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Choudhery MS, Arif T, Mahmood R, Mushtaq A, Niaz A, Hassan Z, Zahid H, Nayab P, Arshad I, Arif M, Majid M, Harris DT. Induced Mesenchymal Stem Cells: An Emerging Source for Regenerative Medicine Applications. J Clin Med 2025; 14:2053. [PMID: 40142860 PMCID: PMC11943107 DOI: 10.3390/jcm14062053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 03/07/2025] [Accepted: 03/10/2025] [Indexed: 03/28/2025] Open
Abstract
Regenerative medicine is gaining interest in the medical field due to the limitations of conventional treatments, which often fail to address the underlying cause of disease. In recent years, stem cell-based therapies have evolved as a promising alternative approach to treat those diseases that cannot be cured using conventional medicine. Adult stem cells, particularly the mesenchymal stem cells (MSCs), have attracted a lot of attention due to their ability to regenerate and repair human tissues and organs. MSCs isolated from adult tissues are well characterized and are currently the most common type of cells for use in regenerative medicine. However, their low number in adult donor tissues, donor-age and cell-source related heterogeneity, limited proliferative and differentiation potential, and early senescence in in vitro cultures, negatively affect MSC regenerative potential. These factors restrict MSC use for research as well as for clinical applications. To overcome these problems, MSCs with superior regenerative potential are required. Induced MSCs (iMSCs) are obtained from induced pluripotent stem cells (iPSCs). These cells are patient-specific, readily available, and have relatively superior regenerative potential and, therefore, can overcome the problems associated with the use of primary MSCs. In this review, the authors aim to discuss the characteristics, regenerative potential, and limitations of MSCs for regenerative medicine applications. The main methods to generate iMSCs from iPSCs have been discussed in detail. In addition, the proposed criteria for their molecular characterization, applications of iMSCs for disease modeling and drug discovery, as well as potential use in regenerative medicine have been explored in detail.
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Affiliation(s)
- Mahmood S. Choudhery
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 50161, Pakistan; (M.S.C.); (T.A.); (A.M.); (A.N.); (Z.H.); (H.Z.); (P.N.); (I.A.); (M.A.); (M.M.)
| | - Taqdees Arif
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 50161, Pakistan; (M.S.C.); (T.A.); (A.M.); (A.N.); (Z.H.); (H.Z.); (P.N.); (I.A.); (M.A.); (M.M.)
| | - Ruhma Mahmood
- Department of Pediatric Surgery, Allama Iqbal Medical College, Jinnah Hospital, Lahore 54700, Pakistan;
| | - Asad Mushtaq
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 50161, Pakistan; (M.S.C.); (T.A.); (A.M.); (A.N.); (Z.H.); (H.Z.); (P.N.); (I.A.); (M.A.); (M.M.)
| | - Ahmad Niaz
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 50161, Pakistan; (M.S.C.); (T.A.); (A.M.); (A.N.); (Z.H.); (H.Z.); (P.N.); (I.A.); (M.A.); (M.M.)
| | - Zaeema Hassan
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 50161, Pakistan; (M.S.C.); (T.A.); (A.M.); (A.N.); (Z.H.); (H.Z.); (P.N.); (I.A.); (M.A.); (M.M.)
| | - Hamda Zahid
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 50161, Pakistan; (M.S.C.); (T.A.); (A.M.); (A.N.); (Z.H.); (H.Z.); (P.N.); (I.A.); (M.A.); (M.M.)
| | - Pakeeza Nayab
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 50161, Pakistan; (M.S.C.); (T.A.); (A.M.); (A.N.); (Z.H.); (H.Z.); (P.N.); (I.A.); (M.A.); (M.M.)
| | - Iqra Arshad
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 50161, Pakistan; (M.S.C.); (T.A.); (A.M.); (A.N.); (Z.H.); (H.Z.); (P.N.); (I.A.); (M.A.); (M.M.)
| | - Mehak Arif
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 50161, Pakistan; (M.S.C.); (T.A.); (A.M.); (A.N.); (Z.H.); (H.Z.); (P.N.); (I.A.); (M.A.); (M.M.)
| | - Mashaim Majid
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 50161, Pakistan; (M.S.C.); (T.A.); (A.M.); (A.N.); (Z.H.); (H.Z.); (P.N.); (I.A.); (M.A.); (M.M.)
| | - David T. Harris
- Department of Immunobiology, University of Arizona Health Sciences Biorepository, College of Medicine, University of Arizona, Tucson, AZ 85721, USA
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Lv J, Yuan L, Chen G, Ma L, Qi Y, Zeng J, Wang X, Jin Y. Distribution characteristics and morphological comparison of telocytes in the aortic bulb and myocardium of yak heart. BMC Vet Res 2025; 21:88. [PMID: 39987074 PMCID: PMC11846454 DOI: 10.1186/s12917-025-04553-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 01/31/2025] [Indexed: 02/24/2025] Open
Abstract
BACKGROUND Telocytes (TCs) are small interstitial cells that extend into multiple bead-like protrusions called telopodes (TPs). TCs are widely found in many tissues and organs, form connections with almost all types of cardiomyocytes, and participate in regulating cardiac microenvironment homeostasis. METHODS In this study, transmission electron microscopy combined with special staining techniques (Gomori's, Masson's trichrome, and toluidine blue staining) were used to analyse the ultrastructure, distribution, and cytochemical characteristics of TCs in yak hearts. Immunohistochemistry and immunofluorescence double staining techniques were combined to identify the immunophenotypic characteristics of TCs functional markers (CD34, CD117, PDGFR-α and α-SMA) and further reveal their potential functions. RESULTS The results showed that the TCs in the aortic bulb of yak hearts had prominent nuclei, and thin, long TPs with abundant secretory vesicles. TCs in the myocardial tissue exhibited irregularly shaped nuclei, shorter TPs, and connections with myocardial fibres and adjacent capillaries, forming a complex TC network. Immunohistochemical results demonstrated the positive expression of functional markers CD34, CD117, α-SMA and PDGFR-α in both the aortic bulb and myocardium. Immunofluorescence double staining results indicated co-expression of CD34/CD117, CD34/α-SMA, and CD117/PDGFR-α in TCs. CONCLUSION This is the first study to report the presence of TCs in the aortic bulb and myocardium of yak hearts and that it may form TC networks that mainly participate in mechanical support and cell communication in the heart. The presence and distribution characteristics of TCs in the heart of yaks provide important clues for further research on the role of TC networks in the adaptability of plateau animals to the environment.
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Affiliation(s)
- Jinhan Lv
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Ligang Yuan
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China.
- College of Veterinary Medicine, Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Gansu Agricultural University, Lanzhou city, Gansu province, 730070, China.
| | - Guojuan Chen
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
- Huangzhong District Animal Disease Control Center of Xining City, Xining, 811600, China
| | - Long Ma
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Yumei Qi
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Jianlin Zeng
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Xiaofen Wang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Yajuan Jin
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
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Shi X, Zhang K, Yu F, Qi Q, Cai X, Zhang Y. Advancements and Innovative Strategies in Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cell Therapy: A Comprehensive Review. Stem Cells Int 2024; 2024:4073485. [PMID: 39377039 PMCID: PMC11458320 DOI: 10.1155/2024/4073485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 06/24/2024] [Accepted: 09/04/2024] [Indexed: 10/09/2024] Open
Abstract
The effectiveness and safety of mesenchymal stem cell (MSC) therapy have been substantiated across various diseases. Nevertheless, challenges such as the restricted in vitro expansion capacity of tissue-derived MSCs and the clinical instability due to the high heterogeneity of isolated cells require urgent resolution. The induced pluripotent stem cell-derived MSCs (iPSC-MSCs), which is differentiated from iPSCs via specific experimental pathways, holds considerable potential as a substitute for tissue derived MSCs. Multiple studies have demonstrated that iPSCs can be differentiated into iPSC-MSCs through diverse differentiation strategies. Research suggests that iPSC-MSCs, when compared to tissue derived MSCs, exhibit superior characteristics in terms of proliferation ability, immune modulation capacity, and biological efficiency. In this review, we meticulously described and summarized the experimental methods of iPSC differentiation into iPSC-MSCs, the application of iPSC-MSCs in various disease models, the latest advancements in clinically relevant iPSC-derived cell products, and the development strategies for the next generation of iPSC-derived therapy products (not only cell products but also their derivatives).
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Affiliation(s)
- Xiaoyu Shi
- State Industrial Base for Stem Cell Engineering Products, Tianjin 300384, China
| | - Kun Zhang
- State Industrial Base for Stem Cell Engineering Products, Tianjin 300384, China
| | - Fengshi Yu
- State Industrial Base for Stem Cell Engineering Products, Tianjin 300384, China
| | - Qi Qi
- State Industrial Base for Stem Cell Engineering Products, Tianjin 300384, China
| | - Xiaoyu Cai
- State Industrial Base for Stem Cell Engineering Products, Tianjin 300384, China
| | - Yu Zhang
- VCANBIO Cell and Gene Engineering Corp. Ltd., Tianjin, China
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Tseng HC, Hsu TF, Lin YY, Lai WY, Liu YH, Yang YP, Chen CF, Wang CY. Efficient induction of pluripotent stem cells differentiated into mesenchymal stem cell lineages. J Chin Med Assoc 2024; 87:267-272. [PMID: 38277620 DOI: 10.1097/jcma.0000000000001058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2024] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have garnered significant attention in the field of cell-based therapy owing to their remarkable capabilities for differentiation and self-renewal. However, primary tissue-derived MSCs are plagued by various limitations, including constrained tissue sources, arduous and invasive retrieval procedures, heterogeneous cell populations, diminished purity, cellular senescence, and a decline in self-renewal and proliferative capacities after extended expansion. Addressing these challenges, our study focuses on establishing a robust differentiation platform to generate mesenchymal stem cells derived from induced pluripotent stem cells (iMSCs). METHODS To achieve this, we used a comprehensive methodology involving the differentiation of induced pluripotent stem cells into MSCss. The process was meticulously designed to ensure the expression of key MSC positive markers (CD73, CD90, and CD105) at elevated levels, coupled with the minimal expression of negative markers (CD34, CD45, CD11b, CD19, and HLA-DR). Moreover, the stability of these characteristics was evaluated across 10th generations. RESULTS Our findings attest to the success of this endeavor. iMSCs exhibited robust expression of positive markers and limited expression of negative markers, confirming their MSC identity. Importantly, these characteristics remained stable even up to the 10th generation, signifying the potential for sustained use in therapeutic applications. Furthermore, our study demonstrated the successful differentiation of iMSCs into osteocytes, chondrocytes, and adipocytes, showcasing their multilineage potential. CONCLUSION In conclusion, the establishment of induced pluripotent stem cell-derived mesenchymal stem cells (iMSCs) presents a significant advancement in overcoming the limitations associated with primary tissue-derived MSCs. The remarkable stability and multilineage differentiation potential exhibited by iMSCs offer a strong foundation for their application in regenerative medicine and tissue engineering. This breakthrough paves the way for further research and development in harnessing the full therapeutic potential of iMSCs.
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Affiliation(s)
- Huan-Chin Tseng
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Teh-Fu Hsu
- Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Yi-Ying Lin
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Wei-Yi Lai
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yu-Hao Liu
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yi-Ping Yang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Cheng-Fong Chen
- Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Exercise and Health Sciences, University of Taipei, Taipei, Taiwan, ROC
| | - Chien-Ying Wang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Critical Care Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Division of Trauma, Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Exercise and Health Sciences, University of Taipei, Taipei, Taiwan, ROC
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Borges LF, Manetti M. Telocytes and Stem Cells. RESIDENT STEM CELLS AND REGENERATIVE THERAPY 2024:305-337. [DOI: 10.1016/b978-0-443-15289-4.00011-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Chiou SH, Ong HKA, Chou SJ, Aldoghachi AF, Loh JK, Verusingam ND, Yang YP, Chien Y. Current trends and promising clinical utility of IPSC-derived MSC (iMSC). PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 199:131-154. [PMID: 37678969 DOI: 10.1016/bs.pmbts.2023.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/09/2023]
Abstract
Mesenchymal stem cells (MSCs) differentiated from human induced pluripotent stem cells (iPSC) or induced MSC (iMSCs) are expected to address issues of scalability and safety as well as the difficulty in producing homogenous clinical grade MSCs as demonstrated by the promising outcomes from preclinical and clinical trials, currently ongoing. The assessment of iMSCs based in vitro and in vivo studies have thus far showed more superior performance as compared to that of the primary or native human MSCs, in terms of cell proliferation, expansion capacity, immunomodulation properties as well as the influence of paracrine signaling and exosomal influence in cell-cell interaction. In this chapter, an overview of current well-established methods in generating a sustainable source of iMSCs involving well defined culture media is discussed followed by the properties of iMSC as compared to that of MSC and its promising prospects for continuous development into potential clinical grade applications.
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Affiliation(s)
- Shih-Hwa Chiou
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Medical Research, Taipei Veteran General Hospital, Taipei, Taiwan
| | - Han Kiat Alan Ong
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Shih-Jie Chou
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Medical Research, Taipei Veteran General Hospital, Taipei, Taiwan
| | - A F Aldoghachi
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Jit Kai Loh
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Nalini Devi Verusingam
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Yi-Ping Yang
- Department of Medical Research, Taipei Veteran General Hospital, Taipei, Taiwan.
| | - Yueh Chien
- Department of Medical Research, Taipei Veteran General Hospital, Taipei, Taiwan
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Aldoghachi AF, Loh JK, Wang ML, Yang YP, Chien CS, Teh HX, Omar AH, Cheong SK, Yeap SK, Ho WY, Ong AHK. Current developments and therapeutic potentials of exosomes from induced pluripotent stem cells-derived mesenchymal stem cells. J Chin Med Assoc 2023; 86:356-365. [PMID: 36762931 DOI: 10.1097/jcma.0000000000000899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/11/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent cells derived from adult human tissues that have the ability to proliferate in vitro and maintain their multipotency, making them attractive cell sources for regenerative medicine. However, MSCs reportedly show limited proliferative capacity with inconsistent therapeutic outcomes due to their heterogeneous nature. On the other hand, induced pluripotent stem cells (iPSC) have emerged as an alternative source for the production of various specialized cell types via their ability to differentiate from all three primary germ layers, leading to applications in regenerative medicine, disease modeling, and drug therapy. Notably, iPSCs can differentiate into MSCs in monolayer, commonly referred to as induced mesenchymal stem cells (iMSCs). These cells show superior therapeutic qualities compared with adult MSCs as the applications of the latter are restricted by passage number and autoimmune rejection when applied in tissue regeneration trials. Furthermore, increasing evidence shows that the therapeutic properties of stem cells are a consequence of the paracrine effects mediated by their secretome such as from exosomes, a type of extracellular vesicle secreted by most cell types. Several studies that investigated the potential of exosomes in regenerative medicine and therapy have revealed promising results. Therefore, this review focuses on the recent findings of exosomes secreted from iMSCs as a potential noncell-based therapy.
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Affiliation(s)
- Ahmed Faris Aldoghachi
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Jit-Kai Loh
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Mong-Lien Wang
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yi-Ping Yang
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Chian-Shiu Chien
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Hui Xin Teh
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Alfaqih Hussain Omar
- Biomedicine Programme, School of Health Sciences, Universiti Sains Malaysia, Malaysia
| | - Soon-Keng Cheong
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
- National Cancer Council (MAKNA), Kuala Lumpur, Malaysia
| | - Swee Keong Yeap
- Marine Biotechnology, China-ASEAN College of Marine Sciences, Xiamen University Malaysia Campus, Jalan Sunsuria, Bandar Sunsuria, Sepang, Selangor, Malaysia
| | - Wan Yong Ho
- Faculty of Sciences and Engineering, University of Nottingham Malaysia, Semenyih, Malaysia
| | - Alan Han-Kiat Ong
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
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Yu S, Klomjit N, Jiang K, Zhu XY, Ferguson CM, Conley SM, Obeidat Y, Kellogg TA, McKenzie T, Heimbach JK, Lerman A, Lerman LO. Human Obesity Attenuates Cardioprotection Conferred by Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells. J Cardiovasc Transl Res 2023; 16:221-232. [PMID: 35616881 DOI: 10.1007/s12265-022-10279-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 05/17/2022] [Indexed: 12/15/2022]
Abstract
To explore the impact of obesity on reparative potency of adipose tissue-derived mesenchymal stromal/stem cells (A-MSC) in hypertensive cardiomyopathy, A-MSC were harvested from subcutaneous fat of obese and age-matched non-obese human subjects during bariatric or kidney donation surgeries, and then injected into mice 2 weeks after inducing renovascular hypertension (RVH) or sham surgery. Two weeks later, left ventricular (LV) function and deformation were estimated in vivo by micro-magnetic resonance imaging and myocardial damage ex vivo. Blood pressure and myocardial wall thickening were elevated in RVH + Vehicle and normalized only by lean-A-MSC. Both A-MSC types reduced LV mass and normalized the reduced LV peak strain radial in RVH, yet obese-A-MSC also impaired LV systolic function. A-MSC alleviated myocardial tissue damage in RVH, but lean-A-MSC decreased oxidative stress more effectively. Obese-A-MSC also showed increased cellular inflammation in vitro. Therefore, obese-A-MSC are less effective than lean-A-MSC in blunting hypertensive cardiomyopathy in mice with RVH.
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Affiliation(s)
- Shasha Yu
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA
- Department of Cardiology, First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Nattawat Klomjit
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA
| | - Kai Jiang
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA
| | - Xiang Y Zhu
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA
| | - Christopher M Ferguson
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA
| | - Sabena M Conley
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA
| | - Yasin Obeidat
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA
| | | | | | | | - Amir Lerman
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
| | - Lilach O Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA.
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
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Cardiac Telocytes 16 Years on-What Have We Learned So Far, and How Close Are We to Routine Application of the Knowledge in Cardiovascular Regenerative Medicine? Int J Mol Sci 2021; 22:ijms222010942. [PMID: 34681601 PMCID: PMC8535888 DOI: 10.3390/ijms222010942] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 10/04/2021] [Accepted: 10/07/2021] [Indexed: 02/06/2023] Open
Abstract
The regeneration of a diseased heart is one of the principal challenges of modern cardiovascular medicine. There has been ongoing research on stem-cell-based therapeutic approaches. A cell population called telocytes (TCs) described only 16 years ago largely contributed to the research area of cardiovascular regeneration. TCs are cells with small bodies and extremely long cytoplasmic projections called telopodes, described in all layers of the heart wall. Their functions include cell-to-cell signaling, stem-cell nursing, mechanical support, and immunoregulation, to name but a few. The functional derangement or quantitative loss of TCs has been implicated in the pathogenesis of myocardial infarction, heart failure, arrhythmias, and many other conditions. The exact pathomechanisms are still unknown, but the loss of regulative, integrative, and nursing functions of TCs may provide important clues. Therefore, a viable avenue in the future modern management of these conditions is TC-based cell therapy. TCs have been previously transplanted into a mouse model of myocardial infarction with promising results. Tandem transplantation with stem cells may provide additional benefit; however, many underresearched areas need to be addressed in future research before routine application of TC-based cell therapy in human subjects. These include the standardization of protocols for isolation, cultivation, and transplantation, quantitative optimization of TC transplants, cost-effectivity analysis, and many others.
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Pluripotent-derived Mesenchymal Stem/stromal Cells: an Overview of the Derivation Protocol Efficacies and the Differences Among the Derived Cells. Stem Cell Rev Rep 2021; 18:94-125. [PMID: 34545529 DOI: 10.1007/s12015-021-10258-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2021] [Indexed: 10/20/2022]
Abstract
Mesenchymal stem/stromal cells (MSCs) are remarkable tools for regenerative medicine. Therapeutic approaches using these cells can promote increased activity and viability in several cell types through diverse mechanisms such as paracrine and immunomodulatory activities, contributing substantially to tissue regeneration and functional recovery. However, biological samples of human MSCs, usually obtained from adult tissues, often exhibit variable behavior during in vitro culture, especially with respect to cell population heterogeneity, replicative senescence, and consequent loss of functionality. Accordingly, it is necessary to establish standard protocols to generate high-quality, stable cell cultures, for example, by using pluripotent stem cells (PSCs) in derivation protocols of MSC-like cells since PSCs maintain their characteristics consistently during culture. However, the available protocols seem to generate distinct populations of PSC-derivedMSCs (PSC-MSCs) with peculiar attributes, which do not always resemble bona fide primary MSCs. The present review addresses the developmental basis behind some of these derivation protocols, exposing the differences among them and discussing the functional properties of PSC-MSCs, shedding light on elements that may help determine standard characterizations and criteria to evaluate and define these cells.
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Dupuis V, Oltra E. Methods to produce induced pluripotent stem cell-derived mesenchymal stem cells: Mesenchymal stem cells from induced pluripotent stem cells. World J Stem Cells 2021; 13:1094-1111. [PMID: 34567428 PMCID: PMC8422924 DOI: 10.4252/wjsc.v13.i8.1094] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/03/2021] [Accepted: 07/14/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have received significant attention in recent years due to their large potential for cell therapy. Indeed, they secrete a wide variety of immunomodulatory factors of interest for the treatment of immune-related disorders and inflammatory diseases. MSCs can be extracted from multiple tissues of the human body. However, several factors may restrict their use for clinical applications: the requirement of invasive procedures for their isolation, their limited numbers, and their heterogeneity according to the tissue of origin or donor. In addition, MSCs often present early signs of replicative senescence limiting their expansion in vitro, and their therapeutic capacity in vivo. Due to the clinical potential of MSCs, a considerable number of methods to differentiate induced pluripotent stem cells (iPSCs) into MSCs have emerged. iPSCs represent a new reliable, unlimited source to generate MSCs (MSCs derived from iPSC, iMSCs) from homogeneous and well-characterized cell lines, which would relieve many of the above mentioned technical and biological limitations. Additionally, the use of iPSCs prevents some of the ethical concerns surrounding the use of human embryonic stem cells. In this review, we analyze the main current protocols used to differentiate human iPSCs into MSCs, which we classify into five different categories: MSC Switch, Embryoid Body Formation, Specific Differentiation, Pathway Inhibitor, and Platelet Lysate. We also evaluate common and method-specific culture components and provide a list of positive and negative markers for MSC characterization. Further guidance on material requirements to produce iMSCs with these methods and on the phenotypic features of the iMSCs obtained is added. The information may help researchers identify protocol options to design and/or refine standardized procedures for large-scale production of iMSCs fitting clinical demands.
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Affiliation(s)
- Victoria Dupuis
- Faculté des Sciences et d’Ingénierie, Sorbonne Université, Paris 75252, France
| | - Elisa Oltra
- Department of Pathology, Universidad Católica de Valencia San Vicente Mártir, Valencia 46001, Spain
- Centro de Investigación Traslacional San Alberto Magno, Universidad Católica de Valencia San Vicente Mártir, Valencia 46001, Spain.
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12
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Zhang D, Song D, Shi L, Sun X, Zheng Y, Zeng Y, Wang X. Mechanisms of interactions between lung-origin telocytes and mesenchymal stem cells to treat experimental acute lung injury. Clin Transl Med 2020; 10:e231. [PMID: 33377639 PMCID: PMC7724099 DOI: 10.1002/ctm2.231] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 10/31/2020] [Accepted: 11/03/2020] [Indexed: 12/13/2022] Open
Abstract
Acute lung injury is a serious form and major cause of patient death and still needs efficient therapies. The present study evidenced that co-transplantation of mesenchymal stem cells (MSCs) and telocytes (TCs) improved the severity of experimental lung tissue inflammation, edema, and injury, where TCs increased MSCs migration into the lung and the capacity of MSCs proliferation and movement. Of molecular mechanisms, Osteopontin-dominant networks were active in MSCs and TCs, and might play supportive and nutrimental roles in the interaction between MSCs and TCs, especially activated TCs by lipopolysaccharide. The interaction between epidermal growth factor and its receptor from MSCs and TCs could play critical roles in communications between MSCs and TCs, responsible for MSCs proliferation and movement, especially after inflammatory activation. Our studies provide the evidence that TCs possess nutrimental and supportive roles in implanted MSCs, and co-transplantation of MSCs and TCs can be a new alternative in the therapy of acute lung injury.
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Affiliation(s)
- Ding Zhang
- Zhongshan Hospital Institute of Clinical ScienceZhongshan HospitalShanghai Medical CollegeFudan UniversityShanghaiChina
- Department of Pulmonary and Critical Care MedicineHuashan HospitalFudan UniversityShanghaiChina
| | - Dongli Song
- Zhongshan Hospital Institute of Clinical ScienceZhongshan HospitalShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Lin Shi
- Zhongshan Hospital Institute of Clinical ScienceZhongshan HospitalShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Xiaoru Sun
- Zhongshan Hospital Institute of Clinical ScienceZhongshan HospitalShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Yonghua Zheng
- Department of Respiratory MedicineShanghai Jinshan Tinglin HospitalShanghaiChina
| | - Yiming Zeng
- Department of Pulmonary and Critical Care MedicineClinical Center for Molecular Diagnosis and TherapyThe Second Affiliated Hospital of Fujian Medical UniversityQuanzhouFujian ProvinceChina
| | - Xiangdong Wang
- Zhongshan Hospital Institute of Clinical ScienceZhongshan HospitalShanghai Medical CollegeFudan UniversityShanghaiChina
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13
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Kim GB, Shon OJ. Current perspectives in stem cell therapies for osteoarthritis of the knee. Yeungnam Univ J Med 2020; 37:149-158. [PMID: 32279478 PMCID: PMC7384917 DOI: 10.12701/yujm.2020.00157] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 04/01/2020] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are emerging as an attractive option for osteoarthritis (OA) of the knee joint, due to their marked disease-modifying ability and chondrogenic potential. MSCs can be isolated from various organ tissues, such as bone marrow, adipose tissue, synovium, umbilical cord blood, and articular cartilage with similar phenotypic characteristics but different proliferation and differentiation potentials. They can be differentiated into a variety of connective tissues such as bone, adipose tissue, cartilage, intervertebral discs, ligaments, and muscles. Although several studies have reported on the clinical efficacy of MSCs in knee OA, the results lack consistency. Furthermore, there is no consensus regarding the proper cell dosage and application method to achieve the optimal effect of stem cells. Therefore, the purpose of this study is to review the characteristics of various type of stem cells in knee OA, especially MSCs. Moreover, we summarize the clinical issues faced during the application of MSCs.
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Affiliation(s)
- Gi Beom Kim
- Department of Orthopedic Surgery, Yeungnam University College of Medicine, Daegu, Korea
| | - Oog-Jin Shon
- Department of Orthopedic Surgery, Yeungnam University College of Medicine, Daegu, Korea
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14
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van Klarenbosch BR, Chamuleau SA, Teske AJ. Deformation imaging to assess global and regional effects of cardiac regenerative therapy in ischaemic heart disease: A systematic review. J Tissue Eng Regen Med 2019; 13:1872-1882. [PMID: 31314949 PMCID: PMC6852417 DOI: 10.1002/term.2937] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 06/14/2019] [Accepted: 07/11/2019] [Indexed: 01/19/2023]
Abstract
Currently, left ventricular ejection fraction (LVEF) is the most common endpoint in cardiovascular stem cell therapy research. However, this global measure of cardiac function might not be suitable to detect the regional effects sorted by this therapy and is hampered by high operator variability and loading dependency. Deformation imaging might be more accurate in detecting potential regional functional improvements by cardiac regenerative therapy. The aim of this systematic review is to provide a comprehensive overview of current literature on the value of deformation imaging in cardiac regenerative therapy. A systematic review of current literature available on PubMed, Embase, and Cochrane databases was performed regarding both animal and patient studies in which deformation imaging was used to study cardiac cell therapy. After critical appraisal, outcomes regarding study design, type of cell therapy, procedural characteristics, outcome measure, method for measuring strain, and efficacy on both LVEF and deformation parameters were depicted. A total of 30 studies, 15 preclinical and 15 clinical, were included for analysis. Deformation outcomes improved significantly in 14 out of 15 preclinical studies and in 10 out of 15 clinical studies, whereas LVEF improved in 12 and 4 articles, respectively. Study designs and used deformation outcomes varied significantly among the included papers. Six studies found a positive effect on deformation outcomes without LVEF improvement. Hence, deformation imaging seems at least equal, and perhaps superior, to LVEF measurement in the assessment of cardiac regenerative therapy. However, strategies varied substantially and call for a standardized approach.
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Affiliation(s)
| | | | - Arco J. Teske
- Department of CardiologyUniversity Medical Center UtrechtUtrechtThe Netherlands
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15
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Guo X, Gu X, Hareshwaree S, Rong X, Li L, Chu M. Induced pluripotent stem cell-conditional medium inhibits H9C2 cardiomyocytes apoptosis via autophagy flux and Wnt/β-catenin pathway. J Cell Mol Med 2019; 23:4358-4374. [PMID: 30957422 PMCID: PMC6533467 DOI: 10.1111/jcmm.14327] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 03/11/2019] [Accepted: 03/21/2019] [Indexed: 12/13/2022] Open
Abstract
Induced pluripotent stem cell‐derived conditioned medium (iPS‐CM) could improve cell viability in many types of cells and may be a better alternative for the treatment of myocardial infarction. This study aimed to examine the influence of iPS‐CM on anti‐apoptosis and the proliferation of H9C2 cardiomyocytes and investigate the underlying mechanisms. H9C2 cardiomyocytes were exposed to 200 μmol/L hydrogen peroxide (H2O2) for 24 hours with or without pre‐treatment with iPS‐CM. The ratio of apoptotic cells, the loss of mitochondrial membrane potential (△Ψm) and the levels of intracellular reactive oxygen species were analysed by flow cytometric analysis. The expression levels of BCL‐2 and BAX proteins were analysed by Western blot. Cell proliferation was assessed using cell cycle and EdU staining assays. To study cell senescence, senescence‐associated β‐galactosidase (SA‐β‐gal) staining was conducted. The levels of malondialdehyde, superoxide dismutase and glutathione were also quantified using commercially available enzymatic kits. The results showed that iPS‐CM containing basic fibroblast growth factor significantly reduced H2O2‐induced H9C2 cardiomyocyte apoptosis by activating the autophagy flux pathway, promoted cardiomyocyte proliferation by up‐regulating the Wnt/β‐catenin pathway and inhibited oxidative stress and cell senescence. In conclusion, iPS‐CM effectively enhanced the cell viability of H9C2 cardiomyocytes and could potentially be used to inhibit cardiomyocytes apoptosis to treat myocardial infarction in the future.
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Affiliation(s)
- Xiaoling Guo
- Center of Scientific Research, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaohong Gu
- Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Sohun Hareshwaree
- Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xing Rong
- Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lei Li
- Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Maoping Chu
- Center of Scientific Research, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
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16
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Cardioprotective microRNAs: Lessons from stem cell-derived exosomal microRNAs to treat cardiovascular disease. Atherosclerosis 2019; 285:1-9. [PMID: 30939341 DOI: 10.1016/j.atherosclerosis.2019.03.016] [Citation(s) in RCA: 158] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 02/28/2019] [Accepted: 03/21/2019] [Indexed: 12/20/2022]
Abstract
The stem cell-based therapy has emerged as a promising therapeutic strategy for treating cardiovascular ischemic diseases (CVIDs), such as myocardial infarction (MI). However, some important functional shortcomings of stem cell transplantation, such as immune rejection, tumorigenicity and infusional toxicity, have overshadowed stem cell therapy in the setting of cardiovascular diseases (CVDs). Accumulating evidence suggests that the therapeutic effects of transplanted stem cells are predominately mediated by secreting paracrine factors, importantly, microRNAs (miRs) present in the secreted exosomes. Therefore, novel cell-free therapy based on the stem cell-secreted exosomal miRs can be considered as a safe and effective alternative tool to stem cell therapy for the treatment of CVDs. Stem cell-derived miRs have recently been found to transfer, via exosomes, from a transplanted stem cell into a recipient cardiac cell, where they regulate various cellular process, such as proliferation, apoptosis, stress responses, as well as differentiation and angiogenesis. The present review aimed to summarize cardioprotective exosomal miRs secreted by transplanted stem cells from various sources, including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), and cardiac stem/progenitor cells, which showed beneficial modulatory effects on the myocardial infracted heart. In summary, stem cell-exosomal miRs, including miR-19a, mirR-21, miR-21-5p, miR-21-a5p, miR-22 miR-24, miR-26a, miR-29, miR-125b-5p, miR-126, miR-201, miR-210, and miR-294, have been shown to have cardioprotective effects by enhancing cardiomyocyte survival and function and attenuating cardiac fibrosis. Additionally, MCS-exosomal miRs, including miR-126, miR-210, miR-21, miR-23a-3p and miR-130a-3p, are found to exert cardioprotective effects through induction of angiogenesis in ischemic heart after MI.
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17
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Wang X, Han Z, Yu Y, Xu Z, Cai B, Yuan Y. Potential Applications of Induced Pluripotent Stem Cells for Cardiovascular Diseases. Curr Drug Targets 2018; 20:763-774. [PMID: 30539693 DOI: 10.2174/1389450120666181211164147] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 12/05/2018] [Accepted: 12/05/2018] [Indexed: 12/13/2022]
Abstract
Owning the high incidence and disability rate in the past decades, to be expected, cardiovascular diseases (CVDs) have become one of the leading death causes worldwide. Currently, induced pluripotent stem cells (iPSCs), with the potential to form fresh myocardium and improve the functions of damaged hearts, have been studied widely in experimental CVD therapy. Moreover, iPSC-derived cardiomyocytes (CMs), as novel disease models, play a significant role in drug screening, drug safety assessment, along with the exploration of pathological mechanisms of diseases. Furthermore, a lot of studies have been carried out to clarify the biological basis of iPSCs and its derived cells in the treatment of CVDs. Their molecular mechanisms were associated with release of paracrine factors, regulation of miRNAs, mechanical support of new tissues, activation of specific pathways and specific enzymes, etc. In addition, a few small chemical molecules and suitable biological scaffolds play positive roles in enhancing the efficiency of iPSC transplantation. This article reviews the development and limitations of iPSCs in CVD therapy, and summarizes the latest research achievements regarding the application of iPSCs in CVDs.
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Affiliation(s)
- Xiaotong Wang
- Department of Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Zhenbo Han
- Department of Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Ying Yu
- Department of Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Zihang Xu
- Department of Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Benzhi Cai
- Department of Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Ye Yuan
- Department of Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
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18
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Kobayashi K, Suzuki K. Mesenchymal Stem/Stromal Cell-Based Therapy for Heart Failure ― What Is the Best Source? ―. Circ J 2018; 82:2222-2232. [DOI: 10.1253/circj.cj-18-0786] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Kazuya Kobayashi
- William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London
| | - Ken Suzuki
- William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London
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19
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Generation and Applications of Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells. Stem Cells Int 2018; 2018:9601623. [PMID: 30154868 PMCID: PMC6091255 DOI: 10.1155/2018/9601623] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 06/12/2018] [Accepted: 06/20/2018] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are adult stem cells with fibroblast-like morphology and isolated from the bone marrow via plastic adhesion. Their multipotency and immunoregulatory properties make MSCs possible therapeutic agents, and an increasing number of publications and clinical trials have highlighted their potential in regenerative medicine. However, the finite proliferative capacity of MSCs limits their scalability and global dissemination as a standardized therapeutic product. Furthermore, adult tissue provenance could constrain accessibility, impinge on cellular potency, and incur greater exposure to disease-causing pathogens based on the donor. These issues could be circumvented by the derivation of MSCs from pluripotent stem cells. In this paper, we review methods that induce and characterize MSCs derived from induced pluripotent stem cells (iPSCs) and introduce MSC applications to disease modeling, pathogenic mechanisms, and drug discovery. We also discuss the potential applications of MSCs in regenerative medicine including cell-based therapies and issues that should be overcome before iPSC-derived MSC therapy will be applied in the clinic.
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20
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Hostiuc S, Marinescu M, Costescu M, Aluaș M, Negoi I. Cardiac telocytes. From basic science to cardiac diseases. II. Acute myocardial infarction. Ann Anat 2018; 218:18-27. [PMID: 29604385 DOI: 10.1016/j.aanat.2018.02.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Revised: 01/28/2018] [Accepted: 02/04/2018] [Indexed: 12/13/2022]
Abstract
INTRODUCTION The purpose of this study was to evaluate the scientific evidence regarding a potential role of telocytes in myocardial infarction. MATERIALS AND METHODS To this purpose, we performed a systematic review of relevant scientific literature, indexed in PubMed, Web of Science, and Scopus. RESULTS AND DISCUSSIONS We found six articles containing relevant studies aimed at liking myocardial infarction and telocytes. The studies that were analysed in this review failed to show, beyond a reasonable doubt, that telocytes do actually have significant roles in myocardial regeneration after myocardial infarction. The main issues to be addressed in future studies are a correct characterization of telocytes, and a differentiation from other cell types that either have similar morphologies (using electron microscopy) or similar immunophenotypes, with emphasis on endothelial progenitors, which were previously shown to have similar morphology, and functions in cardiac regeneration after myocardial infarction.
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Affiliation(s)
- Sorin Hostiuc
- Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
| | - Mihai Marinescu
- Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Mihnea Costescu
- Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Maria Aluaș
- Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Ionut Negoi
- Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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21
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Marini M, Ibba-Manneschi L, Manetti M. Cardiac Telocyte-Derived Exosomes and Their Possible Implications in Cardiovascular Pathophysiology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 998:237-254. [PMID: 28936744 DOI: 10.1007/978-981-10-4397-0_16] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Among cardiac interstitial cells, the recently described telocytes (TCs) display the unique ability to build a supportive three-dimensional network formed by their very long and thin prolongations named telopodes. Cardiac TCs are increasingly regarded as pivotal regulators in intercellular signaling with multiple cell types, such as cardiomyocytes, stem/progenitor cells, microvessels, nerve endings, fibroblasts and immune cells, thus converting the cardiac stromal compartment into an integrated system that may drive either heart development or maintenance of cardiac homeostasis in post-natal life. Besides direct intercellular communications between TCs and neighboring cells, different types of TC-released extracellular vesicles (EVs), namely exosomes, ectosomes and multivesicular cargos, may act as shuttles for paracrine molecular signal exchange between cardiac TCs and cardiomyocytes or putative cardiomyocyte progenitors. In this review, we summarize the recent research findings on cardiac TCs and their EVs. We first provide an overview of the general features of TCs, including their peculiar morphological traits and immunophenotypes, intercellular signaling mechanisms and possible functional roles. Thereafter, we describe the distribution of TCs in normal and diseased hearts, as well as their role as intercellular communicators via the release of exosomes and other types of EVs. Finally, the involvement of cardiac TCs in cardiovascular diseases and the potential utility of TC transplantation and TC-derived exosomes in cardiac regeneration and repair are discussed.
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Affiliation(s)
- Mirca Marini
- Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, Florence, 50134, Italy
| | - Lidia Ibba-Manneschi
- Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, Florence, 50134, Italy
| | - Mirko Manetti
- Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, Florence, 50134, Italy.
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22
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Luzzani CD, Miriuka SG. Pluripotent Stem Cells as a Robust Source of Mesenchymal Stem Cells. Stem Cell Rev Rep 2017; 13:68-78. [PMID: 27815690 DOI: 10.1007/s12015-016-9695-z] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Mesenchymal stem cells (MSC) have been extensively studied over the past years for the treatment of different diseases. Most of the ongoing clinical trials currently involve the use of MSC derived from adult tissues. This source may have some limitations, particularly with therapies that may require extensive and repetitive cell dosage. However, nowadays, there is a staggering growth in literature on a new source of MSC. There is now increasing evidence about the mesenchymal differentiation from pluripotent stem cell (PSC). Here, we summarize the current knowledge of pluripotent-derived mesenchymal stem cells (PD-MSC). We present a historical perspective on the subject, and then discuss some critical questions that remain unanswered.
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Affiliation(s)
- Carlos D Luzzani
- LIAN-CONICET - FLENI, Ruta 9 Km 52, 5 - (B1625XAF) Belén de Escobar, Buenos Aires, Argentina. .,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
| | - Santiago G Miriuka
- LIAN-CONICET - FLENI, Ruta 9 Km 52, 5 - (B1625XAF) Belén de Escobar, Buenos Aires, Argentina. .,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
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23
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A Tale of Two Cells: Telocyte and Stem Cell Unique Relationship. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 913:359-376. [PMID: 27796899 DOI: 10.1007/978-981-10-1061-3_23] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Telocytes have been identified as a distinctive type of interstitial cells and have been recognized in most tissues and organs. Telocytes are characterized by having extraordinary long cytoplasmic processes, telopodes, that extend to form three-dimensional networks and commonly constitute specialized forms of cell-to-cell junctions with other neighboring cells. Telocytes have been localized in the stem cell niche of different organs such as the heart, lung, skeletal muscle, and skin. Electron microscopy and electron tomography revealed a specialized link between telocytes and stem cells that postulates a potential role for telocytes during tissue regeneration and repair. In this review, the distribution of telocytes in different stem cell niches will be explored, highlighting the intimate relationship between the two types of cells and their possible functional relationship.
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24
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Wang N, Chen C, Yang D, Liao Q, Luo H, Wang X, Zhou F, Yang X, Yang J, Zeng C, Wang WE. Mesenchymal stem cells-derived extracellular vesicles, via miR-210, improve infarcted cardiac function by promotion of angiogenesis. Biochim Biophys Acta Mol Basis Dis 2017; 1863:2085-2092. [PMID: 28249798 DOI: 10.1016/j.bbadis.2017.02.023] [Citation(s) in RCA: 172] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Revised: 01/18/2017] [Accepted: 02/21/2017] [Indexed: 01/11/2023]
Abstract
Mesenchymal stem cells (MSCs) exert therapeutic effect on treating acute myocardial infarction. Recent evidence showed that paracrine function rather than direct differentiation predominately contributes to the beneficial effects of MSCs, but how the paracrine factors function are not fully elucidated. In the present study, we tested if extracellular vesicles (EVs) secreted by MSC promotes angiogenesis in infracted heart via microRNAs. Immunostaining of CD31 and matrigel plug assay were performed to detect angiogenesis in a mouse myocardial infarction (MI) model. The cardiac function and structure was examined with echocardiographic analysis. Capillary-like tube formation, migration and proliferation of human umbilical vein endothelial cells (HUVECs) were determined. As a result, MSC-EVs significantly improved angiogenesis and cardiac function in post-MI heart. MSC-EVs increased the proliferation, migration and tube formation capacity of HUVECs. MicroRNA (miR)-210 was found to be enriched in MSC-EVs. The EVs collected from MSCs with miR-210 silence largely lost the pro-angiogenic effect both in-vitro and in-vivo. The miR-210 target gene Efna3, which plays a role in angiogenesis, was down-regulated by MSC-EVs treatment in HUVECs. In conclusion, MSC-EVs are sufficient to improve angiogenesis and exert therapeutic effect on MI, its pro- angiogenesis effect might be associated with a miR-210-Efna3 dependent mechanism. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure - edited by Jun Ren & Megan Yingmei Zhang.
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Affiliation(s)
- Na Wang
- Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Caiyu Chen
- Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Dezhong Yang
- Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Qiao Liao
- Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Hao Luo
- Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Xinquan Wang
- Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Faying Zhou
- Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Xiaoli Yang
- Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Jian Yang
- Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Chunyu Zeng
- Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
| | - Wei Eric Wang
- Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
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25
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Trindade F, Leite-Moreira A, Ferreira-Martins J, Ferreira R, Falcão-Pires I, Vitorino R. Towards the standardization of stem cell therapy studies for ischemic heart diseases: Bridging the gap between animal models and the clinical setting. Int J Cardiol 2016; 228:465-480. [PMID: 27870978 DOI: 10.1016/j.ijcard.2016.11.236] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 11/09/2016] [Accepted: 11/10/2016] [Indexed: 12/20/2022]
Abstract
Today there is an increasing demand for heart transplantations for patients diagnosed with heart failure. Though, shortage of donors as well as the large number of ineligible patients hurdle such treatment option. This, in addition to the considerable number of transplant rejections, has driven the clinical research towards the field of regenerative medicine. Nonetheless, to date, several stem cell therapies tested in animal models fall by the wayside and when they meet the criteria to clinical trials, subjects often exhibit modest improvements. A main issue slowing down the admission of such therapies in the domain of human trials is the lack of protocol standardization between research groups, which hampers comparison between different approaches as well as the lack of thought regarding the clinical translation. In this sense, given the large amount of reports on stem cell therapy studies in animal models reported in the last 3years, we sought to evaluate their advantages and limitations towards the clinical setting and provide some suggestions for the forthcoming investigations. We expect, with this review, to start a new paradigm on regenerative medicine, by evoking the debate on how to plan novel stem cell therapy studies with animal models in order to achieve more consistent scientific production and accelerate the admission of stem cell therapies in the clinical setting.
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Affiliation(s)
- Fábio Trindade
- iBiMED, Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, Portugal; Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Portugal.
| | - Adelino Leite-Moreira
- Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Portugal
| | | | - Rita Ferreira
- QOPNA, Mass Spectrometry Center, Department of Chemistry, University of Aveiro, Portugal
| | - Inês Falcão-Pires
- Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Portugal
| | - Rui Vitorino
- iBiMED, Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, Portugal; Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Portugal.
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26
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Zhu Y, Wu X, Liang Y, Gu H, Song K, Zou X, Zhou G. Repair of cartilage defects in osteoarthritis rats with induced pluripotent stem cell derived chondrocytes. BMC Biotechnol 2016; 16:78. [PMID: 27829414 PMCID: PMC5103600 DOI: 10.1186/s12896-016-0306-5] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 10/18/2016] [Indexed: 12/19/2022] Open
Abstract
Background The incapacity of articular cartilage (AC) for self-repair after damage ultimately leads to the development of osteoarthritis. Stem cell-based therapy has been proposed for the treatment of osteoarthritis (OA) and induced pluripotent stem cells (iPSCs) are becoming a promising stem cell source. Results Three steps were developed to differentiate human iPSCs into chondrocytes which were transplanted into rat OA models induced by monosodium iodoacetate (MIA). After 6 days embryonic body (EB) formation and 2 weeks differentiation, the gene and protein expression of Col2A1, GAG and Sox9 has significantly increased compare to undifferentiated hiPSCs. After 15 weeks transplantation, no immune responses were observed, micro-CT showed gradual engraftment and the improvement of subchondrol plate integrity, and histological examinations demonstrated articular cartilage matrix production. Conclusions hiPSC could be an efficient and clinically translatable approach for cartilage tissue regeneration in OA cartilages.
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Affiliation(s)
- Yanxia Zhu
- Shenzhen Key Laboratory for Anti-ageing and Regenerative Medicine, Health Science Center, Shenzhen University, Shenzhen, 518060, China.
| | - Xiaomin Wu
- Shenzhen Key Laboratory for Anti-ageing and Regenerative Medicine, Health Science Center, Shenzhen University, Shenzhen, 518060, China
| | - Yuhong Liang
- Shenzhen Key Laboratory for Anti-ageing and Regenerative Medicine, Health Science Center, Shenzhen University, Shenzhen, 518060, China
| | - Hongsheng Gu
- Department of Spinal Surgery, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518060, China
| | - Kedong Song
- State Key Laboratory of Fine Chemicals, Dalian R&D Center for Stem Cell and Tissue Engineering, Dalian University of Technology, Dalian, 116024, China
| | - Xuenong Zou
- Department of Spinal Surgery, Orthopaedic Research Institute, Huangpu Division, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Guangqian Zhou
- Shenzhen Key Laboratory for Anti-ageing and Regenerative Medicine, Health Science Center, Shenzhen University, Shenzhen, 518060, China.
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27
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Cretoiu D, Radu BM, Banciu A, Banciu DD, Cretoiu SM. Telocytes heterogeneity: From cellular morphology to functional evidence. Semin Cell Dev Biol 2016; 64:26-39. [PMID: 27569187 DOI: 10.1016/j.semcdb.2016.08.023] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2016] [Accepted: 08/24/2016] [Indexed: 12/19/2022]
Abstract
Telocytes (TCs), located ubiquitously in the internal organs of vertebrates, are a heterogeneous, recently described, cell population of the stromal space. Characterized by lengthy cytoplasmic extensions that can reach tens of microns and are called telopodes (Tps), TCs are difficult to see using conventional microscopes. It was the electron microscopy which led to their first identification and Popescu's team the first responsible for the reconstructions indicating TCs 'organization' in a three-dimensional (3D) network that is believed to be accountable for the complex roles of TCs. Gradually, it became increasingly evident that TCs are difficult to characterize in terms of immunophenotype and that their phenotype is different depending on the location and needs of the tissue at one time. This review discusses the growing body of evidence accumulated since TCs were discovered and highlights how the complex interplay between TCs and stem cells might be of importance for tissue engineering and regenerative medicine.
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Affiliation(s)
- Dragos Cretoiu
- Division of Cellular and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, Bucharest 050474, Romania; 'Victor Babes' National Institute of Pathology, Bucharest 050096, Romania
| | - Beatrice Mihaela Radu
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona 37134, Italy; Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Bucharest 050095, Romania
| | - Adela Banciu
- Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Bucharest 050095, Romania
| | - Daniel Dumitru Banciu
- Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Bucharest 050095, Romania
| | - Sanda Maria Cretoiu
- Division of Cellular and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, Bucharest 050474, Romania; 'Victor Babes' National Institute of Pathology, Bucharest 050096, Romania.
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28
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Ng J, Hynes K, White G, Sivanathan KN, Vandyke K, Bartold PM, Gronthos S. Immunomodulatory Properties of Induced Pluripotent Stem Cell-Derived Mesenchymal Cells. J Cell Biochem 2016; 117:2844-2853. [DOI: 10.1002/jcb.25596] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 05/10/2016] [Indexed: 12/23/2022]
Affiliation(s)
- Jia Ng
- Colgate Australian Clinical Dental Research Centre; School of Dentistry; University of Adelaide; Adelaide South Australia Australia
| | - Kim Hynes
- Colgate Australian Clinical Dental Research Centre; School of Dentistry; University of Adelaide; Adelaide South Australia Australia
| | - Gregory White
- Colgate Australian Clinical Dental Research Centre; School of Dentistry; University of Adelaide; Adelaide South Australia Australia
- Mesenchymal Stem Cell Laboratory; School of Medicine; Faculty of Health Sciences; University of Adelaide; Adelaide South Australia Australia
| | - Kisha Nandini Sivanathan
- Mesenchymal Stem Cell Laboratory; School of Medicine; Faculty of Health Sciences; University of Adelaide; Adelaide South Australia Australia
- Centre for Clinical and Experimental Transplantation; Royal Adelaide Hospital; Adelaide South Australia Australia
| | - Kate Vandyke
- Myeloma Research Laboratory; School of Medicine; Faculty of Health Sciences; University of Adelaide; Adelaide South Australia Australia
- South Australian Health and Medical Research Institute; Adelaide South Australia Australia
- SA Pathology; Adelaide; South Australia Australia
| | - Peter Mark Bartold
- Colgate Australian Clinical Dental Research Centre; School of Dentistry; University of Adelaide; Adelaide South Australia Australia
| | - Stan Gronthos
- Mesenchymal Stem Cell Laboratory; School of Medicine; Faculty of Health Sciences; University of Adelaide; Adelaide South Australia Australia
- South Australian Health and Medical Research Institute; Adelaide South Australia Australia
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29
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Tanavde V, Vaz C, Rao MS, Vemuri MC, Pochampally RR. Research using Mesenchymal Stem/Stromal Cells: quality metric towards developing a reference material. Cytotherapy 2016; 17:1169-77. [PMID: 26276001 DOI: 10.1016/j.jcyt.2015.07.008] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Revised: 06/25/2015] [Accepted: 07/09/2015] [Indexed: 02/07/2023]
Abstract
Mesenchymal stem/stromal cells (MSCs) have been extensively investigated for their regenerative, immune-modulatory, and wound healing properties. While the laboratory studies have suggested that MSC's have a unique potential for modulating the etiopathology of multiple diseases, the results from clinical trials have not been encouraging or reproducible. One of the explanations for such variability is explained by the "art" of isolating and propagating MSCs. Therefore, establishing more than minimal criteria to define MSC would help understand best protocols to isolate, propagate and deliver MSCs. Developing a calibration standard, a database and a set of functional tests would be a better quality metric for MSCs. In this review, we discuss the importance of selecting a standard, issues associated with coming up with such a standard and how these issues can be mitigated.
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Affiliation(s)
- Vivek Tanavde
- Bioinformatics Institute, Agency for Science Technology and Research (A*STAR), Singapore 138671; Institute for Medical Biology, A∗STAR, Singapore 138648
| | - Candida Vaz
- Bioinformatics Institute, Agency for Science Technology and Research (A*STAR), Singapore 138671
| | - Mahendra S Rao
- Q Thera, NYSCF, Regenerative Medicine, NYSTEM, Albany, NY
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30
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Chen G, Yue A, Yu H, Ruan Z, Yin Y, Wang R, Ren Y, Zhu L. Mesenchymal Stem Cells and Mononuclear Cells From Cord Blood: Cotransplantation Provides a Better Effect in Treating Myocardial Infarction. Stem Cells Transl Med 2016; 5:350-357. [PMID: 26798061 PMCID: PMC4807668 DOI: 10.5966/sctm.2015-0199] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 10/28/2015] [Indexed: 11/16/2022] Open
Abstract
The aim of this study was to evaluate the effect of cotransplanting mononuclear cells from cord blood (CB-MNCs) and mesenchymal stem cells (MSCs) as treatment for myocardial infarction (MI). Transplanting CD34+ cells or MSCs separately has been shown effective in treating MI, but the effect of cotransplanting CB-MNCs and MSCs is not clear. In this study, MSCs were separated by their adherence to the tissue culture. The morphology, immunophenotype, and multilineage potential of MSCs were analyzed. CB-MNCs were separated in lymphocyte separation medium 1.077. CD34+ cell count and viability were analyzed by flow cytometry. Infarcted male Sprague-Dawley rats in a specific-pathogen-free grade were divided into four treatment groups randomly: group I, saline; group II, CB-MNCs; group III, MSCs; and group IV, CB-MNCs plus MSCs. The saline, and CB-MNCs and/or MSCs were injected intramyocardially in infarcted rats. Their cardiac function was evaluated by echocardiography. The myocardial capillary density was analyzed by immunohistochemistry. Both cell types induced an improvement in the left ventricular cardiac function and increased tissue cell proliferation in myocardial tissue and neoangiogenesis. However, CB-MNCs plus MSCs were more effective in reducing the infarct size and preventing ventricular remodeling. Scar tissue was reduced significantly in the CB-MNCs plus MSCs group. MSCs facilitate engraftment of CD34+ cells and immunomodulation after allogeneic CD34+ cell transplantation. Cotransplanting MSCs and CB-MNCs might be more effective than transplanting MSCs or CB-MNCs separately for treating MI. This study contributes knowledge toward effective treatment strategies for MI.
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Affiliation(s)
- Gecai Chen
- Department of Cardiology, Taizhou People Hospital, Taizhou, Jiangsu Province, People's Republic of China
| | - Aihuan Yue
- Jiangsu Province Stem Cell Bank, Taizhou, Jiangsu Province, People's Republic of China
| | - Hong Yu
- Department of Pathology, Taizhou People Hospital, Taizhou, Jiangsu Province, People's Republic of China
| | - Zhongbao Ruan
- Department of Cardiology, Taizhou People Hospital, Taizhou, Jiangsu Province, People's Republic of China
| | - Yigang Yin
- Department of Cardiology, Taizhou People Hospital, Taizhou, Jiangsu Province, People's Republic of China
| | - Ruzhu Wang
- Department of Cardiology, Taizhou People Hospital, Taizhou, Jiangsu Province, People's Republic of China
| | - Yin Ren
- Department of Cardiology, Taizhou People Hospital, Taizhou, Jiangsu Province, People's Republic of China
| | - Li Zhu
- Department of Cardiology, Taizhou People Hospital, Taizhou, Jiangsu Province, People's Republic of China
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31
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A Shh coreceptor Cdo is required for efficient cardiomyogenesis of pluripotent stem cells. J Mol Cell Cardiol 2016; 93:57-66. [PMID: 26906632 DOI: 10.1016/j.yjmcc.2016.01.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 01/13/2016] [Indexed: 11/20/2022]
Abstract
Sonic hedgehog (Shh) signaling plays an important role for early heart development, such as heart looping and cardiomyogenesis of pluripotent stem cells. A multifunctional receptor Cdo functions as a Shh coreceptor together with Boc and Gas1 to activate Shh signaling and these coreceptors seem to play compensatory roles in early heart development. Thus in this study, we examined the role of Cdo in cardiomyogenesis by utilizing an in vitro differentiation of pluripotent stem cells. Here we show that Cdo is required for efficient cardiomyogenesis of pluripotent stem cells by activation of Shh signaling. Cdo is induced concurrently with Shh signaling activation upon induction of cardiomyogenesis of P19 embryonal carcinoma (EC) cells. Cdo-depleted P19 EC and Cdo(-/-) mouse embryonic stem (ES) cells display decreased expression of key cardiac regulators, including Gata4, Nkx2.5 and Mef2c and this decrease coincides with reduced Shh signaling activities. Furthermore Cdo deficiency causes a stark reduction in formation of mature contractile cardiomyocytes. This defect in cardiomyogenesis is overcome by reactivation of Shh signaling at the early specification stage of cardiomyogenesis. The Shh agonist treatment restores differentiation capacities of Cdo-deficient ES cells into contractile cardiomyocytes by recovering both the expression of early cardiac regulators and structural genes such as cardiac troponin T and Connexin 43. Therefore Cdo is required for efficient cardiomyogenesis of pluripotent stem cells and an excellent target to improve the differentiation potential of stem cells for generation of transplantable cells to treat cardiomyopathies.
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32
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Bei Y, Zhou Q, Sun Q, Xiao J. Telocytes in cardiac regeneration and repair. Semin Cell Dev Biol 2016; 55:14-21. [PMID: 26826525 DOI: 10.1016/j.semcdb.2016.01.037] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2016] [Accepted: 01/24/2016] [Indexed: 02/08/2023]
Abstract
Telocytes (TCs) are a novel type of stromal cells reported by Popescu's group in 2010. The unique feature that distinguishes TCs from other "classical" stromal cells is their extremely long and thin telopodes (Tps). As evidenced by electron microscopy, TCs are widely distributed in almost all tissues and organs. TCs contribute to form a three-dimensional interstitial network and play as active regulators in intercellular communication via homocellular/heterocellular junctions or shed vesicles. Interestingly, increasing evidence suggests the potential role of TCs in regenerative medicine. Although the heart retains some limited endogenous regenerative capacity, cardiac regenerative and repair response is however insufficient to make up the loss of cardiomyocytes upon injury. Developing novel strategies to increase cardiomyocyte renewal and repair is of great importance for the treatment of cardiac diseases. In this review, we focus on the role of TCs in cardiac regeneration and repair. We particularly describe the intercellular communication between TCs and cardiomyocytes, stem/progenitor cells, endothelial cells, and fibroblasts. Also, we discuss the current knowledge about TCs in cardiac repair after myocardial injury, as well as their potential roles in cardiac development and aging. TC-based therapy or TC-derived exosome delivery might be used as novel therapeutic strategies to promote cardiac regeneration and repair.
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Affiliation(s)
- Yihua Bei
- Regeneration and Aging Lab, Experimental Center of Life Sciences, School of Life Science, Shanghai University, Shanghai 200444, China; Shanghai Key Laboratory of Bio-Energy Crops, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Qiulian Zhou
- Regeneration and Aging Lab, Experimental Center of Life Sciences, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Qi Sun
- Regeneration and Aging Lab, Experimental Center of Life Sciences, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Junjie Xiao
- Regeneration and Aging Lab, Experimental Center of Life Sciences, School of Life Science, Shanghai University, Shanghai 200444, China; Shanghai Key Laboratory of Bio-Energy Crops, School of Life Science, Shanghai University, Shanghai 200444, China.
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33
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Ibba-Manneschi L, Rosa I, Manetti M. Telocyte implications in human pathology: An overview. Semin Cell Dev Biol 2016; 55:62-9. [PMID: 26805444 DOI: 10.1016/j.semcdb.2016.01.022] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 01/18/2016] [Indexed: 12/23/2022]
Abstract
Telocytes are a recently described interstitial cell population widely distributed in the stromal compartment of many organs in vertebrates, including humans. Owing to their close spatial relationship with multiple cell types, telocytes are universally considered as 'connecting cells' mostly committed to intercellular signaling by converting the interstitium into an integrated system that drives organ development and contributes to the maintenance of local tissue homeostasis. Increasing evidence indicates that telocytes may cooperate with tissue-resident stem cells to foster organ repair and regeneration, and that telocyte damage and dysfunction may occur in several disorders. The goal of this review is to provide an overview of the most recent findings concerning the implication of telocytes in a variety of pathologic conditions in humans, including heart disease, chronic inflammation and multiorgan fibrosis. Based on recent promising experimental data, there is realistic hope that by targeting telocytes alone or in tandem with stem cells, we might be able to promote organ regeneration and/or prevent irreversible end-stage organ damage in different pathologies.
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Affiliation(s)
- Lidia Ibba-Manneschi
- Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, 50134 Florence, Italy
| | - Irene Rosa
- Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, 50134 Florence, Italy
| | - Mirko Manetti
- Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, 50134 Florence, Italy.
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34
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Shim W. Myocardial Telocytes: A New Player in Electric Circuitry of the Heart. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 913:241-251. [PMID: 27796892 DOI: 10.1007/978-981-10-1061-3_16] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
The heart is an electrically conducting organ with networked bioelectric currents that transverse a large segment of interstitial space interspersed with the muscular parenchyma. Non-excitable connective cells in the interstitial space contributed importantly to many structural, biochemical, and physiological activities of cardiac homeostasis. However, contribution of interstitial cells in the cardiac niche has long been neglected. Telocyte is recently recognized as a distinct class of interstitial cell that resides in a wide array of tissues including in the epicardium, myocardium, and endocardium of the heart. They are increasingly described to conduct ionic currents that may have significant implications in bioelectric signaling. In this review, we highlight the significance of telocytes in such connectivity and conductivity within the interstitial bioelectric network in tissue homeostasis.
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Affiliation(s)
- Winston Shim
- National Heart Research Institute Singapore, 5 Hospital Drive, National Heart Centre Singapore, Singapore, 169609, Singapore.
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore.
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35
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Sun QW, Zhen L, Wang Q, Sun Y, Yang J, Li YJ, Li RJ, Ma N, Li ZA, Wang LY, Nie SP, Yang Y. Assessment of Retrograde Coronary Venous Infusion of Mesenchymal Stem Cells Combined with Basic Fibroblast Growth Factor in Canine Myocardial Infarction Using Strain Values Derived from Speckle-Tracking Echocardiography. ULTRASOUND IN MEDICINE & BIOLOGY 2016; 42:272-281. [PMID: 26520563 DOI: 10.1016/j.ultrasmedbio.2015.09.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/14/2015] [Revised: 08/29/2015] [Accepted: 09/08/2015] [Indexed: 06/05/2023]
Abstract
Speckle-tracking echocardiography was used to assess retrograde coronary venous infusion of mesenchymal stem cells (MSCs) combined with basic fibroblast growth factor (bFGF) in a canine model of acute myocardial infarction (AMI). AMI was induced by ligation of the left anterior descending coronary artery. Coronary venous retroperfusion was performed at 1 wk after AMI. Twenty-eight animals were randomized into four groups: saline, bFGF+saline, saline+MSCs and bFGF+MSCs. Echocardiography was performed before AMI, at 7 d post-AMI and 40 d after retroperfusion. Apoptotic cardiomyocytes in the border zone of the ischemic region were evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling. Vascular endothelial growth factor and factor VIII concentrations were measured by western blotting. The left ventricular end-systolic volume increased significantly, whereas the left ventricular ejection fraction and global and segmental strain values decreased significantly after AMI. After retroperfusion, the strain values of the infarct zone, but not conventional echocardiographic parameters, were significantly different between control and bFGF+MSC groups. Cardiomyocyte apoptosis decreased, whereas vascular endothelial growth factor and factor VIII concentrations were higher in the bFGF+MSC, bFGF and MSC groups. Cardiomyocyte apoptosis was well correlated with the strain values. Although retrograde coronary venous infusion of bFGF and MSCs promoted neo-vascularization of the infarcted myocardium and inhibited apoptosis, there was only a slight strain improvement without a substantial increase in global cardiac functions.
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Affiliation(s)
- Qi-Wei Sun
- Ultrasound Department, Beijing AnZhen Hospital Affiliated with Capital Medical University, Beijing, China
| | - Lei Zhen
- Emergency & Critical Care Center of Beijing AnZhen Hospital Affiliated with Capital Medical University, Beijing, China
| | - Qin Wang
- Ultrasound Department, Beijing AnZhen Hospital Affiliated with Capital Medical University, Beijing, China
| | - Yan Sun
- Ultrasound Department, Beijing AnZhen Hospital Affiliated with Capital Medical University, Beijing, China
| | - Jiao Yang
- Ultrasound Department, Beijing AnZhen Hospital Affiliated with Capital Medical University, Beijing, China
| | - Yi-Jia Li
- Ultrasound Department, Beijing AnZhen Hospital Affiliated with Capital Medical University, Beijing, China
| | - Rong-Juan Li
- Ultrasound Department, Beijing AnZhen Hospital Affiliated with Capital Medical University, Beijing, China
| | - Ning Ma
- Ultrasound Department, Beijing AnZhen Hospital Affiliated with Capital Medical University, Beijing, China
| | - Zhi-An Li
- Ultrasound Department, Beijing AnZhen Hospital Affiliated with Capital Medical University, Beijing, China
| | - Lu-Ya Wang
- Beijing Institute of Heart, Lung, and Blood Vessel Diseases and The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China
| | - Shao-Ping Nie
- Emergency & Critical Care Center of Beijing AnZhen Hospital Affiliated with Capital Medical University, Beijing, China
| | - Ya Yang
- Ultrasound Department, Beijing AnZhen Hospital Affiliated with Capital Medical University, Beijing, China.
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36
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Telocytes in Cardiac Tissue Architecture and Development. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 913:127-137. [PMID: 27796884 DOI: 10.1007/978-981-10-1061-3_8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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37
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Ja KPMM, Miao Q, Zhen Tee NG, Lim SY, Nandihalli M, Ramachandra CJA, Mehta A, Shim W. iPSC-derived human cardiac progenitor cells improve ventricular remodelling via angiogenesis and interstitial networking of infarcted myocardium. J Cell Mol Med 2015; 20:323-32. [PMID: 26612359 PMCID: PMC4727567 DOI: 10.1111/jcmm.12725] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Accepted: 09/29/2015] [Indexed: 12/27/2022] Open
Abstract
We investigate the effects of myocardial transplantation of human induced pluripotent stem cell (iPSC)‐derived progenitors and cardiomyocytes into acutely infarcted myocardium in severe combined immune deficiency mice. A total of 2 × 105 progenitors, cardiomyocytes or cell‐free saline were injected into peri‐infarcted anterior free wall. Sham‐operated animals received no injection. Myocardial function was assessed at 2‐week and 4‐week post‐infarction by using echocardiography and pressure‐volume catheterization. Early myocardial remodelling was observed at 2‐week with echocardiography derived stroke volume (SV) in saline (20.45 ± 7.36 μl, P < 0.05) and cardiomyocyte (19.52 ± 3.97 μl, P < 0.05) groups, but not in progenitor group (25.65 ± 3.61 μl), significantly deteriorated as compared to sham control group (28.41 ± 4.41 μl). Consistently, pressure–volume haemodynamic measurements showed worsening chamber dilation in saline (EDV: 23.24 ± 5.01 μl, P < 0.05; ESV: 17.08 ± 5.82 μl, P < 0.05) and cardiomyocyte (EDV: 26.45 ± 5.69 μl, P < 0.05; ESV: 18.03 ± 6.58 μl, P < 0.05) groups by 4‐week post‐infarction as compared to control (EDV: 15.26 ± 2.96 μl; ESV: 8.41 ± 2.94 μl). In contrast, cardiac progenitors (EDV: 20.09 ± 7.76 μl; ESV: 13.98 ± 6.74 μl) persistently protected chamber geometry against negative cardiac remodelling. Similarly, as compared to sham control (54.64 ± 11.37%), LV ejection fraction was preserved in progenitor group from 2‐(38.68 ± 7.34%) to 4‐week (39.56 ± 13.26%) while cardiomyocyte (36.52 ± 11.39%, P < 0.05) and saline (35.34 ± 11.86%, P < 0.05) groups deteriorated early at 2‐week. Improvements of myocardial function in the progenitor group corresponded to increased vascularization (16.12 ± 1.49/mm2 to 25.48 ± 2.08/mm2 myocardial tissue, P < 0.05) and coincided with augmented networking of cardiac telocytes in the interstitial space of infarcted zone.
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Affiliation(s)
- K P Myu Mia Ja
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore
| | - Qingfeng Miao
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore.,Department of Pharmacology, Hebei Medical University, Shijiazhuang, China
| | - Nicole Gui Zhen Tee
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore
| | - Sze Yun Lim
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore
| | - Manasi Nandihalli
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore
| | | | - Ashish Mehta
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore.,DUKE-NUS Graduate Medical School
| | - Winston Shim
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore.,DUKE-NUS Graduate Medical School
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38
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Ong SG, Huber BC, Lee WH, Kodo K, Ebert AD, Ma Y, Nguyen PK, Diecke S, Chen WY, Wu JC. Microfluidic Single-Cell Analysis of Transplanted Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes After Acute Myocardial Infarction. Circulation 2015; 132:762-771. [PMID: 26304668 DOI: 10.1161/circulationaha.114.015231] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Human induced pluripotent stem cells (iPSCs) are attractive candidates for therapeutic use, with the potential to replace deficient cells and to improve functional recovery in injury or disease settings. Here, we test the hypothesis that human iPSC-derived cardiomyocytes (iPSC-CMs) can secrete cytokines as a molecular basis to attenuate adverse cardiac remodeling after myocardial infarction. METHODS AND RESULTS Human iPSCs were generated from skin fibroblasts and differentiated in vitro with a small molecule-based protocol. Troponin(+) iPSC-CMs were confirmed by immunohistochemistry, quantitative polymerase chain reaction, fluorescence-activated cell sorting, and electrophysiological measurements. Afterward, 2×10(6) iPSC-CMs derived from a cell line transduced with a vector expressing firefly luciferase and green fluorescent protein were transplanted into adult NOD/SCID mice with acute left anterior descending artery ligation. Control animals received PBS injection. Bioluminescence imaging showed limited engraftment on transplantation into ischemic myocardium. However, magnetic resonance imaging of animals transplanted with iPSC-CMs showed significant functional improvement and attenuated cardiac remodeling compared with PBS-treated control animals. To understand the underlying molecular mechanism, microfluidic single-cell profiling of harvested iPSC-CMs, laser capture microdissection of host myocardium, and in vitro ischemia stimulation were used to demonstrate that the iPSC-CMs could release significant levels of proangiogenic and antiapoptotic factors in the ischemic microenvironment. CONCLUSIONS Transplantation of human iPSC-CMs into an acute mouse myocardial infarction model can improve left ventricular function and attenuate cardiac remodeling. Because of limited engraftment, most of the effects are possibly explained by paracrine activity of these cells.
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Affiliation(s)
- Sang-Ging Ong
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.,Depts of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA.,Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA
| | - Bruno C Huber
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.,Depts of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA.,Ludwig-Maximilians-University, Medical Department I, Campus Grosshadern, Munich, Germany
| | - Won Hee Lee
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.,Depts of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA
| | - Kazuki Kodo
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.,Depts of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA
| | - Antje D Ebert
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.,Depts of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA
| | - Yu Ma
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.,Depts of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA
| | - Patricia K Nguyen
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.,Depts of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA
| | - Sebastian Diecke
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.,Depts of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA
| | - Wen-Yi Chen
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.,Depts of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA
| | - Joseph C Wu
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.,Depts of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA.,Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA
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39
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Bei Y, Wang F, Yang C, Xiao J. Telocytes in regenerative medicine. J Cell Mol Med 2015; 19:1441-54. [PMID: 26059693 PMCID: PMC4511344 DOI: 10.1111/jcmm.12594] [Citation(s) in RCA: 110] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 03/15/2015] [Indexed: 12/13/2022] Open
Abstract
Telocytes (TCs) are a distinct type of interstitial cells characterized by a small cell body and extremely long and thin telopodes (Tps). The presence of TCs has been documented in many tissues and organs (go to http://www.telocytes.com). Functionally, TCs form a three-dimensional (3D) interstitial network by homocellular and heterocellular communication and are involved in the maintenance of tissue homeostasis. As important interstitial cells to guide or nurse putative stem and progenitor cells in stem cell niches in a spectrum of tissues and organs, TCs contribute to tissue repair and regeneration. This review focuses on the latest progresses regarding TCs in the repair and regeneration of different tissues and organs, including heart, lung, skeletal muscle, skin, meninges and choroid plexus, eye, liver, uterus and urinary system. By targeting TCs alone or in tandem with stem cells, we might promote regeneration and prevent the evolution to irreversible tissue damage. Exploring pharmacological or non-pharmacological methods to enhance the growth of TCs would be a novel therapeutic strategy besides exogenous transplantation for many diseased disorders.
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Affiliation(s)
- Yihua Bei
- Regeneration and Ageing Lab, Experimental Center of Life Sciences, School of Life Science, Shanghai UniversityShanghai, China
| | - Fei Wang
- Division of Gastroenterology and Hepatology, Digestive Disease Institute, Shanghai Tongji Hospital, Tongji University School of MedicineShanghai, China
| | - Changqing Yang
- Division of Gastroenterology and Hepatology, Digestive Disease Institute, Shanghai Tongji Hospital, Tongji University School of MedicineShanghai, China
| | - Junjie Xiao
- Regeneration and Ageing Lab, Experimental Center of Life Sciences, School of Life Science, Shanghai UniversityShanghai, China
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40
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Geuss LR, Allen ACB, Ramamoorthy D, Suggs LJ. Maintenance of HL-1 cardiomyocyte functional activity in PEGylated fibrin gels. Biotechnol Bioeng 2015; 112:1446-56. [PMID: 25657056 DOI: 10.1002/bit.25553] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Revised: 01/13/2015] [Accepted: 01/18/2015] [Indexed: 01/16/2023]
Abstract
Successful cellular cardiomyoplasty is dependent on biocompatible materials that can retain the cells in the myocardium in order to promote host tissue repair following myocardial infarction. A variety of methods have been explored for incorporating a cell-seeded matrix into the heart, the most popular options being direct application of an injectable system or surgical implantation of a patch. Fibrin-based gels are suitable for either of these approaches, as they are biocompatible and have mechanical properties that can be tailored by adjusting the initial fibrinogen concentration. We have previously demonstrated that conjugating amine-reactive homo-bifunctional polyethylene glycol (PEG) to the fibrinogen prior to crosslinking with thrombin can increase stability both in vivo and in vitro. Similarly, when mesenchymal stem cells are combined with PEGylated fibrin and injected into the myocardium, cell retention can be significantly increased and scar tissue reduced following myocardial infarction. We hypothesized that this gel system could similarly promote cardiomyocyte viability and function in vitro, and that optimizing the mechanical properties of the hydrogel would enhance contractility. In this study, we cultured HL-1 cardiomyocytes either on top of plated PEGylated fibrin (2D) or embedded in 3D gels and evaluated cardiomyocyte function by assessing the expression of cardiomyocyte specific markers, sarcomeric α-actin, and connexin 43, as well as contractile activity. We observed that the culture method can drastically affect the functional phenotype of HL-1 cardiomyocytes, and we present data suggesting the potential use of PEGylated fibrin gel layers to prepare a sheet-like construct for myocardial regeneration.
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Affiliation(s)
- Laura R Geuss
- Institute of Cell and Molecular Biology, The University of Texas at Austin, Austin, Texas
| | - Alicia C B Allen
- Department of Biomedical Engineering, The University of Texas at Austin, 107 W. Dean Keeton, C0800, Austin, Texas, 78712
| | - Divya Ramamoorthy
- Department of Biomedical Engineering, The University of Texas at Austin, 107 W. Dean Keeton, C0800, Austin, Texas, 78712
| | - Laura J Suggs
- Department of Biomedical Engineering, The University of Texas at Austin, 107 W. Dean Keeton, C0800, Austin, Texas, 78712.
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