ausra Imbrasaite
- Dept. of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Centre, Vilnius University, Saulėtekio al. 7, LT-10257, Lithuania
| | - Natalija Krestnikova
- Dept. of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Centre, Vilnius University, Saulėtekio al. 7, LT-10257, Lithuania
| | - Ausra Unguryte
- Centre for Innovative Medicine, Santariškių g. 5, LT-08406, Lithuania
| | - Audrone V Kalvelyte
- Dept. of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Centre, Vilnius University, Saulėtekio al. 7, LT-10257, Lithuania.
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Li J, Hu S, Zhu D, Huang K, Mei X, López de Juan Abad B, Cheng K. All Roads Lead to Rome (the Heart): Cell Retention and Outcomes From Various Delivery Routes of Cell Therapy Products to the Heart. J Am Heart Assoc 2021; 10:e020402. [PMID: 33821664 PMCID: PMC8174178 DOI: 10.1161/jaha.120.020402] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In the past decades, numerous preclinical studies and several clinical trials have evidenced the feasibility of cell transplantation in treating heart diseases. Over the years, different delivery routes of cell therapy have emerged and broadened the width of the field. However, a common hurdle is shared by all current delivery routes: low cell retention. A myriad of studies confirm that cell retention plays a crucial role in the success of cell-mediated cardiac repair. It is important for any delivery route to maintain donor cells in the recipient heart for enough time to not only proliferate by themselves, but also to send paracrine signals to surrounding damaged heart cells and repair them. In this review, we first undertake an in-depth study of primary theories of cell loss, including low efficiency in cell injection, "washout" effects, and cell death, and then organize the literature from the past decade that focuses on cell transplantation to the heart using various cell delivery routes, including intracoronary injection, systemic intravenous injection, retrograde coronary venous injection, and intramyocardial injection. In addition to a recapitulation of these approaches, we also clearly evaluate their strengths and weaknesses. Furthermore, we conduct comparative research on the cell retention rate and functional outcomes of these delivery routes. Finally, we extend our discussion to state-of-the-art bioengineering techniques that enhance cell retention, as well as alternative delivery routes, such as intrapericardial delivery. A combination of these novel strategies and more accurate assessment methods will help to address the hurdle of low cell retention and boost the efficacy of cell transplantation to the heart.
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Affiliation(s)
- Junlang Li
- Department of Molecular Biomedical SciencesNorth Carolina State UniversityRaleighNC
- Joint Department of Biomedical EngineeringNorth Carolina State University and University of North Carolina at Chapel HillRaleighNC
| | - Shiqi Hu
- Department of Molecular Biomedical SciencesNorth Carolina State UniversityRaleighNC
- Joint Department of Biomedical EngineeringNorth Carolina State University and University of North Carolina at Chapel HillRaleighNC
| | - Dashuai Zhu
- Department of Molecular Biomedical SciencesNorth Carolina State UniversityRaleighNC
- Joint Department of Biomedical EngineeringNorth Carolina State University and University of North Carolina at Chapel HillRaleighNC
| | - Ke Huang
- Department of Molecular Biomedical SciencesNorth Carolina State UniversityRaleighNC
- Joint Department of Biomedical EngineeringNorth Carolina State University and University of North Carolina at Chapel HillRaleighNC
| | - Xuan Mei
- Department of Molecular Biomedical SciencesNorth Carolina State UniversityRaleighNC
- Joint Department of Biomedical EngineeringNorth Carolina State University and University of North Carolina at Chapel HillRaleighNC
| | - Blanca López de Juan Abad
- Department of Molecular Biomedical SciencesNorth Carolina State UniversityRaleighNC
- Joint Department of Biomedical EngineeringNorth Carolina State University and University of North Carolina at Chapel HillRaleighNC
| | - Ke Cheng
- Department of Molecular Biomedical SciencesNorth Carolina State UniversityRaleighNC
- Joint Department of Biomedical EngineeringNorth Carolina State University and University of North Carolina at Chapel HillRaleighNC
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45
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Scaffold-free cell-based tissue engineering therapies: advances, shortfalls and forecast. NPJ Regen Med 2021; 6:18. [PMID: 33782415 PMCID: PMC8007731 DOI: 10.1038/s41536-021-00133-3] [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: 11/23/2020] [Accepted: 02/24/2021] [Indexed: 02/01/2023] Open
Abstract
Cell-based scaffold-free therapies seek to develop in vitro organotypic three-dimensional (3D) tissue-like surrogates, capitalising upon the inherent capacity of cells to create tissues with efficiency and sophistication that is still unparalleled by human-made devices. Although automation systems have been realised and (some) success stories have been witnessed over the years in clinical and commercial arenas, in vitro organogenesis is far from becoming a standard way of care. This limited technology transfer is largely attributed to scalability-associated costs, considering that the development of a borderline 3D implantable device requires very high number of functional cells and prolonged ex vivo culture periods. Herein, we critically discuss advancements and shortfalls of scaffold-free cell-based tissue engineering strategies, along with pioneering concepts that have the potential to transform regenerative and reparative medicine.
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Simeoni RB, Mogharbel BF, Francisco JC, Miyague NI, Irioda AC, Souza CMCO, Souza D, Stricker PEF, da Rosa NN, Souza CF, Franco CRC, Sierakowski MR, Abdelwaid E, Guarita-Souza LC, Carvalho KA. Beneficial Roles of Cellulose Patch-Mediated Cell Therapy in Myocardial Infarction: A Preclinical Study. Cells 2021; 10:424. [PMID: 33671407 PMCID: PMC7922134 DOI: 10.3390/cells10020424] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 02/04/2021] [Accepted: 02/10/2021] [Indexed: 12/27/2022] Open
Abstract
Biological scaffolds have become an attractive approach for repairing the infarcted myocardium and have been shown to facilitate constructive remodeling in injured tissues. This study aimed to investigate the possible utilization of bacterial cellulose (BC) membrane patches containing cocultured cells to limit myocardial postinfarction pathology. Myocardial infarction (MI) was induced by ligating the left anterior descending coronary artery in 45 Wistar rats, and patches with or without cells were attached to the hearts. After one week, the animals underwent echocardiography to assess for ejection fraction and left ventricular end-diastolic and end-systolic volumes. Following patch formation, the cocultured cells retained viability of >90% over 14 days in culture. The patch was applied to the myocardial surface of the infarcted area after staying 14 days in culture. Interestingly, the BC membrane without cellular treatment showed higher preservation of cardiac dimensions; however, we did not observe improvement in the left ventricular ejection fraction of this group compared to coculture-treated membranes. Our results demonstrated an important role for BC in supporting cells known to produce cardioprotective soluble factors and may thus provide effective future therapeutic outcomes for patients suffering from ischemic heart disease.
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Affiliation(s)
- Rossana B. Simeoni
- Experimental Laboratory of Institute of Biological and Health Sciences of Pontifical Catholic University of Paraná (PUCPR), Street Imaculada Conceição, 1155, 80215-901 Curitiba, Paraná, Brazil; (R.B.S.); (J.C.F.); (N.I.M.); (L.C.G.-S.)
| | - Bassam F. Mogharbel
- Cell Therapy and Biotechnology in Regenerative Medicine Research Group, Pelé Pequeno Príncipe Research Institute & Pequeno Príncipe Faculties, Ave., Silva Jardim, 1632, 80240-020 Curitiba, Paraná, Brazil; (B.F.M.); (A.C.I.); (C.M.C.O.S.); (D.S.); (P.E.F.S.); (N.N.d.R.)
| | - Julio C. Francisco
- Experimental Laboratory of Institute of Biological and Health Sciences of Pontifical Catholic University of Paraná (PUCPR), Street Imaculada Conceição, 1155, 80215-901 Curitiba, Paraná, Brazil; (R.B.S.); (J.C.F.); (N.I.M.); (L.C.G.-S.)
| | - Nelson I. Miyague
- Experimental Laboratory of Institute of Biological and Health Sciences of Pontifical Catholic University of Paraná (PUCPR), Street Imaculada Conceição, 1155, 80215-901 Curitiba, Paraná, Brazil; (R.B.S.); (J.C.F.); (N.I.M.); (L.C.G.-S.)
| | - Ana C. Irioda
- Cell Therapy and Biotechnology in Regenerative Medicine Research Group, Pelé Pequeno Príncipe Research Institute & Pequeno Príncipe Faculties, Ave., Silva Jardim, 1632, 80240-020 Curitiba, Paraná, Brazil; (B.F.M.); (A.C.I.); (C.M.C.O.S.); (D.S.); (P.E.F.S.); (N.N.d.R.)
| | - Carolina M. C. O. Souza
- Cell Therapy and Biotechnology in Regenerative Medicine Research Group, Pelé Pequeno Príncipe Research Institute & Pequeno Príncipe Faculties, Ave., Silva Jardim, 1632, 80240-020 Curitiba, Paraná, Brazil; (B.F.M.); (A.C.I.); (C.M.C.O.S.); (D.S.); (P.E.F.S.); (N.N.d.R.)
| | - Daiany Souza
- Cell Therapy and Biotechnology in Regenerative Medicine Research Group, Pelé Pequeno Príncipe Research Institute & Pequeno Príncipe Faculties, Ave., Silva Jardim, 1632, 80240-020 Curitiba, Paraná, Brazil; (B.F.M.); (A.C.I.); (C.M.C.O.S.); (D.S.); (P.E.F.S.); (N.N.d.R.)
| | - Priscila E. Ferreira Stricker
- Cell Therapy and Biotechnology in Regenerative Medicine Research Group, Pelé Pequeno Príncipe Research Institute & Pequeno Príncipe Faculties, Ave., Silva Jardim, 1632, 80240-020 Curitiba, Paraná, Brazil; (B.F.M.); (A.C.I.); (C.M.C.O.S.); (D.S.); (P.E.F.S.); (N.N.d.R.)
| | - Nádia Nascimento da Rosa
- Cell Therapy and Biotechnology in Regenerative Medicine Research Group, Pelé Pequeno Príncipe Research Institute & Pequeno Príncipe Faculties, Ave., Silva Jardim, 1632, 80240-020 Curitiba, Paraná, Brazil; (B.F.M.); (A.C.I.); (C.M.C.O.S.); (D.S.); (P.E.F.S.); (N.N.d.R.)
| | - Clayton F. Souza
- Biopol, Chemistry Department, Federal University of Paraná, Avenue Cel. Francisco Heráclito dos Santos, 200, 81530-900 Curitiba, Paraná, Brazil; (C.F.S.); (M.-R.S.)
- Chemistry Undergraduate Program, School of Education and Humanities of Pontifical Catholic University of Paraná (PUCPR), Street Imaculada Conceição, 1155, 80215-901 Curitiba, Paraná, Brazil
| | - Celia R. Cavichiolo Franco
- Molecular Biology Department, Federal University of Paraná, Avenue Cel. Francisco Heráclito dos Santos, 100, 81530-900 Curitiba, Paraná, Brazil;
| | - Maria-Rita Sierakowski
- Biopol, Chemistry Department, Federal University of Paraná, Avenue Cel. Francisco Heráclito dos Santos, 200, 81530-900 Curitiba, Paraná, Brazil; (C.F.S.); (M.-R.S.)
| | - Eltyeb Abdelwaid
- Feinberg School of Medicine, Feinberg Cardiovascular Research Institute, Northwestern University, 303 E. Chicago Ave., Tarry 14–725, Chicago, IL 60611, USA;
| | - Luiz C. Guarita-Souza
- Experimental Laboratory of Institute of Biological and Health Sciences of Pontifical Catholic University of Paraná (PUCPR), Street Imaculada Conceição, 1155, 80215-901 Curitiba, Paraná, Brazil; (R.B.S.); (J.C.F.); (N.I.M.); (L.C.G.-S.)
| | - Katherine A.T. Carvalho
- Cell Therapy and Biotechnology in Regenerative Medicine Research Group, Pelé Pequeno Príncipe Research Institute & Pequeno Príncipe Faculties, Ave., Silva Jardim, 1632, 80240-020 Curitiba, Paraná, Brazil; (B.F.M.); (A.C.I.); (C.M.C.O.S.); (D.S.); (P.E.F.S.); (N.N.d.R.)
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Castelli V, Antonucci I, d'Angelo M, Tessitore A, Zelli V, Benedetti E, Ferri C, Desideri G, Borlongan C, Stuppia L, Cimini A. Neuroprotective effects of human amniotic fluid stem cells-derived secretome in an ischemia/reperfusion model. Stem Cells Transl Med 2021; 10:251-266. [PMID: 33027557 PMCID: PMC7848376 DOI: 10.1002/sctm.20-0268] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 08/03/2020] [Accepted: 08/24/2020] [Indexed: 12/11/2022] Open
Abstract
Stem cells offer the basis for the promotion of robust new therapeutic approaches for a variety of human disorders. There are still many limitations to be overcome before clinical therapeutic application, including a better understanding of the mechanism by which stem cell therapies may lead to enhanced recovery. In vitro investigations are necessary to dissect the mechanisms involved and to support the potential development in stem cell-based therapies. In spite of growing interest in human amniotic fluid stem cells, not much is known about the characteristics of their secretome and regarding the potential neuroprotective mechanism in different pathologies, including stroke. To get more insight on amniotic fluid cells therapeutic potential, signal transduction pathways activated by human amniotic fluid stem cells (hAFSCs)-derived secretome in a stroke in vitro model (ischemia/reperfusion [I/R] model) were investigated by Western blot. Moreover, miRNA expression in the exosomal fraction of the conditioned medium was analyzed. hAFSCs-derived secretome was able to activate pro-survival and anti-apoptotic pathways. MicroRNA analysis in the exosomal component revealed a panel of 16 overexpressed miRNAs involved in the regulation of coherent signaling pathways. In particular, the pathways of relevance in ischemia/reperfusion, such as neurotrophin signaling, and those related to neuroprotection and neuronal cell death, were analyzed. The results obtained strongly point toward the neuroprotective effects of the hAFSCs-conditioned medium in the in vitro stroke model here analyzed. This can be achieved by the modulation and activation of pro-survival processes, at least in part, due to the activity of secreted miRNAs.
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Affiliation(s)
- Vanessa Castelli
- Department of Life, Health and Environmental SciencesUniversity of L'AquilaL'AquilaItaly
| | - Ivana Antonucci
- Department of Psychological, Health and Territorial Sciences, School of Medicine and Health Sciences“G. d'Annunzio” UniversityChieti‐PescaraItaly
- Center for Advanced Studies and Technology (CAST)‘G. d'Annunzio’ UniversityChieti‐PescaraItaly
| | - Michele d'Angelo
- Department of Life, Health and Environmental SciencesUniversity of L'AquilaL'AquilaItaly
| | - Alessandra Tessitore
- Department of Biotechnological and Applied Clinical Sciences (DISCAB)University of L'AquilaL'AquilaItaly
| | - Veronica Zelli
- Department of Biotechnological and Applied Clinical Sciences (DISCAB)University of L'AquilaL'AquilaItaly
| | - Elisabetta Benedetti
- Department of Life, Health and Environmental SciencesUniversity of L'AquilaL'AquilaItaly
| | - Claudio Ferri
- Department of Life, Health and Environmental SciencesUniversity of L'AquilaL'AquilaItaly
| | | | - Cesar Borlongan
- Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain RepairUniversity of South Florida College of MedicineTampaFloridaUSA
| | - Liborio Stuppia
- Department of Psychological, Health and Territorial Sciences, School of Medicine and Health Sciences“G. d'Annunzio” UniversityChieti‐PescaraItaly
- Center for Advanced Studies and Technology (CAST)‘G. d'Annunzio’ UniversityChieti‐PescaraItaly
| | - Annamaria Cimini
- Department of Life, Health and Environmental SciencesUniversity of L'AquilaL'AquilaItaly
- Sbarro Institute for Cancer Research and Molecular Medicine and Centre for BiotechnologyTemple UniversityPhiladelphiaPennsylvaniaUSA
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Carresi C, Scicchitano M, Scarano F, Macrì R, Bosco F, Nucera S, Ruga S, Zito MC, Mollace R, Guarnieri L, Coppoletta AR, Gliozzi M, Musolino V, Maiuolo J, Palma E, Mollace V. The Potential Properties of Natural Compounds in Cardiac Stem Cell Activation: Their Role in Myocardial Regeneration. Nutrients 2021; 13:275. [PMID: 33477916 PMCID: PMC7833367 DOI: 10.3390/nu13010275] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 01/07/2021] [Accepted: 01/12/2021] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular diseases (CVDs), which include congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, and many other cardiac disorders, cause about 30% of deaths globally; representing one of the main health problems worldwide. Among CVDs, ischemic heart diseases (IHDs) are one of the major causes of morbidity and mortality in the world. The onset of IHDs is essentially due to an unbalance between the metabolic demands of the myocardium and its supply of oxygen and nutrients, coupled with a low regenerative capacity of the heart, which leads to great cardiomyocyte (CM) loss; promoting heart failure (HF) and myocardial infarction (MI). To date, the first strategy recommended to avoid IHDs is prevention in order to reduce the underlying risk factors. In the management of IHDs, traditional therapeutic options are widely used to improve symptoms, attenuate adverse cardiac remodeling, and reduce early mortality rate. However, there are no available treatments that aim to improve cardiac performance by replacing the irreversible damaged cardiomyocytes (CMs). Currently, heart transplantation is the only treatment being carried out for irreversibly damaged CMs. Hence, the discovery of new therapeutic options seems to be necessary. Interestingly, recent experimental evidence suggests that regenerative stem cell medicine could be a useful therapeutic approach to counteract cardiac damage and promote tissue regeneration. To this end, researchers are tasked with answering one main question: how can myocardial regeneration be stimulated? In this regard, natural compounds from plant extracts seem to play a particularly promising role. The present review will summarize the recent advances in our knowledge of stem cell therapy in the management of CVDs; focusing on the main properties and potential mechanisms of natural compounds in stimulating and activating stem cells for myocardial regeneration.
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Affiliation(s)
- Cristina Carresi
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Miriam Scicchitano
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Federica Scarano
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Roberta Macrì
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Francesca Bosco
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Saverio Nucera
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Stefano Ruga
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Maria Caterina Zito
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Rocco Mollace
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Lorenza Guarnieri
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Anna Rita Coppoletta
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Micaela Gliozzi
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Vincenzo Musolino
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Jessica Maiuolo
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Ernesto Palma
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
- Nutramed S.c.a.r.l., Complesso Ninì Barbieri, Roccelletta di Borgia, 88100 Catanzaro, Italy
| | - Vincenzo Mollace
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
- Nutramed S.c.a.r.l., Complesso Ninì Barbieri, Roccelletta di Borgia, 88100 Catanzaro, Italy
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Jiang Y, Sun SJ, Zhen Z, Wei R, Zhang N, Liao SY, Tse HF. Myocardial repair of bioengineered cardiac patches with decellularized placental scaffold and human-induced pluripotent stem cells in a rat model of myocardial infarction. Stem Cell Res Ther 2021; 12:13. [PMID: 33413626 PMCID: PMC7791702 DOI: 10.1186/s13287-020-02066-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 12/02/2020] [Indexed: 12/13/2022] Open
Abstract
Background The creation of a bioengineered cardiac patch (BCP) is a potential novel strategy for myocardial repair. Nevertheless, the ideal scaffold for BCP is unknown. Objective We investigated whether the decellularized placenta (DP) could serve as natural scaffold material to create a BCP for myocardial repair. Methods and results A BCP was created by seeding human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs; 1 × 106/cm2) onto DP. The functional and electrophysiological properties of the BCP were first characterized by in vitro analysis and optical mapping. Next, in vivo therapeutic efficacy of the BCP was evaluated in a rat model of myocardial infarction (MI), created by left descending coronary artery ligation (MI + BCP group), and compared with MI alone (MI group), transplantation of DP (MI + DP group), and hiPSC-CMs (MI + CM group). Cytokine profiling demonstrated that the BCP contained multiple growth and angiogenic factors, including vascular endothelial growth factor, platelet-derived growth factor, insulin-like growth factor-1, basic fibroblast growth factor, angiogenin, and angiopoietin-2. In vitro optical mapping showed that the BCP exhibited organized mechanical contraction and synchronized electrical propagation. RNA sequencing showed that DP enhanced the maturation of hiPSC-CMs compared with the monolayer of cultured hiPSC-CMs. At 4 weeks follow-up, the BCP significantly improved left ventricular (LV) function, as determined by LV ejection fraction, fractional shortening, + dP/dtmax, and end-systolic pressure-volume relationship, compared with the MI, MI + DP, and MI + CM groups. Moreover, histological examination revealed that engraftment of the BCP at the infarct zone decreased infarct size and increased cell retention and neovascularization compared with the MI, MI + DP, and MI + CM groups. Conclusions Our results demonstrate that a DP scaffold contains multiple growth and angiogenic factors that enhance the maturation and survival of seeded hiPSC-CMs. Transplantation of a BCP is superior to DP or hiPSC-CMs alone in reducing infarct size and improving cell retention and neovascularization, thus providing a novel therapy for myocardial repair following MI. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-020-02066-y.
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Affiliation(s)
- Yu Jiang
- Cardiology Division, Department of Medicine, Queen Mary Hospital, the University of Hong Kong, Hong Kong, SAR, China
| | - Si-Jia Sun
- Cardiology Division, Department of Medicine, Queen Mary Hospital, the University of Hong Kong, Hong Kong, SAR, China
| | - Zhe Zhen
- Cardiology Division, Department of Medicine, Queen Mary Hospital, the University of Hong Kong, Hong Kong, SAR, China
| | - Rui Wei
- Cardiology Division, Department of Medicine, Queen Mary Hospital, the University of Hong Kong, Hong Kong, SAR, China
| | - Nannan Zhang
- Cardiology Division, Department of Medicine, Queen Mary Hospital, the University of Hong Kong, Hong Kong, SAR, China
| | - Song-Yan Liao
- Cardiology Division, Department of Medicine, Queen Mary Hospital, the University of Hong Kong, Hong Kong, SAR, China. .,Shenzhen Institutes of Research and Innovation, the University of Hong Kong, Shenzhen, China.
| | - Hung-Fat Tse
- Cardiology Division, Department of Medicine, Queen Mary Hospital, the University of Hong Kong, Hong Kong, SAR, China. .,Department of Medicine, Shenzhen Hong Kong University Hospital, Shenzhen, China. .,Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, the University of Hong Kong, Hong Kong, SAR, China.
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Kingsbury C, Stuppia L. Stem cell secretome derived from human amniotic fluid affords neuroprotection in an ischemic model. Brain Circ 2021; 7:18-22. [PMID: 34084972 PMCID: PMC8057106 DOI: 10.4103/bc.bc_8_21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 01/03/2021] [Accepted: 01/20/2021] [Indexed: 11/08/2022] Open
Abstract
Human amniotic fluid stem cells (hAFSCs) are growing in interest; yet, little is understood about their secretome and neuroprotective actions in different diseases, including stroke. When stem cells are grown in vitro, they release an array of cytokines and growth factors that can stimulate neuroprotective processes. Furthermore, administering secretome rather than cells may be a safer route for patients who are at risk for rejection, promoting innate restorative processes. Current literature implicates that the miRNA contents of such secretome, more specifically exosomes, may regulate the effectiveness of secretome administration. In this review, we explore what factors may promote pro-survival and pro-apoptotic pathways after the administration of hAFSCs-derived secretome in ischemic models.
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Affiliation(s)
- Chase Kingsbury
- Judy Genshaft Honors College, University of South Florida, Tampa, FL 33612, USA
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