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1
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Shabo I, Midtbö K, Bränström R, Lindström A. Monocyte-cancer cell fusion is mediated by phosphatidylserine-CD36 receptor interaction and induced by ionizing radiation. PLoS One 2025; 20:e0311027. [PMID: 39752516 PMCID: PMC11698428 DOI: 10.1371/journal.pone.0311027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 09/11/2024] [Indexed: 01/06/2025] Open
Abstract
Emerging evidence suggests that fusion of cancer cells with leucocytes, such as macrophages, plays a significant role in cancer metastasis and results in tumor hybrid cells that acquire resistance to chemo- and radiation therapy. However, the precise mechanisms behind the leukocyte-cancer cell fusion remain unclear. The present in vitro study explores the presence of fusion between the monocyte cell line (THP-1) and the breast cancer cell line (MCF-7) in relation to the expression of CD36 and phosphatidylserine with and without treatment of these cells with ionizing radiation. The study reveals that spontaneous THP-1/MCF-7 cell fusion increases significantly from 2.8% to 6% after irradiation. The interaction between CD36 and phosphatidylserine plays a pivotal role in THP-1/MCF-7 cell fusion, as inhibiting this interaction using anti-CD36 antibodies significantly reduces cell fusion. While irradiation leads to a dose-dependent escalation in phosphatidylserine expression in MCF-7 cells, it does not impact the expression of CD36 in either THP-1 or MCF-7 cells. To the best of our knowledge, this is the first study to demonstrate the involvement of the CD36-phosphatidylserine interaction in the fusion between monocytes and cancer cells, shedding light on a novel explanatory mechanism for the roles of CD36 and phosphatidylserine in tumor progression.
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Affiliation(s)
- Ivan Shabo
- Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Breast Cancer, Sarcoma and Endocrine Tumors, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden
| | - Kristine Midtbö
- Division of Cell- and Neurobiology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Robert Bränström
- Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Breast Cancer, Sarcoma and Endocrine Tumors, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden
| | - Annelie Lindström
- Division of Cell- and Neurobiology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
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2
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Fiorino E, Rossin D, Vanni R, Aubry M, Giachino C, Rastaldo R. Recent Insights into Endogenous Mammalian Cardiac Regeneration Post-Myocardial Infarction. Int J Mol Sci 2024; 25:11747. [PMID: 39519298 PMCID: PMC11546116 DOI: 10.3390/ijms252111747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 10/29/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024] Open
Abstract
Myocardial infarction (MI) is a critical global health issue and a leading cause of heart failure. Indeed, while neonatal mammals can regenerate cardiac tissue mainly through cardiomyocyte proliferation, this ability is lost shortly after birth, resulting in the adult heart's inability to regenerate after injury effectively. In adult mammals, the adverse cardiac remodelling, which compensates for the loss of cardiac cells, impairs cardiac function due to the non-contractile nature of fibrotic tissue. Moreover, the neovascularisation after MI is inadequate to restore blood flow to the infarcted myocardium. This review aims to synthesise the most recent insights into the molecular and cellular players involved in endogenous myocardial and vascular regeneration, facilitating the identification of mechanisms that could be targeted to trigger cardiac regeneration, reduce fibrosis, and improve functional recovery post-MI. Reprogramming adult cardiomyocytes to regain their proliferative potential, along with the modulation of target cells responsible for neovascularisation, represents promising therapeutic strategies. An updated overview of endogenous mechanisms that regulate both myocardial and coronary vasculature regeneration-including stem and progenitor cells, growth factors, cell cycle regulators, and key signalling pathways-could help identify new critical intervention points for therapeutic applications.
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Affiliation(s)
| | | | | | | | | | - Raffaella Rastaldo
- Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, 10043 Orbassano, Italy; (E.F.); (D.R.); (R.V.); (M.A.); (C.G.)
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3
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Prencipe G, Cerveró-Varona A, Perugini M, Sulcanese L, Iannetta A, Haidar-Montes AA, Stöckl J, Canciello A, Berardinelli P, Russo V, Barboni B. Amphiregulin orchestrates the paracrine immune-suppressive function of amniotic-derived cells through its interplay with COX-2/PGE 2/EP4 axis. iScience 2024; 27:110508. [PMID: 39156643 PMCID: PMC11326934 DOI: 10.1016/j.isci.2024.110508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 06/10/2024] [Accepted: 07/11/2024] [Indexed: 08/20/2024] Open
Abstract
The paracrine crosstalk between amniotic-derived membranes (AMs)/epithelial cells (AECs) and immune cells is pivotal in tissue healing following inflammation. Despite evidence collected to date, gaps in understanding the underlying molecular mechanisms have hindered clinical applications. The present study represents a significant step forward demonstrating that amphiregulin (AREG) orchestrates the native immunomodulatory functions of amniotic derivatives via the COX-2/PGE2/EP4 axis. The results highlight the immunosuppressive efficacy of PGE2-dependent AREG release, dampening PBMCs' activation, and NFAT pathway in Jurkat reporter cells via TGF-β signaling. Moreover, AREG emerges as a key protein mediator by attenuating acute inflammatory response in Tg(lysC:DsRed2) zebrafish larvae. Notably, the interplay of diverse COX-2/PGE2 pathway activators enables AM/AEC to adapt rapidly to external stimuli (LPS and/or stretching) through a responsive positive feedback loop on the AREG/EGFR axis. These findings offer valuable insights for developing innovative cell-free therapies leveraging the potential of amniotic derivatives in immune-mediated diseases and regenerative medicine.
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Affiliation(s)
- Giuseppe Prencipe
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Adrián Cerveró-Varona
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Monia Perugini
- Department of Bioscience and Agro-Food and Environmental Technology, University of Teramo, Teramo, Italy
| | - Ludovica Sulcanese
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Annamaria Iannetta
- Department of Bioscience and Agro-Food and Environmental Technology, University of Teramo, Teramo, Italy
| | - Arlette Alina Haidar-Montes
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Johannes Stöckl
- Centre for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Medical University of Vienna, Vienna 1090, Austria
| | - Angelo Canciello
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Paolo Berardinelli
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Valentina Russo
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Barbara Barboni
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
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Kaviani M, Soleimanian S, Keshtkar S, Azarpira N, Asvar Z, Pakbaz S. Molecular Prospective on Malignant Transformation of Mesenchymal Stem Cells: An Issue in Cell Therapy. Cell Reprogram 2024; 26:96-106. [PMID: 38917438 DOI: 10.1089/cell.2024.0026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/27/2024] Open
Abstract
Mesenchymal stem cell (MSCs) therapy, as a rapidly developing area of medicine, holds great promise for the treatment of a variety of medical conditions. MSCs are multipotent stem cells that can be isolated from various tissues and could self-renew and differentiate. They secrete cytokines and trophic factors that create a regenerative microenvironment and have immunomodulatory properties. Although clinical trials have been conducted with MSCs in various diseases, concerns regarding the possibility of malignant transformation of these cells have been raised. The studies showed a higher rate of hematological malignancy and carcinogenesis in experimental models after MSC transplantation. The mechanisms underlying malignant transformation of MSCs are complex and not fully understood, but they are believed to involve the presence of special signaling molecules and alterations in cell behavior regulation pathways. Possible pathways that lead to MSCs' oncogenic transformation occur through two mechanisms: spontaneous and stimulated malignant transformation, including cell fusion, fusion proteins, and the tumor microenvironment. MSC-based therapies have the potential to revolutionize medicine, and addressing the issue of malignancy is crucial to ensure their safety and efficacy. Therefore, the purpose of the present review is to summarize the potential mechanisms of the malignant transformation of MSCs. [Figure: see text].
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Affiliation(s)
- Maryam Kaviani
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saeede Soleimanian
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Allergy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Somayeh Keshtkar
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Molecular Dermatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Asvar
- Nanotechnology School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sara Pakbaz
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine & Pathobiology, Mount Sinai Hospital, Toronto, ON, Canada
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5
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Budzynska K, Siemionow M, Stawarz K, Chambily L, Siemionow K. Chimeric Cell Therapies as a Novel Approach for Duchenne Muscular Dystrophy (DMD) and Muscle Regeneration. Biomolecules 2024; 14:575. [PMID: 38785982 PMCID: PMC11117592 DOI: 10.3390/biom14050575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/06/2024] [Accepted: 05/11/2024] [Indexed: 05/25/2024] Open
Abstract
Chimerism-based strategies represent a pioneering concept which has led to groundbreaking advancements in regenerative medicine and transplantation. This new approach offers therapeutic potential for the treatment of various diseases, including inherited disorders. The ongoing studies on chimeric cells prompted the development of Dystrophin-Expressing Chimeric (DEC) cells which were introduced as a potential therapy for Duchenne Muscular Dystrophy (DMD). DMD is a genetic condition that leads to premature death in adolescent boys and remains incurable with current methods. DEC therapy, created via the fusion of human myoblasts derived from normal and DMD-affected donors, has proven to be safe and efficacious when tested in experimental models of DMD after systemic-intraosseous administration. These studies confirmed increased dystrophin expression, which correlated with functional and morphological improvements in DMD-affected muscles, including cardiac, respiratory, and skeletal muscles. Furthermore, the application of DEC therapy in a clinical study confirmed its long-term safety and efficacy in DMD patients. This review summarizes the development of chimeric cell technology tested in preclinical models and clinical studies, highlighting the potential of DEC therapy in muscle regeneration and repair, and introduces chimeric cell-based therapies as a promising, novel approach for muscle regeneration and the treatment of DMD and other neuromuscular disorders.
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Affiliation(s)
- Katarzyna Budzynska
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, IL 60607, USA; (K.B.); (K.S.); (L.C.); (K.S.)
| | - Maria Siemionow
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, IL 60607, USA; (K.B.); (K.S.); (L.C.); (K.S.)
- Chair and Department of Traumatology, Orthopaedics, and Surgery of the Hand, Poznan University of Medical Sciences, 61-545 Poznan, Poland
| | - Katarzyna Stawarz
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, IL 60607, USA; (K.B.); (K.S.); (L.C.); (K.S.)
| | - Lucile Chambily
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, IL 60607, USA; (K.B.); (K.S.); (L.C.); (K.S.)
| | - Krzysztof Siemionow
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, IL 60607, USA; (K.B.); (K.S.); (L.C.); (K.S.)
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6
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Elkhoury K, Kodeih S, Enciso‐Martínez E, Maziz A, Bergaud C. Advancing Cardiomyocyte Maturation: Current Strategies and Promising Conductive Polymer-Based Approaches. Adv Healthc Mater 2024; 13:e2303288. [PMID: 38349615 PMCID: PMC11468390 DOI: 10.1002/adhm.202303288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 01/31/2024] [Indexed: 02/21/2024]
Abstract
Cardiovascular diseases are a leading cause of mortality and pose a significant burden on healthcare systems worldwide. Despite remarkable progress in medical research, the development of effective cardiovascular drugs has been hindered by high failure rates and escalating costs. One contributing factor is the limited availability of mature cardiomyocytes (CMs) for accurate disease modeling and drug screening. Human induced pluripotent stem cell-derived CMs offer a promising source of CMs; however, their immature phenotype presents challenges in translational applications. This review focuses on the road to achieving mature CMs by summarizing the major differences between immature and mature CMs, discussing the importance of adult-like CMs for drug discovery, highlighting the limitations of current strategies, and exploring potential solutions using electro-mechano active polymer-based scaffolds based on conductive polymers. However, critical considerations such as the trade-off between 3D systems and nutrient exchange, biocompatibility, degradation, cell adhesion, longevity, and integration into wider systems must be carefully evaluated. Continued advancements in these areas will contribute to a better understanding of cardiac diseases, improved drug discovery, and the development of personalized treatment strategies for patients with cardiovascular disorders.
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Affiliation(s)
- Kamil Elkhoury
- LAAS‐CNRS, Université de Toulouse, CNRSToulouseF‐31400France
| | - Sacha Kodeih
- Faculty of Medicine and Medical SciencesUniversity of BalamandTripoliP.O. Box 100Lebanon
| | | | - Ali Maziz
- LAAS‐CNRS, Université de Toulouse, CNRSToulouseF‐31400France
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7
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Eschenhagen T, Weinberger F. Challenges and perspectives of heart repair with pluripotent stem cell-derived cardiomyocytes. NATURE CARDIOVASCULAR RESEARCH 2024; 3:515-524. [PMID: 39195938 DOI: 10.1038/s44161-024-00472-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 04/04/2024] [Indexed: 08/29/2024]
Abstract
Here we aim at providing a concise but comprehensive overview of the perspectives and challenges of heart repair with pluripotent stem cell-derived cardiomyocytes. This Review comes at a time when consensus has been reached about the lack of relevant proliferative capacity of adult mammalian cardiomyocytes and the lack of new heart muscle formation with autologous cell sources. While alternatives to cell-based approaches will be shortly summarized, the focus lies on pluripotent stem cell-derived cardiomyocyte repair, which entered first clinical trials just 2 years ago. In the view of the authors, these early trials are important but have to be viewed as early proof-of-concept trials in humans that will hopefully provide first answers on feasibility, safety and the survival of allogeneic pluripotent stem cell-derived cardiomyocyte in the human heart. Better approaches have to be developed to make this approach clinically applicable.
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Affiliation(s)
- Thomas Eschenhagen
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
- German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
| | - Florian Weinberger
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg Eppendorf, Hamburg, Germany
- German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
- Cardiovascular Regeneration Program, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
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8
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Bonney EA, Lintao RCV, Zelop CM, Kammala AK, Menon R. Are fetal microchimerism and circulating fetal extracellular vesicles important links between spontaneous preterm delivery and maternal cardiovascular disease risk? Bioessays 2024; 46:e2300170. [PMID: 38359068 DOI: 10.1002/bies.202300170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 01/25/2024] [Accepted: 01/29/2024] [Indexed: 02/17/2024]
Abstract
Trafficking and persistence of fetal microchimeric cells (fMCs) and circulating extracellular vesicles (EVs) have been observed in animals and humans, but their consequences in the maternal body and their mechanistic contributions to maternal physiology and pathophysiology are not yet fully defined. Fetal cells and EVs may help remodel maternal organs after pregnancy-associated changes, but the cell types and EV cargos reaching the mother in preterm pregnancies after exposure to various risk factors can be distinct from term pregnancies. As preterm delivery-associated maternal complications are rising, revisiting this topic and formulating scientific questions for future research to reduce the risk of maternal morbidities are timely. Epidemiological studies report maternal cardiovascular risk as one of the major complications after preterm delivery. This paper suggests a potential link between fMCs and circulating EVs and adverse maternal cardiovascular outcomes post-pregnancies, the underlying mechanisms, consequences, and methods for and how this link might be assessed.
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Affiliation(s)
- Elizabeth A Bonney
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA
| | - Ryan C V Lintao
- Division of Basic Science and Translational Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA
- College of Medicine, University of the Philippines Manila, Manila, Philippines
| | - Carolyn M Zelop
- The Valley Hospital, Ridgewood, Paramus, New Jersey, USA
- Grossman School of Medicine, New York University, New York City, New York, USA
| | - Ananth Kumar Kammala
- Division of Basic Science and Translational Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA
| | - Ramkumar Menon
- Division of Basic Science and Translational Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA
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Tajima Y, Shibasaki F, Masai H. Cell fusion upregulates PD-L1 expression for evasion from immunosurveillance. Cancer Gene Ther 2024; 31:158-173. [PMID: 37990063 DOI: 10.1038/s41417-023-00693-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 10/22/2023] [Accepted: 11/07/2023] [Indexed: 11/23/2023]
Abstract
MSCs (mesenchymal stem cells), responsible for tissue repair, rarely undergo cell fusion with somatic cells. Here, we show that ~5% of bladder cancer cells (UMUC-3) fuses with bone marrow-derived MSC (BM-MSC) in co-culture and maintains high tumorigenicity. In eleven fusion cell clones that have been established, Mb-scale deletions carried by the bladder cancer cells are mostly absent in the fusion cells, but copy number gains contributed by the cancer cells have stayed. Fusion cells exhibit increased populations of mitotic cells with 3-polar spindles, indicative of genomic instability. They grow faster in vitro and exhibit higher colony formation in anchorage-independent growth assay in soft agar than the parent UMUC-3 does. Fusion cells develop tumors, after 4 weeks of time lag, as efficiently as the parent UMUC-3 does in xenograft experiments. 264 genes are identified whose expression is specifically altered in the fusion cells. Many of them are interferon-stimulated genes (ISG), but are activated in a manner independent of interferon. Among them, we show that PD-L1 is induced in fusion cells, and its knockout decreases tumorigenesis in a xenograft model. PD-L1 is induced in a manner independent of STAT1 known to regulate PD-L1 expression, but is regulated by histone modification, and is likely to inhibit phagocytosis by PD1-expressing macrophages, thus protecting cancer cells from immunological attacks. The fusion cells overexpress multiple cytokines including CCL2 that cause tumor progression by converting infiltrating macrophages to tumor-associated-macrophage (TAM). The results present mechanisms of how cell fusion promotes tumorigenesis, revealing a novel link between cell fusion and PD-L1, and underscore the efficacy of cancer immunotherapy.
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Affiliation(s)
- Youichi Tajima
- Genome Dynamics Project, Department of Basic Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
| | - Futoshi Shibasaki
- Center for Medical Research Cooperation, Tokyo Metropolitan Institute of Medical Science, Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan
| | - Hisao Masai
- Genome Dynamics Project, Department of Basic Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
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White JS, Su JJ, Ruark EM, Hua J, Hutson MS, Page-McCaw A. Wound-Induced Syncytia Outpace Mononucleate Neighbors during Drosophila Wound Repair. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.25.546442. [PMID: 37425719 PMCID: PMC10327115 DOI: 10.1101/2023.06.25.546442] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/11/2023]
Abstract
All organisms have evolved to respond to injury. Cell behaviors like proliferation, migration, and invasion replace missing cells and close wounds. However, the role of other wound-induced cell behaviors is not understood, including the formation of syncytia (multinucleated cells). Wound-induced epithelial syncytia were first reported around puncture wounds in post-mitotic Drosophila epidermal tissues, but have more recently been reported in mitotically competent tissues such as the Drosophila pupal epidermis and zebrafish epicardium. The presence of wound-induced syncytia in mitotically active tissues suggests that syncytia offer adaptive benefits, but it is unknown what those benefits are. Here, we use in vivo live imaging to analyze wound-induced syncytia in mitotically competent Drosophila pupae. We find that almost half the epithelial cells near a wound fuse to form large syncytia. These syncytia use several routes to speed wound repair: they outpace diploid cells to complete wound closure; they reduce cell intercalation during wound closure; and they pool the resources of their component cells to concentrate them toward the wound. In addition to wound healing, these properties of syncytia are likely to contribute to their roles in development and pathology.
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Affiliation(s)
- James S. White
- Dept. Cell and Developmental Biology, Vanderbilt School of Medicine, Nashville, TN
- Program in Developmental Biology, Vanderbilt University Nashville, TN
| | - Jasmine J. Su
- Dept. Cell and Developmental Biology, Vanderbilt School of Medicine, Nashville, TN
- Dept. Biological Sciences, Vanderbilt University, Nashville, TN
| | - Elizabeth M. Ruark
- Dept. Cell and Developmental Biology, Vanderbilt School of Medicine, Nashville, TN
| | - Junmin Hua
- Dept. Cell and Developmental Biology, Vanderbilt School of Medicine, Nashville, TN
| | - M. Shane Hutson
- Dept. Physics and Astronomy Vanderbilt University Nashville, TN
- Dept. Biological Sciences, Vanderbilt University, Nashville, TN
| | - Andrea Page-McCaw
- Dept. Cell and Developmental Biology, Vanderbilt School of Medicine, Nashville, TN
- Program in Developmental Biology, Vanderbilt University Nashville, TN
- Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN
- Lead Contact
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Lintao RCV, Kammala AK, Radnaa E, Bettayeb M, Vincent KL, Patrikeev I, Yaklic J, Bonney EA, Menon R. Characterization of fetal microchimeric immune cells in mouse maternal hearts during physiologic and pathologic pregnancies. Front Cell Dev Biol 2023; 11:1256945. [PMID: 37808080 PMCID: PMC10556483 DOI: 10.3389/fcell.2023.1256945] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 09/13/2023] [Indexed: 10/10/2023] Open
Abstract
Introduction: During pregnancy, fetal cells can be incorporated into maternal tissues (fetal microchimerism), where they can persist postpartum. Whether these fetal cells are beneficial or detrimental to maternal health is unknown. This study aimed to characterize fetal microchimeric immune cells in the maternal heart during pregnancy and postpartum, and to identify differences in these fetal microchimeric subpopulations between normal and pregnancies complicated by spontaneous preterm induced by ascending infection. Methods: A Cre reporter mouse model, which when mated with wild-type C57BL/6J females resulted in cells and tissues of progeny expressing red fluorescent protein tandem dimer Tomato (mT+), was used to detect fetal microchimeric cells. On embryonic day (E)15, 104 colony-forming units (CFU) E. coli was administered intravaginally to mimic ascending infection, with delivery on or before E18.5 considered as preterm delivery. A subset of pregnant mice was sacrificed at E16 and postpartum day 28 to harvest maternal hearts. Heart tissues were processed for immunofluorescence microscopy and high-dimensional mass cytometry by time-of-flight (CyTOF) using an antibody panel of immune cell markers. Changes in cardiac physiologic parameters were measured up to 60 days postpartum via two-dimensional echocardiography. Results: Intravaginal E. coli administration resulted in preterm delivery of live pups in 70% of the cases. mT + expressing cells were detected in maternal uterus and heart, implying that fetal cells can migrate to different maternal compartments. During ascending infection, more fetal antigen-presenting cells (APCs) and less fetal hematopoietic stem cells (HSCs) and fetal double-positive (DP) thymocytes were observed in maternal hearts at E16 compared to normal pregnancy. These HSCs were cleared while DP thymocytes persisted 28 days postpartum following an ascending infection. No significant changes in cardiac physiologic parameters were observed postpartum except a trend in lowering the ejection fraction rate in preterm delivered mothers. Conclusion: Both normal pregnancy and ascending infection revealed distinct compositions of fetal microchimeric immune cells within the maternal heart, which could potentially influence the maternal cardiac microenvironment via (1) modulation of cardiac reverse modeling processes by fetal stem cells, and (2) differential responses to recognition of fetal APCs by maternal T cells.
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Affiliation(s)
- Ryan C. V. Lintao
- Division of Basic Science and Translational Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, TX, United States
- Department of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines Manila, Manila, Philippines
| | - Ananth Kumar Kammala
- Division of Basic Science and Translational Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, TX, United States
| | - Enkhtuya Radnaa
- Division of Basic Science and Translational Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, TX, United States
| | - Mohamed Bettayeb
- Division of Basic Science and Translational Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, TX, United States
| | - Kathleen L. Vincent
- Division of Basic Science and Translational Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, TX, United States
- Biomedical Engineering and Imaging Sciences Group, The University of Texas Medical Branch at Galveston, Galveston, TX, United States
| | - Igor Patrikeev
- Biomedical Engineering and Imaging Sciences Group, The University of Texas Medical Branch at Galveston, Galveston, TX, United States
| | - Jerome Yaklic
- Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, TX, United States
| | - Elizabeth A. Bonney
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Larner College of Medicine, The University of Vermont, Burlington, VT, United States
| | - Ramkumar Menon
- Division of Basic Science and Translational Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, TX, United States
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12
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Pezhouman A, Nguyen NB, Kay M, Kanjilal B, Noshadi I, Ardehali R. Cardiac regeneration - Past advancements, current challenges, and future directions. J Mol Cell Cardiol 2023; 182:75-85. [PMID: 37482238 DOI: 10.1016/j.yjmcc.2023.07.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 07/13/2023] [Accepted: 07/18/2023] [Indexed: 07/25/2023]
Abstract
Cardiovascular disease is the leading cause of mortality and morbidity worldwide. Despite improvements in the standard of care for patients with heart diseases, including innovation in pharmacotherapy and surgical interventions, none have yet been proven effective to prevent the progression to heart failure. Cardiac transplantation is the last resort for patients with severe heart failure, but donor shortages remain a roadblock. Cardiac regenerative strategies include cell-based therapeutics, gene therapy, direct reprogramming of non-cardiac cells, acellular biologics, and tissue engineering methods to restore damaged hearts. Significant advancements have been made over the past several decades within each of these fields. This review focuses on the advancements of: 1) cell-based cardiac regenerative therapies, 2) the use of noncoding RNA to induce endogenous cell proliferation, and 3) application of bioengineering methods to promote retention and integration of engrafted cells. Different cell sources have been investigated, including adult stem cells derived from bone marrow and adipose cells, cardiosphere-derived cells, skeletal myoblasts, and pluripotent stem cells. In addition to cell-based transplantation approaches, there have been accumulating interest over the past decade in inducing endogenous CM proliferation for heart regeneration, particularly with the use of noncoding RNAs such as miRNAs and lncRNAs. Bioengineering applications have focused on combining cell-transplantation approaches with fabrication of a porous, vascularized scaffold using biomaterials and advanced bio-fabrication techniques that may offer enhanced retention of transplanted cells, with the hope that these cells would better engraft with host tissue to improve cardiac function. This review summarizes the present status and future challenges of cardiac regenerative therapies.
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Affiliation(s)
- Arash Pezhouman
- Baylor College of Medicine, Department of Medicine, Division of Cardiology, Houston, Texas 77030, United States; Texas Heart Institute, Houston, Texas 77030, United States
| | - Ngoc B Nguyen
- Baylor College of Medicine, Department of Internal Medicine, Houston, Texas 77030, United States
| | - Maryam Kay
- Department of Medicine, Division of Cardiology, University of California, Los Angeles, CA 90095, United States
| | - Baishali Kanjilal
- Department of Bioengineering, University of California, Riverside, Riverside, CA 92521, United States
| | - Iman Noshadi
- Department of Bioengineering, University of California, Riverside, Riverside, CA 92521, United States
| | - Reza Ardehali
- Baylor College of Medicine, Department of Medicine, Division of Cardiology, Houston, Texas 77030, United States; Texas Heart Institute, Houston, Texas 77030, United States.
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13
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Xu G, Fatima A, Breitbach M, Kuzmenkin A, Fügemann CJ, Ivanyuk D, Kim KP, Cantz T, Pfannkuche K, Schoeler HR, Fleischmann BK, Hescheler J, Šarić T. Electrophysiological Properties of Tetraploid Cardiomyocytes Derived from Murine Pluripotent Stem Cells Generated by Fusion of Adult Somatic Cells with Embryonic Stem Cells. Int J Mol Sci 2023; 24:ijms24076546. [PMID: 37047520 PMCID: PMC10095437 DOI: 10.3390/ijms24076546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 03/20/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
Most cardiomyocytes (CMs) in the adult mammalian heart are either binucleated or contain a single polyploid nucleus. Recent studies have shown that polyploidy in CMs plays an important role as an adaptive response to physiological demands and environmental stress and correlates with poor cardiac regenerative ability after injury. However, knowledge about the functional properties of polyploid CMs is limited. In this study, we generated tetraploid pluripotent stem cells (PSCs) by fusion of murine embryonic stem cells (ESCs) and somatic cells isolated from bone marrow or spleen and performed a comparative analysis of the electrophysiological properties of tetraploid fusion-derived PSCs and diploid ESC-derived CMs. Fusion-derived PSCs exhibited characteristics of genuine ESCs and contained a near-tetraploid genome. Ploidy features and marker expression were also retained during the differentiation of fusion-derived cells. Fusion-derived PSCs gave rise to CMs, which were similar to their diploid ESC counterparts in terms of their expression of typical cardiospecific markers, sarcomeric organization, action potential parameters, response to pharmacologic stimulation with various drugs, and expression of functional ion channels. These results suggest that the state of ploidy does not significantly affect the structural and electrophysiological properties of murine PSC-derived CMs. These results extend our knowledge of the functional properties of polyploid CMs and contribute to a better understanding of their biological role in the adult heart.
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14
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Marzoog BA. Transcription Factors - the Essence of Heart Regeneration: A Potential Novel Therapeutic Strategy. Curr Mol Med 2023; 23:232-238. [PMID: 35170408 DOI: 10.2174/1566524022666220216123650] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 12/02/2021] [Accepted: 12/07/2021] [Indexed: 02/08/2023]
Abstract
Myocardial cell injury and following sequelae are the primary reasons for death globally. Unfortunately, myocardiocytes in adults have limited regeneration capacity. Therefore, the generation of neo myocardiocytes from non-myocardial cells is a surrogate strategy. Transcription factors (TFs) can be recruited to achieve this tremendous goal. Transcriptomic analyses have suggested that GATA, Mef2c, and Tbx5 (GMT cocktail) are master TFs to transdifferentiate/reprogram cell linage of fibroblasts, somatic cells, mesodermal cells into myocardiocytes. However, adding MESP1, MYOCD, ESRRG, and ZFPM2 TFs induces the generation of more efficient and physiomorphological features for induced myocardiocytes. Moreover, the same cocktail of transcription factors can induce the proliferation and differentiation of induced/pluripotent stem cells into myocardial cells. Amelioration of impaired myocardial cells involves the activation of healing transcription factors, which are induced by inflammation mediators; IL6, tumor growth factor β, and IL22. Transcription factors regulate the cellular and subcellular physiology of myocardiocytes to include mitotic cell cycling regulation, karyokinesis and cytokinesis, hypertrophic growth, adult sarcomeric contractile protein gene expression, fatty acid metabolism, and mitochondrial biogenesis and maturation. Cell therapy by transcription factors can be applied to cardiogenesis and ameliorating impaired cardiocytes. Transcription factors are the cornerstone in cell differentiation.
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Affiliation(s)
- Basheer Abdullah Marzoog
- Department of Normal and Pathological Physiology, National Research Mordovia State University, Bolshevitskaya Street, 68, Saransk, Rep. Mordovia, 430005, Russia
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15
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Mabotuwana NS, Rech L, Lim J, Hardy SA, Murtha LA, Rainer PP, Boyle AJ. Paracrine Factors Released by Stem Cells of Mesenchymal Origin and their Effects in Cardiovascular Disease: A Systematic Review of Pre-clinical Studies. Stem Cell Rev Rep 2022; 18:2606-2628. [PMID: 35896860 PMCID: PMC9622561 DOI: 10.1007/s12015-022-10429-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2022] [Indexed: 11/30/2022]
Abstract
Mesenchymal stem cell (MSC) therapy has gained significant traction in the context of cardiovascular repair, and have been proposed to exert their regenerative effects via the secretion of paracrine factors. In this systematic review, we examined the literature and consolidated available evidence for the "paracrine hypothesis". Two Ovid SP databases were searched using a strategy encompassing paracrine mediated MSC therapy in the context of ischemic heart disease. This yielded 86 articles which met the selection criteria for inclusion in this study. We found that the MSCs utilized in these articles were primarily derived from bone marrow, cardiac tissue, and adipose tissue. We identified 234 individual protective factors across these studies, including VEGF, HGF, and FGF2; which are proposed to exert their effects in a paracrine manner. The data collated in this systematic review identifies secreted paracrine factors that could decrease apoptosis, and increase angiogenesis, cell proliferation, and cell viability. These included studies have also demonstrated that the administration of MSCs and indirectly, their secreted factors can reduce infarct size, and improve left ventricular ejection fraction, contractility, compliance, and vessel density. Furthering our understanding of the way these factors mediate repair could lead to the identification of therapeutic targets for cardiac regeneration.
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Affiliation(s)
- Nishani S Mabotuwana
- College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia
- Hunter Medical Research Institute, Lot 1, Kookaburra Circuit, Newcastle, NSW, 2305, Australia
- Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Graz, Austria
| | - Lavinia Rech
- Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Graz, Austria
- Department of Cardiac Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
| | - Joyce Lim
- College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia
- Hunter Medical Research Institute, Lot 1, Kookaburra Circuit, Newcastle, NSW, 2305, Australia
- Department of Cardiovascular Medicine, John Hunter Hospital, Newcastle, NSW, Australia
| | - Sean A Hardy
- College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia
- Hunter Medical Research Institute, Lot 1, Kookaburra Circuit, Newcastle, NSW, 2305, Australia
- Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Graz, Austria
| | - Lucy A Murtha
- College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia
- Hunter Medical Research Institute, Lot 1, Kookaburra Circuit, Newcastle, NSW, 2305, Australia
| | - Peter P Rainer
- Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Graz, Austria
- BioTechMed Graz, Graz, Austria
| | - Andrew J Boyle
- College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia.
- Hunter Medical Research Institute, Lot 1, Kookaburra Circuit, Newcastle, NSW, 2305, Australia.
- Department of Cardiovascular Medicine, John Hunter Hospital, Newcastle, NSW, Australia.
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16
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Ahlenius H. Past, Present, and Future of Direct Cell Reprogramming. Cell Reprogram 2022; 24:205-211. [DOI: 10.1089/cell.2022.0110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Henrik Ahlenius
- Stem Cells, Aging and Neurodegeneration, Division of Neurology, Department of Clinical Sciences Lund, Lund Stem Cell Center, Lund University, Lund, Sweden
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17
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Chen C, Park B, Ragonnaud E, Bodogai M, Wang X, Zong L, Lee JM, Beerman I, Biragyn A. Cancer co-opts differentiation of B-cell precursors into macrophage-like cells. Nat Commun 2022; 13:5376. [PMID: 36104343 PMCID: PMC9474882 DOI: 10.1038/s41467-022-33117-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 08/31/2022] [Indexed: 11/08/2022] Open
Abstract
We have recently reported that some cancers induce accumulation of bone marrow (BM) B-cell precursors in the spleen to convert them into metastasis-promoting, immunosuppressive B cells. Here, using various murine tumor models and samples from humans with breast and ovarian cancers, we provide evidence that cancers also co-opt differentiation of these B-cell precursors to generate macrophage-like cells (termed B-MF). We link the transdifferentiation to a small subset of CSF1R+ Pax5Low cells within BM pre-B and immature B cells responding to cancer-secreted M-CSF with downregulation of the transcription factor Pax5 via CSF1R signaling. Although the primary source of tumor-associated macrophages is monocytes, B-MFs are phenotypically and functionally distinguishable. Compared to monocyte-derived macrophages, B-MFs more efficiently phagocytize apoptotic cells, suppress proliferation of T cells and induce FoxP3+ regulatory T cells. In mouse tumor models, B-MFs promote shrinkage of the tumor-infiltrating IFNγ+ CD4 T cell pool and increase cancer progression and metastasis, suggesting that this cancer-induced transdifferentiation pathway is functionally relevant and hence could serve as an immunotherapeutic target.
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Affiliation(s)
- Chen Chen
- Immunoregulation Section, Laboratory of Immunology and Molecular Biology, National Institute on Aging, Baltimore, MD, USA
| | - Bongsoo Park
- Epigenetics and Stem Cell Aging Unit, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA
| | - Emeline Ragonnaud
- Immunoregulation Section, Laboratory of Immunology and Molecular Biology, National Institute on Aging, Baltimore, MD, USA
| | - Monica Bodogai
- Immunoregulation Section, Laboratory of Immunology and Molecular Biology, National Institute on Aging, Baltimore, MD, USA
| | - Xin Wang
- Immunoregulation Section, Laboratory of Immunology and Molecular Biology, National Institute on Aging, Baltimore, MD, USA
| | - Le Zong
- Epigenetics and Stem Cell Aging Unit, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA
| | - Jung-Min Lee
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Isabel Beerman
- Epigenetics and Stem Cell Aging Unit, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA
| | - Arya Biragyn
- Immunoregulation Section, Laboratory of Immunology and Molecular Biology, National Institute on Aging, Baltimore, MD, USA.
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18
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Guglielmo M, Marta B. Stem Cells and the Microenvironment: Reciprocity with Asymmetry in Regenerative Medicine. Acta Biotheor 2022; 70:24. [PMID: 35962861 DOI: 10.1007/s10441-022-09448-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 07/20/2022] [Accepted: 07/21/2022] [Indexed: 11/29/2022]
Abstract
Much of the current research in regenerative medicine concentrates on stem-cell therapy that exploits the regenerative capacities of stem cells when injected into different types of human tissues. Although new therapeutic paths have been opened up by induced pluripotent cells and human mesenchymal cells, the rate of success is still low and mainly due to the difficulties of managing cell proliferation and differentiation, giving rise to non-controlled stem cell differentiation that ultimately leads to cancer. Despite being still far from becoming a reality, these studies highlight the role of physical and biological constraints (e.g., cues and morphogenetic fields) placed by tissue microenvironment on stem cell fate. This asks for a clarification of the coupling of stem cells and microenvironmental factors in regenerative medicine. We argue that extracellular matrix and stem cells have a causal reciprocal and asymmetric relationship in that the 3D organization and composition of the extracellular matrix establish a spatial, temporal, and mechanical control over the fate of stem cells, which enable them to interact and control (as well as be controlled by) the cellular components and soluble factors of microenvironment. Such an account clarifies the notions of stemness and stem cell regeneration consistently with that of microenvironment.
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Affiliation(s)
- Militello Guglielmo
- IAS-Research Centre, University of the Basque Country, San Sebastián, Spain.
| | - Bertolaso Marta
- University Campus Bio-Medico of Rome, Institute of Scientific and Technological Practice, Rome, Italy
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19
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Li Y, Alnojeidi H, Kilani RT, Ghahary A. M-CSF-stimulated myeloid cells can convert into epithelial cells to participate in re-epithelialization and hair follicle regeneration during dermal wound healing. PLoS One 2022; 17:e0262060. [PMID: 35737933 PMCID: PMC9225457 DOI: 10.1371/journal.pone.0262060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 03/31/2022] [Indexed: 12/03/2022] Open
Abstract
Dermal wound healing is a complex process which requires the interaction of many cell types and mediators in a highly sophisticated temporal sequence. Myeloid cells which compose of a significant proportion of the inflammatory cells infiltrate to the to a wound site where they play important roles in clearance of damaged tissue and microorganisms. Myeloid cells have the capacity to be converted into fibroblast-like cells and endothelial cells during wound healing process. However, whether myeloid cells in wounds can convert into epithelial cells where they contribute to healing process is not clear. In this study, we performed double immunofluorescent staining with antibodies for hematopoietic cells and keratinocytes as well as cell tracing technique to investigate hematopoietic cell conversion. The result showed that during the healing process, some of the CD45-positive hematopoietic cells also expressed keratin 14, a marker for keratinocytes. Further, double immunofluorescent staining in dermal wounds, using CD11b and K14 antibodies indicated that CD11b-positive myeloid cells were the origin of newly generated epithelial cells. Through tracing injected labeled splenocyte-derived myeloid cells in skin, we confirmed that myeloid cells were able to convert into keratinocytes in repaired skin. Furthermore, our results from in vivo experiments provided new information on contribution of myeloid cells in hair follicle regeneration. In conclusion, this work highlights the myeloid cell contributions in wound repair and hair follicle regeneration through conversion of M-CSF-stimulated CD11b-positive myeloid cells into epithelial cells in a murine model.
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Affiliation(s)
- Yunyuan Li
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | - Hatem Alnojeidi
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | - Ruhangiz T. Kilani
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | - Aziz Ghahary
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
- * E-mail:
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20
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Signaling cascades in the failing heart and emerging therapeutic strategies. Signal Transduct Target Ther 2022; 7:134. [PMID: 35461308 PMCID: PMC9035186 DOI: 10.1038/s41392-022-00972-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/13/2022] [Accepted: 03/20/2022] [Indexed: 12/11/2022] Open
Abstract
Chronic heart failure is the end stage of cardiac diseases. With a high prevalence and a high mortality rate worldwide, chronic heart failure is one of the heaviest health-related burdens. In addition to the standard neurohormonal blockade therapy, several medications have been developed for chronic heart failure treatment, but the population-wide improvement in chronic heart failure prognosis over time has been modest, and novel therapies are still needed. Mechanistic discovery and technical innovation are powerful driving forces for therapeutic development. On the one hand, the past decades have witnessed great progress in understanding the mechanism of chronic heart failure. It is now known that chronic heart failure is not only a matter involving cardiomyocytes. Instead, chronic heart failure involves numerous signaling pathways in noncardiomyocytes, including fibroblasts, immune cells, vascular cells, and lymphatic endothelial cells, and crosstalk among these cells. The complex regulatory network includes protein-protein, protein-RNA, and RNA-RNA interactions. These achievements in mechanistic studies provide novel insights for future therapeutic targets. On the other hand, with the development of modern biological techniques, targeting a protein pharmacologically is no longer the sole option for treating chronic heart failure. Gene therapy can directly manipulate the expression level of genes; gene editing techniques provide hope for curing hereditary cardiomyopathy; cell therapy aims to replace dysfunctional cardiomyocytes; and xenotransplantation may solve the problem of donor heart shortages. In this paper, we reviewed these two aspects in the field of failing heart signaling cascades and emerging therapeutic strategies based on modern biological techniques.
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21
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Bonilla-Pons SÀ, Nakagawa S, Bahima EG, Fernández-Blanco Á, Pesaresi M, D'Antin JC, Sebastian-Perez R, Greco D, Domínguez-Sala E, Gómez-Riera R, Compte RIB, Dierssen M, Pulido NM, Cosma MP. Müller glia fused with adult stem cells undergo neural differentiation in human retinal models. EBioMedicine 2022; 77:103914. [PMID: 35278743 PMCID: PMC8917309 DOI: 10.1016/j.ebiom.2022.103914] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 02/09/2022] [Accepted: 02/18/2022] [Indexed: 12/15/2022] Open
Abstract
Background Visual impairments are a critical medical hurdle to be addressed in modern society. Müller glia (MG) have regenerative potential in the retina in lower vertebrates, but not in mammals. However, in mice, in vivo cell fusion between MG and adult stem cells forms hybrids that can partially regenerate ablated neurons. Methods We used organotypic cultures of human retina and preparations of dissociated cells to test the hypothesis that cell fusion between human MG and adult stem cells can induce neuronal regeneration in human systems. Moreover, we established a microinjection system for transplanting human retinal organoids to demonstrate hybrid differentiation. Findings We first found that cell fusion occurs between MG and adult stem cells, in organotypic cultures of human retina as well as in cell cultures. Next, we showed that the resulting hybrids can differentiate and acquire a proto-neural electrophysiology profile when the Wnt/beta-catenin pathway is activated in the adult stem cells prior fusion. Finally, we demonstrated the engraftment and differentiation of these hybrids into human retinal organoids. Interpretation We show fusion between human MG and adult stem cells, and demonstrate that the resulting hybrid cells can differentiate towards neural fate in human model systems. Our results suggest that cell fusion-mediated therapy is a potential regenerative approach for treating human retinal dystrophies. Funding This work was supported by La Caixa Health (HR17-00231), Velux Stiftung (976a) and the Ministerio de Ciencia e Innovación, (BFU2017-86760-P) (AEI/FEDER, UE), AGAUR (2017 SGR 689, 2017 SGR 926).
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Affiliation(s)
- Sergi Àngel Bonilla-Pons
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, C/Dr. Aiguader 88, Barcelona 08003, Spain; Universitat de Barcelona (UB), Barcelona, Spain
| | - Shoma Nakagawa
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, C/Dr. Aiguader 88, Barcelona 08003, Spain
| | - Elena Garreta Bahima
- Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Álvaro Fernández-Blanco
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, C/Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Martina Pesaresi
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, C/Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Justin Christopher D'Antin
- Centro de Oftalmología Barraquer, Barcelona, Spain; Institut Universitari Barraquer, Universitat Autónoma de Barcelona, Barcelona, Spain
| | - Ruben Sebastian-Perez
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, C/Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Daniela Greco
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, C/Dr. Aiguader 88, Barcelona 08003, Spain
| | - Eduardo Domínguez-Sala
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, C/Dr. Aiguader 88, Barcelona 08003, Spain
| | - Raúl Gómez-Riera
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, C/Dr. Aiguader 88, Barcelona 08003, Spain
| | - Rafael Ignacio Barraquer Compte
- Centro de Oftalmología Barraquer, Barcelona, Spain; Institut Universitari Barraquer, Universitat Autónoma de Barcelona, Barcelona, Spain
| | - Mara Dierssen
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, C/Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; Biomedical Research Networking Centre On Rare Diseases (CIBERER), Institute of Health Carlos III, Madrid, Spain
| | - Nuria Montserrat Pulido
- Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain; ICREA, Pg. Lluis Companys 23, Barcelona 08010, Spain
| | - Maria Pia Cosma
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, C/Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; ICREA, Pg. Lluis Companys 23, Barcelona 08010, Spain; Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China; CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell an Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, Guangzhou 510530, China.
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22
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Chen H, Xue R, Huang P, Wu Y, Fan W, He X, Dong Y, Liu C. Modified Exosomes: a Good Transporter for miRNAs within Stem Cells to Treat Ischemic Heart Disease. J Cardiovasc Transl Res 2022; 15:514-523. [PMID: 35229250 DOI: 10.1007/s12265-022-10216-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 02/07/2022] [Indexed: 12/11/2022]
Abstract
Stem cell-based therapy for ischemic heart disease (IHD) has become a promising but controversial strategy during the past two decades. The fate and effects of stem cells engrafted into ischemia myocardium are still not fully understood. Stem cell-derived exosomes, a subcategory of extracellular vesicles with nano size, have been considered as an efficient and safe transporter for microRNAs (miRNAs) and a central mediator of the cardioprotective potentials of the parental cells. Hypoxia, pharmacological intervention, and gene manipulation could alter the exosomal miRNAs cargos from stem cells and promote therapeutic potential. Furthermore, several bioengineering methods were also successfully applied to modify miRNAs content and components of exosomal membrane proteins recently. In this review, we outline relevant results about exosomal miRNAs from stem cells and focus on the current strategies to promote their therapeutic efficiency in IHD.
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Affiliation(s)
- Hao Chen
- NHC Key Laboratory of Assisted Circulation, Sun Yat-Sen University, Guangzhou, China.,National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Ruicong Xue
- NHC Key Laboratory of Assisted Circulation, Sun Yat-Sen University, Guangzhou, China.,National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.,Department of Cardiology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Peisen Huang
- NHC Key Laboratory of Assisted Circulation, Sun Yat-Sen University, Guangzhou, China.,National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.,Department of Cardiology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yuzhong Wu
- NHC Key Laboratory of Assisted Circulation, Sun Yat-Sen University, Guangzhou, China.,National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.,Department of Cardiology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Wendong Fan
- NHC Key Laboratory of Assisted Circulation, Sun Yat-Sen University, Guangzhou, China.,National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.,Department of Cardiology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xin He
- NHC Key Laboratory of Assisted Circulation, Sun Yat-Sen University, Guangzhou, China.,National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.,Department of Cardiology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yugang Dong
- NHC Key Laboratory of Assisted Circulation, Sun Yat-Sen University, Guangzhou, China.,National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.,Department of Cardiology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Chen Liu
- NHC Key Laboratory of Assisted Circulation, Sun Yat-Sen University, Guangzhou, China. .,National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. .,Department of Cardiology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
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Andrianto , Pikir BS, Ferdiansyah , Pristianto T, Hermawan HO, Zaini BSI, Muhammad AR. Efficiency Comparison of Direct Reprogramming CD34+ Cells into Cardiomyocytes Using Cardiomyocyte Differentiation Medium vs MicroRNA-1. Cell Reprogram 2022; 24:21-25. [DOI: 10.1089/cell.2021.0075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Andrianto
- Cardiology and Vascular Medicine Department, Medical Faculty of Airlangga University—Dr. Soetomo General Hospital, Surabaya, Indonesia
| | - Budi Susetyo Pikir
- Cardiology and Vascular Medicine Department, Medical Faculty of Airlangga University—Dr. Soetomo General Hospital, Surabaya, Indonesia
| | - Ferdiansyah
- Orthopedy and Traumatology Department, Medical Faculty of Airlangga University—Dr. Soetomo General Hospital, Surabaya, Indonesia
| | - Tinton Pristianto
- Cardiology and Vascular Medicine Department, Medical Faculty of Airlangga University—Dr. Soetomo General Hospital, Surabaya, Indonesia
| | - Hanestya Oky Hermawan
- Cardiology and Vascular Medicine Department, Medical Faculty of Airlangga University—Dr. Soetomo General Hospital, Surabaya, Indonesia
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24
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Jiang L, Liang J, Huang W, Ma J, Park KH, Wu Z, Chen P, Zhu H, Ma JJ, Cai W, Paul C, Niu L, Fan GC, Wang HS, Kanisicak O, Xu M, Wang Y. CRISPR activation of endogenous genes reprograms fibroblasts into cardiovascular progenitor cells for myocardial infarction therapy. Mol Ther 2022; 30:54-74. [PMID: 34678511 PMCID: PMC8753567 DOI: 10.1016/j.ymthe.2021.10.015] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/27/2021] [Accepted: 10/18/2021] [Indexed: 01/07/2023] Open
Abstract
Fibroblasts can be reprogrammed into cardiovascular progenitor cells (CPCs) using transgenic approaches, although the underlying mechanism remains unclear. We determined whether activation of endogenous genes such as Gata4, Nkx2.5, and Tbx5 can rapidly establish autoregulatory loops and initiate CPC generation in adult extracardiac fibroblasts using a CRISPR activation system. The induced fibroblasts (>80%) showed phenotypic changes as indicated by an Nkx2.5 cardiac enhancer reporter. The progenitor characteristics were confirmed by colony formation and expression of cardiovascular genes. Cardiac sphere induction segregated the early and late reprogrammed cells that can generate functional cardiomyocytes and vascular cells in vitro. Therefore, they were termed CRISPR-induced CPCs (ciCPCs). Transcriptomic analysis showed that cell cycle and heart development pathways were important to accelerate CPC formation during the early reprogramming stage. The CRISPR system opened the silenced chromatin locus, thereby allowing transcriptional factors to access their own promoters and eventually forming a positive feedback loop. The regenerative potential of ciCPCs was assessed after implantation in mouse myocardial infarction models. The engrafted ciCPCs differentiated into cardiovascular cells in vivo but also significantly improved contractile function and scar formation. In conclusion, multiplex gene activation was sufficient to drive CPC reprogramming, providing a new cell source for regenerative therapeutics.
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Affiliation(s)
- Lin Jiang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Jialiang Liang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
| | - Wei Huang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Jianyong Ma
- Department of Pharmacology and Systems Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Ki Ho Park
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Zhichao Wu
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Peng Chen
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Hua Zhu
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Jian-Jie Ma
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Wenfeng Cai
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Christian Paul
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Liang Niu
- Division of Biostatistics and Bioinformatics, Department of Environmental Health, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Guo-Chang Fan
- Department of Pharmacology and Systems Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Hong-Sheng Wang
- Department of Pharmacology and Systems Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Onur Kanisicak
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Meifeng Xu
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Yigang Wang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
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25
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Endothelial Progenitor Cells: An Appraisal of Relevant Data from Bench to Bedside. Int J Mol Sci 2021; 22:ijms222312874. [PMID: 34884679 PMCID: PMC8657735 DOI: 10.3390/ijms222312874] [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: 09/09/2021] [Revised: 11/15/2021] [Accepted: 11/24/2021] [Indexed: 11/16/2022] Open
Abstract
The mobilization of endothelial progenitor cells (EPCs) into circulation from bone marrow is well known to be present in several clinical settings, including acute coronary syndrome, heart failure, diabetes and peripheral vascular disease. The aim of this review was to explore the current literature focusing on the great opportunity that EPCs can have in terms of regenerative medicine.
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Rowton M, Guzzetta A, Rydeen AB, Moskowitz IP. Control of cardiomyocyte differentiation timing by intercellular signaling pathways. Semin Cell Dev Biol 2021; 118:94-106. [PMID: 34144893 PMCID: PMC8968240 DOI: 10.1016/j.semcdb.2021.06.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 05/19/2021] [Accepted: 06/03/2021] [Indexed: 02/06/2023]
Abstract
Congenital Heart Disease (CHD), malformations of the heart present at birth, is the most common class of life-threatening birth defect (Hoffman (1995) [1], Gelb (2004) [2], Gelb (2014) [3]). A major research challenge is to elucidate the genetic determinants of CHD and mechanistically link CHD ontogeny to a molecular understanding of heart development. Although the embryonic origins of CHD are unclear in most cases, dysregulation of cardiovascular lineage specification, patterning, proliferation, migration or differentiation have been described (Olson (2004) [4], Olson (2006) [5], Srivastava (2006) [6], Dunwoodie (2007) [7], Bruneau (2008) [8]). Cardiac differentiation is the process whereby cells become progressively more dedicated in a trajectory through the cardiac lineage towards mature cardiomyocytes. Defects in cardiac differentiation have been linked to CHD, although how the complex control of cardiac differentiation prevents CHD is just beginning to be understood. The stages of cardiac differentiation are highly stereotyped and have been well-characterized (Kattman et al. (2011) [9], Wamstad et al. (2012) [10], Luna-Zurita et al. (2016) [11], Loh et al. (2016) [12], DeLaughter et al. (2016) [13]); however, the developmental and molecular mechanisms that promote or delay the transition of a cell through these stages have not been as deeply investigated. Tight temporal control of progenitor differentiation is critically important for normal organ size, spatial organization, and cellular physiology and homeostasis of all organ systems (Raff et al. (1985) [14], Amthor et al. (1998) [15], Kopan et al. (2014) [16]). This review will focus on the action of signaling pathways in the control of cardiomyocyte differentiation timing. Numerous signaling pathways, including the Wnt, Fibroblast Growth Factor, Hedgehog, Bone Morphogenetic Protein, Insulin-like Growth Factor, Thyroid Hormone and Hippo pathways, have all been implicated in promoting or inhibiting transitions along the cardiac differentiation trajectory. Gaining a deeper understanding of the mechanisms controlling cardiac differentiation timing promises to yield insights into the etiology of CHD and to inform approaches to restore function to damaged hearts.
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Kasai-Brunswick TH, Carvalho AB, Campos de Carvalho AC. Stem cell therapies in cardiac diseases: Current status and future possibilities. World J Stem Cells 2021; 13:1231-1247. [PMID: 34630860 PMCID: PMC8474720 DOI: 10.4252/wjsc.v13.i9.1231] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 07/26/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular diseases represent the world's leading cause of death. In this heterogeneous group of diseases, ischemic cardiomyopathies are the most devastating and prevalent, estimated to cause 17.9 million deaths per year. Despite all biomedical efforts, there are no effective treatments that can replace the myocytes lost during an ischemic event or progression of the disease to heart failure. In this context, cell therapy is an emerging therapeutic alternative to treat cardiovascular diseases by cell administration, aimed at cardiac regeneration and repair. In this review, we will cover more than 30 years of cell therapy in cardiology, presenting the main milestones and drawbacks in the field and signaling future challenges and perspectives. The outcomes of cardiac cell therapies are discussed in three distinct aspects: The search for remuscularization by replacement of lost cells by exogenous adult cells, the endogenous stem cell era, which pursued the isolation of a progenitor with the ability to induce heart repair, and the utilization of pluripotent stem cells as a rich and reliable source of cardiomyocytes. Acellular therapies using cell derivatives, such as microvesicles and exosomes, are presented as a promising cell-free therapeutic alternative.
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Affiliation(s)
- Tais Hanae Kasai-Brunswick
- National Center of Structural Biology and Bioimaging, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Adriana Bastos Carvalho
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Antonio Carlos Campos de Carvalho
- National Center of Structural Biology and Bioimaging, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil.
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Beliën H, Evens L, Hendrikx M, Bito V, Bronckaers A. Combining stem cells in myocardial infarction: The road to superior repair? Med Res Rev 2021; 42:343-373. [PMID: 34114238 DOI: 10.1002/med.21839] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 05/04/2021] [Accepted: 05/29/2021] [Indexed: 12/25/2022]
Abstract
Myocardial infarction irreversibly destroys millions of cardiomyocytes in the ventricle, making it the leading cause of heart failure worldwide. Over the past two decades, many progenitor and stem cell types were proposed as the ideal candidate to regenerate the heart after injury. The potential of stem cell therapy has been investigated thoroughly in animal and human studies, aiming at cardiac repair by true tissue replacement, by immune modulation, or by the secretion of paracrine factors that stimulate endogenous repair processes. Despite some successful results in animal models, the outcome from clinical trials remains overall disappointing, largely due to the limited stem cell survival and retention after transplantation. Extensive interest was developed regarding the combinational use of stem cells and various priming strategies to improve the efficacy of regenerative cell therapy. In this review, we provide a critical discussion of the different stem cell types investigated in preclinical and clinical studies in the field of cardiac repair. Moreover, we give an update on the potential of stem cell combinations as well as preconditioning and explore the future promises of these novel regenerative strategies.
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Affiliation(s)
- Hanne Beliën
- Biomedical Research Institute (BIOMED), Department of Cardio and Organ Systems, UHasselt-Hasselt University, Agoralaan, Diepenbeek, Belgium
| | - Lize Evens
- Biomedical Research Institute (BIOMED), Department of Cardio and Organ Systems, UHasselt-Hasselt University, Agoralaan, Diepenbeek, Belgium
| | - Marc Hendrikx
- Faculty of Medicine and Life Sciences, UHasselt-Hasselt University, Agoralaan, Diepenbeek, Belgium
| | - Virginie Bito
- Biomedical Research Institute (BIOMED), Department of Cardio and Organ Systems, UHasselt-Hasselt University, Agoralaan, Diepenbeek, Belgium
| | - Annelies Bronckaers
- Biomedical Research Institute (BIOMED), Department of Cardio and Organ Systems, UHasselt-Hasselt University, Agoralaan, Diepenbeek, Belgium
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29
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Cwykiel J, Jundzill A, Klimczak A, Madajka-Niemeyer M, Siemionow M. Donor Recipient Chimeric Cells Induce Chimerism and Extend Survival of Vascularized Composite Allografts. Arch Immunol Ther Exp (Warsz) 2021; 69:13. [PMID: 33970329 PMCID: PMC8110509 DOI: 10.1007/s00005-021-00614-9] [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: 02/13/2021] [Accepted: 04/08/2021] [Indexed: 11/30/2022]
Abstract
This study evaluated the efficacy of donor recipient chimeric cell (DRCC) therapy created by fusion of donor and recipient derived bone marrow cells (BMC) in chimerism and tolerance induction in a rat vascularized composite allograft (VCA) model. Twenty-four VCA (groin flaps) from MHC-mismatched ACI (RT1a) donors were transplanted to Lewis (RT1l) recipients. Rats were randomly divided into (n = 6/group): Group 1—untreated controls, Groups 2—7-day immunosuppression controls, Group 3—DRCC, and Group 4—DRCC with 7-day anti-αβTCR monoclonal antibody and cyclosporine A protocol. DRCC created by polyethylene glycol-mediated fusion of ACI and Lewis BMC were cultured and transplanted (2–4 × 106) to VCA recipients via intraosseous delivery route. Flow cytometry assessed peripheral blood chimerism while fluorescent microscopy and PCR tested the presence of DRCC in the recipient’s blood, bone marrow (BM), and lymphoid organs at the study endpoint (VCA rejection). No complications were observed after DRCC intraosseous delivery. Group 4 presented the longest average VCA survival (79.3 ± 30.9 days) followed by Group 2 (53.3 ± 13.6 days), Group 3 (18 ± 7.5 days), and Group 1 (8.5 ± 1 days). The highest chimerism level was detected in Group 4 (57.9 ± 6.2%) at day 7 post-transplant. The chimerism declined at day 21 post-transplant and remained at 10% level during the entire follow-up period. Single dose of DRCC therapy induced long-term multilineage chimerism and extended VCA survival. DRCC introduces a novel concept of customized donor-recipient cell-based therapy supporting solid organ and VCA transplants.
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Affiliation(s)
- Joanna Cwykiel
- Department of Orthopaedics, University of Illinois At Chicago, Molecular Biology Research Building, 900 S. Ashland Ave. Room# 3356, Chicago, IL, 60607, USA.,Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Arkadiusz Jundzill
- Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH, USA.,Chair of Urology, Department of Regenerative Medicine, Nicolaus Copernicus University in Torun, Ludwik Rydygier Medical College in Bydgoszcz, Bydgoszcz, Poland.,Department of Plastic, Reconstructive and Aesthetic Surgery, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland
| | - Aleksandra Klimczak
- Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH, USA.,Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | | | - Maria Siemionow
- Department of Orthopaedics, University of Illinois At Chicago, Molecular Biology Research Building, 900 S. Ashland Ave. Room# 3356, Chicago, IL, 60607, USA. .,Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH, USA. .,Department of Surgery, Poznan University of Medical Sciences, Poznan, Poland.
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30
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Zhang LL, Xiong YY, Yang YJ. The Vital Roles of Mesenchymal Stem Cells and the Derived Extracellular Vesicles in Promoting Angiogenesis After Acute Myocardial Infarction. Stem Cells Dev 2021; 30:561-577. [PMID: 33752473 DOI: 10.1089/scd.2021.0006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Acute myocardial infarction (AMI) is an event of ischemic myocardial necrosis caused by acute coronary artery occlusion, which ultimately leads to a large loss of cardiomyocytes. The prerequisite of salvaging ischemic myocardium and improving cardiac function of patients is to provide adequate blood perfusion in the infarcted area. Apart from reperfusion therapy, it is also urgent and imperative to promote angiogenesis. Recently, growing evidence based on promising preclinical data indicates that mesenchymal stem cells (MSCs) can provide therapeutic effects on AMI by promoting angiogenesis. Extracellular vesicles (EVs), membrane-encapsulated vesicles with complex cargoes, including proteins, nucleic acids, and lipids, can be derived from MSCs and represent part of their functions, so EVs also possess the ability to promote angiogenesis. However, poor control of the survival and localization of MSCs hindered clinical transformation and made scientists start looking for new approaches based on MSCs. Identifying the role of MSCs and their derived EVs in promoting angiogenesis can provide a theoretical basis for improved MSC-based methods, and ultimately promote the clinical treatment of AMI. This review highlights potential proangiogenic mechanisms of transplanted MSCs and the derived EVs after AMI and summarizes the latest literature concerning the novel methods based on MSCs to maximize the angiogenesis capability.
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Affiliation(s)
- Li-Li Zhang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Yu-Yan Xiong
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Yue-Jin Yang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
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31
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Cwykiel J, Madajka-Niemeyer M, Siemionow M. Development of Donor Recipient Chimeric Cells of bone marrow origin as a novel approach for tolerance induction in transplantation. Stem Cell Investig 2021; 8:8. [PMID: 33969113 DOI: 10.21037/sci-2020-044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 03/03/2021] [Indexed: 12/14/2022]
Abstract
Background Cell therapies and chimerism-based strategies are currently the most successful approach for tolerance induction in transplantation. This study aimed to establish and characterize novel Donor Recipient Chimeric Ccell (DRCC) therapy of bone marrow (BM) origin presenting donor-recipient phenotype to support tolerance induction. Methods Ex vivo fusions of fully MHC-mismatched BM cells from ACI (RT1a) and Lewis (RT1l) rats were performed using polyethylene-glycol (PEG). The creation of rat DRCC was tested by flow cytometry (FC), confocal microscopy and PCR. FC characterized DRCC's phenotype (CD3, CD4, CD8, CD45, CD90, CD11b/c, CD45RA, OX-82, or CD4/CD25) and apoptosis, while mixed lymphocyte reaction assessed DRCC's immunogenicity and colony forming unit assay tested DRCC's differentiation and proliferation. DRCC's polyploidy was evaluated using Hoechst33342 staining and COMET assay tested genotoxicity of fusion procedure. ELISA analyzed the secretion of IL-2, IL-4, IL-10, TGFß1, IFNγ and TNFα by DRCC at day 1, 5 and 14 post-fusion. The DRCC's phenotype after long-term culturing was assessed by reverse-transcription PCR. Results The chimeric state of DRCC was confirmed. Fusion did not change the expression of hematopoietic markers compared to BM controls. Although an increased number of early and late apoptotic (Annexin V+/Sytox blue- and Annexin V+/Sytox blue+, respectively) DRCC was detected at 24h post-fusion, the number significantly decreased at day 5 (38.4%±3.1% and 22.6%±2.5%, vs. 28.3%±2.5% and 13.9%±2.6%, respectively, P<0.05). DRCC presented decreased immunogenicity, increased expression of IL-10 and TGFβ1 and proliferative potential comparable to BM controls. The average percentage of tetraploid DRCC was 3.1%±0.2% compared to 0.96%±0.1% in BM controls. The lack of damage to the DRCC's DNA content supported the DRCC's safety. In culture, DRCC maintained proliferation for up to 28 days while preserving hematopoietic profile. Conclusions This study confirmed feasibility of DRCC creation via ex vivo PEG mediated fusion. The created DRCC revealed pro-tolerogenic properties indicating potential immunomodulatory effect of DRCC therapy when applied in vivo to support tolerance induction in solid organ and vascularized composite allograft transplantation.
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Affiliation(s)
- Joanna Cwykiel
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, IL, USA.,Department of Plastic Surgery, Cleveland Clinic, Cleveland, Ohio, USA
| | | | - Maria Siemionow
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, IL, USA.,Department of Plastic Surgery, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Surgery, Poznan University of Medical Sciences, Poznan, Poland
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32
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Cell-cell fusions and cell-in-cell phenomena in healthy cells and cancer: Lessons from protists and invertebrates. Semin Cancer Biol 2021; 81:96-105. [PMID: 33713795 DOI: 10.1016/j.semcancer.2021.03.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 02/28/2021] [Accepted: 03/04/2021] [Indexed: 02/08/2023]
Abstract
Herein we analyze two special routes of the multinucleated cells' formation - the fusion of mononuclear cells and the formation of cell-in-cell structures - in the healthy tissues and in tumorigenesis. There are many theories of tumorigenesis based on the phenomenon of emergence of the hybrid cancer cells. We consider the phenomena, which are rarely mentioned in those theories: namely, cellularization of syncytium or coenocytes, and the reversible or irreversible somatogamy. The latter includes the short-term and the long-term vegetative (somatic) cells' fusions in the life cycles of unicellular organisms. The somatogamy and multinuclearity have repeatedly and independently emerged in various groups of unicellular eukaryotes. These phenomena are among dominant survival and biodiversity sustaining strategies in protists and we admit that they can likely play an analogous role in cancer cells.
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Povsic TJ, Gersh BJ. Stem Cells in Cardiovascular Diseases: 30,000-Foot View. Cells 2021; 10:cells10030600. [PMID: 33803227 PMCID: PMC8001267 DOI: 10.3390/cells10030600] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/01/2021] [Accepted: 03/03/2021] [Indexed: 12/15/2022] Open
Abstract
Stem cell and regenerative approaches that might rejuvenate the heart have immense intuitive appeal for the public and scientific communities. Hopes were fueled by initial findings from preclinical models that suggested that easily obtained bone marrow cells might have significant reparative capabilities; however, after initial encouraging pre-clinical and early clinical findings, the realities of clinical development have placed a damper on the field. Clinical trials were often designed to detect exceptionally large treatment effects with modest patient numbers with subsequent disappointing results. First generation approaches were likely overly simplistic and relied on a relatively primitive understanding of regenerative mechanisms and capabilities. Nonetheless, the field continues to move forward and novel cell derivatives, platforms, and cell/device combinations, coupled with a better understanding of the mechanisms that lead to regenerative capabilities in more primitive models and modifications in clinical trial design suggest a brighter future.
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Affiliation(s)
- Thomas J. Povsic
- Department of Medicine, and Duke Clinical Research Institute, Duke University, Durham, NC 27705, USA
- Correspondence:
| | - Bernard J. Gersh
- Department of Cardiovascular Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA;
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Wang L, Serpooshan V, Zhang J. Engineering Human Cardiac Muscle Patch Constructs for Prevention of Post-infarction LV Remodeling. Front Cardiovasc Med 2021; 8:621781. [PMID: 33718449 PMCID: PMC7952323 DOI: 10.3389/fcvm.2021.621781] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 02/04/2021] [Indexed: 12/20/2022] Open
Abstract
Tissue engineering combines principles of engineering and biology to generate living tissue equivalents for drug testing, disease modeling, and regenerative medicine. As techniques for reprogramming human somatic cells into induced pluripotent stem cells (iPSCs) and subsequently differentiating them into cardiomyocytes and other cardiac cells have become increasingly efficient, progress toward the development of engineered human cardiac muscle patch (hCMP) and heart tissue analogs has accelerated. A few pilot clinical studies in patients with post-infarction LV remodeling have been already approved. Conventional methods for hCMP fabrication include suspending cells within scaffolds, consisting of biocompatible materials, or growing two-dimensional sheets that can be stacked to form multilayered constructs. More recently, advanced technologies, such as micropatterning and three-dimensional bioprinting, have enabled fabrication of hCMP architectures at unprecedented spatiotemporal resolution. However, the studies working on various hCMP-based strategies for in vivo tissue repair face several major obstacles, including the inadequate scalability for clinical applications, poor integration and engraftment rate, and the lack of functional vasculature. Here, we review many of the recent advancements and key concerns in cardiac tissue engineering, focusing primarily on the production of hCMPs at clinical/industrial scales that are suitable for administration to patients with myocardial disease. The wide variety of cardiac cell types and sources that are applicable to hCMP biomanufacturing are elaborated. Finally, some of the key challenges remaining in the field and potential future directions to address these obstacles are discussed.
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Affiliation(s)
- Lu Wang
- Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Vahid Serpooshan
- Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, GA, United States
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States
- Children's Healthcare of Atlanta, Atlanta, GA, United States
| | - Jianyi Zhang
- Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham, Birmingham, AL, United States
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Intercellular mitochondrial transfer as a means of tissue revitalization. Signal Transduct Target Ther 2021; 6:65. [PMID: 33589598 PMCID: PMC7884415 DOI: 10.1038/s41392-020-00440-z] [Citation(s) in RCA: 207] [Impact Index Per Article: 51.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 11/04/2020] [Accepted: 11/24/2020] [Indexed: 01/31/2023] Open
Abstract
As the crucial powerhouse for cell metabolism and tissue survival, the mitochondrion frequently undergoes morphological or positional changes when responding to various stresses and energy demands. In addition to intracellular changes, mitochondria can also be transferred intercellularly. Besides restoring stressed cells and damaged tissues due to mitochondrial dysfunction, the intercellular mitochondrial transfer also occurs under physiological conditions. In this review, the phenomenon of mitochondrial transfer is described according to its function under both physiological and pathological conditions, including tissue homeostasis, damaged tissue repair, tumor progression, and immunoregulation. Then, the mechanisms that contribute to this process are summarized, such as the trigger factors and transfer routes. Furthermore, various perspectives are explored to better understand the mysteries of cell-cell mitochondrial trafficking. In addition, potential therapeutic strategies for mitochondria-targeted application to rescue tissue damage and degeneration, as well as the inhibition of tumor progression, are discussed.
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Chandy M, Wu JC. Molecular Imaging of Stem Cell Therapy in Ischemic Cardiomyopathy. Mol Imaging 2021. [DOI: 10.1016/b978-0-12-816386-3.00065-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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Apoptotic Bodies of Cardiomyocytes and Fibroblasts - Regulators of Directed Differentiation of Heart Stem Cells. Bull Exp Biol Med 2020; 170:112-117. [PMID: 33237531 DOI: 10.1007/s10517-020-05015-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Indexed: 12/22/2022]
Abstract
We studied the effects of apoptotic bodies of cardiomyocytes (ApBc) and fibroblasts (ApBf) on myocardial regeneration and contractility in rats and the dynamics of RNA concentrations in cardiomyocytes and fibroblasts at different stages of apoptosis. ApBc increase the contractility of rat myocardium, while ApBf reduce it. ApBc stimulate the development of clones of cardiomyocyte precursors in the myocardium, while ApBf stimulate the formation of endothelial precursor clones. In doxorubicin cardiomyopathy, ApBc, similar to the reference drug (ACE inhibitor) improve animal survival, while ApBf produce no such effect. RNA concentrations in cardiomyocytes and fibroblasts before apoptosis and at the beginning of cell death significantly differed, while in apoptotic bodies of these cells, it was practically the same. It has been hypothesized that RNA complex present in ApBc and ApBf represents an "epigenetic code" of directed differentiation of cardiac stem cells.
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Abstract
The regenerative capacity of the heart has long fascinated scientists. In contrast to other organs such as liver, skin, and skeletal muscle, the heart possesses only a minimal regenerative capacity. It lacks a progenitor cell population, and cardiomyocytes exit the cell cycle shortly after birth and do not re-enter after injury. Thus, any loss of cardiomyocytes is essentially irreversible and can lead to or exaggerate heart failure, which represents a major public health problem. New therapeutic options are urgently needed, but regenerative therapies have remained an unfulfilled promise in cardiovascular medicine until today. Yet, through a clearer comprehension of signaling pathways that regulate the cardiomyocyte cell cycle and advances in stem cell technology, strategies have evolved that demonstrate the potential to generate new myocytes and thereby fulfill an essential central criterion for heart repair.
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Affiliation(s)
- Florian Weinberger
- Institute for Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; , .,German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany
| | - Thomas Eschenhagen
- Institute for Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; , .,German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany
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A. Everts P, Flanagan II G, Rothenberg J, Mautner K. The Rationale of Autologously Prepared Bone Marrow Aspirate Concentrate for use in Regenerative Medicine Applications. Regen Med 2020. [DOI: 10.5772/intechopen.91310] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
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Selvakumar D, Clayton ZE, Chong JJH. Robust Cardiac Regeneration: Fulfilling the Promise of Cardiac Cell Therapy. Clin Ther 2020; 42:1857-1879. [PMID: 32943195 DOI: 10.1016/j.clinthera.2020.08.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 08/12/2020] [Accepted: 08/14/2020] [Indexed: 12/16/2022]
Abstract
PURPOSE We review the history of cardiac cell therapy, highlighting lessons learned from initial adult stem cell (ASC) clinical trials. We present pluripotent stem cell-derived cardiomyocytes (PSC-CMs) as a leading candidate for robust regeneration of infarcted myocardium but identify several issues that must be addressed before successful clinical translation. METHODS We conducted an unstructured literature review of PubMed-listed articles, selecting the most comprehensive and relevant research articles, review articles, clinical trials, and basic or translation articles in the field of cardiac cell therapy. Articles were identified using the search terms adult stem cells, pluripotent stem cells, cardiac stem cell, and cardiac regeneration or from references of relevant articles, Articles were prioritized and selected based on their impact, originality, or potential clinical applicability. FINDINGS Since its inception, the ASC therapy field has been troubled by conflicting preclinical data, academic controversies, and inconsistent trial designs. These issues have damaged perceptions of cardiac cell therapy among investors, the academic community, health care professionals, and, importantly, patients. In hindsight, the key issue underpinning these problems was the inability of these cell types to differentiate directly into genuine cardiomyocytes, rendering them unable to replace damaged myocardium. Despite this, beneficial effects through indirect paracrine or immunomodulatory effects remain possible and continue to be investigated. However, in preclinical models, PSC-CMs have robustly remuscularized infarcted myocardium with functional, force-generating cardiomyocytes. Hence, PSC-CMs have now emerged as a leading candidate for cardiac regeneration, and unpublished reports of first-in-human delivery of these cells have recently surfaced. However, the cardiac cell therapy field's history should serve as a cautionary tale, and we identify several translational hurdles that still remain. Preclinical solutions to issues such as arrhythmogenicity, immunogenicity, and poor engraftment rates are needed, and next-generation clinical trials must draw on robust knowledge of mechanistic principles of the therapy. IMPLICATIONS The clinical transplantation of functional stem cell-derived heart tissue with seamless integration into native myocardium is a lofty goal. However, considerable advances have been made during the past 2 decades. Currently, PSC-CMs appear to be the best prospect to reach this goal, but several hurdles remain. The history of adult stem cell trials has taught us that shortcuts cannot be taken without dire consequences, and it is essential that progress not be hurried and that a worldwide, cross-disciplinary approach be used to ensure safe and effective clinical translation.
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Affiliation(s)
- Dinesh Selvakumar
- Centre for Heart Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia; Department of Cardiology, Westmead Hospital, Westmead, New South Wales, Australia
| | - Zoe E Clayton
- Centre for Heart Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia
| | - James J H Chong
- Centre for Heart Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia; Department of Cardiology, Westmead Hospital, Westmead, New South Wales, Australia.
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41
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Zhang LN, Zhang DD, Yang L, Gu YX, Zuo QP, Wang HY, Xu J, Liu DX. Roles of cell fusion between mesenchymal stromal/stem cells and malignant cells in tumor growth and metastasis. FEBS J 2020; 288:1447-1456. [PMID: 33070450 DOI: 10.1111/febs.15483] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 06/21/2020] [Accepted: 07/08/2020] [Indexed: 01/02/2023]
Abstract
Invasion and metastasis are the basic characteristics and important markers of malignant tumors, which are also the main cause of death in cancer patients. Epithelial-mesenchymal transition (EMT) is recognized as the first step of tumor invasion and metastasis. Many studies have demonstrated that cell fusion is a common phenomenon and plays a critical role in cancer development and progression. At present, cancer stem cell fusion has been considered as a new mechanism of cancer metastasis. Mesenchymal stromal/stem cell (MSC) is a kind of adult stem cells with high self-renewal ability and multidifferentiation potential, which is used as a very promising fusogenic candidate in the tumor microenvironment and has a crucial role in cancer progression. Many research results have shown that MSCs are involved in the regulation of tumor growth and metastasis through cell fusion. However, the role of cell fusion between MSCs and malignant cells in tumor growth and metastasis is still controversial. Several studies have demonstrated that MSCs can enhance malignant characteristics, promoting tumor growth and metastasis by fusing with malignant cells, while other conflicting reports believe that MSCs can reduce tumorigenicity upon fusion with malignant cells. In this review, we summarize the recent research on cell fusion events between MSCs and malignant cells in tumor growth and metastasis. The elucidation of the molecular mechanisms between MSC fusion and tumor metastasis may provide an effective strategy for tumor biotherapy.
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Affiliation(s)
- Li-Na Zhang
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China
| | - Di-Di Zhang
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China
| | - Lei Yang
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China
| | - Yu-Xuan Gu
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China
| | - Qiu-Ping Zuo
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China
| | - Hao-Yi Wang
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China
| | - Jia Xu
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China
| | - Dian-Xin Liu
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China
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42
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He L, Nguyen NB, Ardehali R, Zhou B. Heart Regeneration by Endogenous Stem Cells and Cardiomyocyte Proliferation: Controversy, Fallacy, and Progress. Circulation 2020; 142:275-291. [PMID: 32687441 DOI: 10.1161/circulationaha.119.045566] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Ischemic heart disease is the leading cause of death worldwide. Myocardial infarction results in an irreversible loss of cardiomyocytes with subsequent adverse remodeling and heart failure. Identifying new sources for cardiomyocytes and promoting their formation represents a goal of cardiac biology and regenerative medicine. Within the past decade, many types of putative cardiac stem cells (CSCs) have been reported to regenerate the injured myocardium by differentiating into new cardiomyocytes. Some of these CSCs have been translated from bench to bed with reported therapeutic effectiveness. However, recent basic research studies on stem cell tracing have begun to question their fundamental biology and mechanisms of action, raising serious concerns over the myogenic potential of CSCs. We review the history of different types of CSCs within the past decade and provide an update of recent cell tracing studies that have challenged the origin and existence of CSCs. In addition to the potential role of CSCs in heart regeneration, proliferation of preexisting cardiomyocytes has recently gained more attention. This review will also evaluate the methodologic and technical aspects of past and current studies on CSCs and cardiomyocyte proliferation, with emphasis on technical strengths, advantages, and potential limitations of research approaches. While our understanding of cardiomyocyte generation and regeneration continues to evolve, it is important to address the shortcomings and inaccuracies in this field. This is best achieved by embracing technological advancements and improved methods to label single cardiomyocytes/progenitors and accurately investigate their developmental potential and fate/lineage commitment.
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Affiliation(s)
- Lingjuan He
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China (L.H., B.Z.)
| | - Ngoc B Nguyen
- Division of Cardiology, Department of Internal Medicine, David Geffen School of Medicine (N.B.N., R.A.), University of California, Los Angeles.,Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (N.B.N., R.A.), University of California, Los Angeles
| | - Reza Ardehali
- Division of Cardiology, Department of Internal Medicine, David Geffen School of Medicine (N.B.N., R.A.), University of California, Los Angeles.,Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (N.B.N., R.A.), University of California, Los Angeles
| | - Bin Zhou
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China (L.H., B.Z.).,School of Life Science and Technology, ShanghaiTech University, Shanghai, China (B.Z.).,School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China (B.Z.).,Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, China (B.Z.)
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Tal A, Tal R, Shaikh S, Gidicsin S, Mamillapalli R, Taylor HS. Characterization of cell fusion in an experimental mouse model of endometriosis†. Biol Reprod 2020; 100:390-397. [PMID: 30304517 DOI: 10.1093/biolre/ioy221] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2018] [Revised: 09/29/2018] [Accepted: 10/08/2018] [Indexed: 02/01/2023] Open
Abstract
Cell fusion is involved in the development of some adult organs, is implicated in the pathogenesis of specific types of cancer, and is known to participate in repair/regeneration processes mediated by bone-marrow-derived cells (BMDCs). Endometriosis is a disease characterized by growth of functional endometrial tissue outside of the uterine cavity. Endometriosis shares some molecular properties with cancer and BMDCs home to endometriosis lesions in a mouse model. Our objective was to determine if cell fusion can occur in endometriosis and establish whether bone-marrow-derived cells participate in cell fusion events in lesions. We employed a Cre-Lox system to identify cell fusion events in a mouse model of endometriosis. Fused cells were detected in endometriotic lesions, albeit at a low frequency (∼1 in 400 cells), localized to the stromal compartment, and displayed restricted proliferation. Using 5-fluorouracil-based nongonadotoxic bone marrow transplantation model, we demonstrate that bone marrow cells represent a principal cell source for fusion events in lesions. Cell fusion progeny uniformly lacked expression of selected markers of hematopoietic, endothelial, and epithelial markers, though they expressed the mesenchymal/stromal markers Sca-1 and CD29. This study is the first to describe the phenomenon of cell fusion in endometriosis and points to a mesenchymal population derived from cell fusion events with limited proliferative activity, properties previously attributed to endometrial stem cells. Their putative role in the pathogenesis of the disease remains to be elucidated.
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Affiliation(s)
- A Tal
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
| | - R Tal
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
| | - S Shaikh
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
| | - S Gidicsin
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
| | - R Mamillapalli
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
| | - H S Taylor
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
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Shabo I, Svanvik J, Lindström A, Lechertier T, Trabulo S, Hulit J, Sparey T, Pawelek J. Roles of cell fusion, hybridization and polyploid cell formation in cancer metastasis. World J Clin Oncol 2020; 11:121-135. [PMID: 32257843 PMCID: PMC7103524 DOI: 10.5306/wjco.v11.i3.121] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 01/02/2020] [Accepted: 03/01/2020] [Indexed: 02/06/2023] Open
Abstract
Cell-cell fusion is a normal biological process playing essential roles in organ formation and tissue differentiation, repair and regeneration. Through cell fusion somatic cells undergo rapid nuclear reprogramming and epigenetic modifications to form hybrid cells with new genetic and phenotypic properties at a rate exceeding that achievable by random mutations. Factors that stimulate cell fusion are inflammation and hypoxia. Fusion of cancer cells with non-neoplastic cells facilitates several malignancy-related cell phenotypes, e.g., reprogramming of somatic cell into induced pluripotent stem cells and epithelial to mesenchymal transition. There is now considerable in vitro, in vivo and clinical evidence that fusion of cancer cells with motile leucocytes such as macrophages plays a major role in cancer metastasis. Of the many changes in cancer cells after hybridizing with leucocytes, it is notable that hybrids acquire resistance to chemo- and radiation therapy. One phenomenon that has been largely overlooked yet plays a role in these processes is polyploidization. Regardless of the mechanism of polyploid cell formation, it happens in response to genotoxic stresses and enhances a cancer cell’s ability to survive. Here we summarize the recent progress in research of cell fusion and with a focus on an important role for polyploid cells in cancer metastasis. In addition, we discuss the clinical evidence and the importance of cell fusion and polyploidization in solid tumors.
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Affiliation(s)
- Ivan Shabo
- Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE 171 77, Sweden
- Patient Area of Breast Cancer, Sarcoma and Endocrine Tumours, Theme Cancer, Karolinska University Hospital, Stockholm SE 171 76, Sweden
| | - Joar Svanvik
- The Transplant Institute, Sahlgrenska University Hospital, Gothenburg SE 413 45, Sweden
- Division of Surgery, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping SE 581 83, Sweden
| | - Annelie Lindström
- Division of Cell Biology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping SE 581 85, Sweden
| | - Tanguy Lechertier
- Novintum Bioscience Ltd, London Bioscience Innovation Centre, London NW1 0NH, United Kingdom
| | - Sara Trabulo
- Novintum Bioscience Ltd, London Bioscience Innovation Centre, London NW1 0NH, United Kingdom
| | - James Hulit
- Novintum Bioscience Ltd, London Bioscience Innovation Centre, London NW1 0NH, United Kingdom
| | - Tim Sparey
- Novintum Bioscience Ltd, London Bioscience Innovation Centre, London NW1 0NH, United Kingdom
| | - John Pawelek
- Department of Dermatology and the Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, United States
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45
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Fine B, Vunjak-Novakovic G. Heart regeneration in mouse and human: A bioengineering perspective. CURRENT OPINION IN PHYSIOLOGY 2020; 14:56-63. [PMID: 32095673 DOI: 10.1016/j.cophys.2020.01.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
In this short review, we draw parallels and stress differences between heart regeneration in mice and human, from a bioengineering perspective. As the prevailing dogma that the adult heart is completely post-mitotic is starting to change, there are multiple opportunities for augmenting the limited but definitive turnover of cardiomyocytes, to the extent necessary developing clinically relevant modalities for enhancing heart repair. We discuss some of the most promising among these new directions: mobilization of paracrine signaling by therapeutic cells, cell-free therapy of the heart using extracellular vesicles, and direct reprograming of endogenous cells. These new directions share the cell-free, mechanistic approach to heart repair that could be translated into the clinic faster and safer than the traditional cell therapies.
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Affiliation(s)
- Barry Fine
- Department of Medicine, Engineering Columbia University, New York NY 10032
| | - Gordana Vunjak-Novakovic
- Department of Medicine, Engineering Columbia University, New York NY 10032.,Department of Biomedical Engineering Columbia University, New York NY 10032
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46
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Yellamilli A, Ren Y, McElmurry RT, Lambert JP, Gross P, Mohsin S, Houser SR, Elrod JW, Tolar J, Garry DJ, van Berlo JH. Abcg2-expressing side population cells contribute to cardiomyocyte renewal through fusion. FASEB J 2020; 34:5642-5657. [PMID: 32100368 DOI: 10.1096/fj.201902105r] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 02/10/2020] [Accepted: 02/13/2020] [Indexed: 12/15/2022]
Abstract
The adult mammalian heart has a limited regenerative capacity. Therefore, identification of endogenous cells and mechanisms that contribute to cardiac regeneration is essential for the development of targeted therapies. The side population (SP) phenotype has been used to enrich for stem cells throughout the body; however, SP cells isolated from the heart have been studied exclusively in cell culture or after transplantation, limiting our understanding of their function in vivo. We generated a new Abcg2-driven lineage-tracing mouse model with efficient labeling of SP cells. Labeled SP cells give rise to terminally differentiated cells in bone marrow and intestines. In the heart, labeled SP cells give rise to lineage-traced cardiomyocytes under homeostatic conditions with an increase in this contribution following cardiac injury. Instead of differentiating into cardiomyocytes like proposed cardiac progenitor cells, cardiac SP cells fuse with preexisting cardiomyocytes to stimulate cardiomyocyte cell cycle reentry. Our study is the first to show that fusion between cardiomyocytes and non-cardiomyocytes, identified by the SP phenotype, contribute to endogenous cardiac regeneration by triggering cardiomyocyte cell cycle reentry in the adult mammalian heart.
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Affiliation(s)
- Amritha Yellamilli
- Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis, MN, USA.,Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, USA.,Stem Cell Institute, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Yi Ren
- Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Ron T McElmurry
- Stem Cell Institute, University of Minnesota Medical School, Minneapolis, MN, USA.,Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Jonathan P Lambert
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Polina Gross
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Sadia Mohsin
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Steven R Houser
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - John W Elrod
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Jakub Tolar
- Stem Cell Institute, University of Minnesota Medical School, Minneapolis, MN, USA.,Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Daniel J Garry
- Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Jop H van Berlo
- Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis, MN, USA.,Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, USA.,Stem Cell Institute, University of Minnesota Medical School, Minneapolis, MN, USA
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47
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Andrejew R, Glaser T, Oliveira-Giacomelli Á, Ribeiro D, Godoy M, Granato A, Ulrich H. Targeting Purinergic Signaling and Cell Therapy in Cardiovascular and Neurodegenerative Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1201:275-353. [PMID: 31898792 DOI: 10.1007/978-3-030-31206-0_14] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Extracellular purines exert several functions in physiological and pathophysiological mechanisms. ATP acts through P2 receptors as a neurotransmitter and neuromodulator and modulates heart contractility, while adenosine participates in neurotransmission, blood pressure, and many other mechanisms. Because of their capability to differentiate into mature cell types, they provide a unique therapeutic strategy for regenerating damaged tissue, such as in cardiovascular and neurodegenerative diseases. Purinergic signaling is pivotal for controlling stem cell differentiation and phenotype determination. Proliferation, differentiation, and apoptosis of stem cells of various origins are regulated by purinergic receptors. In this chapter, we selected neurodegenerative and cardiovascular diseases with clinical trials using cell therapy and purinergic receptor targeting. We discuss these approaches as therapeutic alternatives to neurodegenerative and cardiovascular diseases. For instance, promising results were demonstrated in the utilization of mesenchymal stem cells and bone marrow mononuclear cells in vascular regeneration. Regarding neurodegenerative diseases, in general, P2X7 and A2A receptors mostly worsen the degenerative state. Stem cell-based therapy, mainly through mesenchymal and hematopoietic stem cells, showed promising results in improving symptoms caused by neurodegeneration. We propose that purinergic receptor activity regulation combined with stem cells could enhance proliferative and differentiation rates as well as cell engraftment.
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Affiliation(s)
- Roberta Andrejew
- Neuroscience Laboratory, Institute of Chemistry, Department of Biochemistry, University of São Paulo, São Paulo, Brazil
| | - Talita Glaser
- Neuroscience Laboratory, Institute of Chemistry, Department of Biochemistry, University of São Paulo, São Paulo, Brazil
| | - Ágatha Oliveira-Giacomelli
- Neuroscience Laboratory, Institute of Chemistry, Department of Biochemistry, University of São Paulo, São Paulo, Brazil
| | - Deidiane Ribeiro
- Neuroscience Laboratory, Institute of Chemistry, Department of Biochemistry, University of São Paulo, São Paulo, Brazil
| | - Mariana Godoy
- Neuroscience Laboratory, Institute of Chemistry, Department of Biochemistry, University of São Paulo, São Paulo, Brazil.,Laboratory of Neurodegenerative Diseases, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Alessandro Granato
- Neuroscience Laboratory, Institute of Chemistry, Department of Biochemistry, University of São Paulo, São Paulo, Brazil
| | - Henning Ulrich
- Neuroscience Laboratory, Institute of Chemistry, Department of Biochemistry, University of São Paulo, São Paulo, Brazil.
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48
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Hocum Stone LL, Swingen C, Wright C, Qi SS, Rassette M, McFalls EO, Kelly RF. Recovery of hibernating myocardium using stem cell patch with coronary bypass surgery. J Thorac Cardiovasc Surg 2020; 162:e3-e16. [PMID: 32059928 DOI: 10.1016/j.jtcvs.2019.12.073] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 12/03/2019] [Accepted: 12/05/2019] [Indexed: 12/19/2022]
Abstract
OBJECTIVE This study aims to investigate the utility of mesenchymal stem cells (MSCs) applied as an epicardial patch during coronary artery bypass graft (CABG) to target hibernating myocardium; that is, tissue with persistently decreased myocardial function, in a large animal model. METHODS Hibernating myocardium was induced in juvenile swine (n = 12) using a surgically placed constrictor on the left anterior descending artery, causing stenosis without infarction. After 12 weeks, single-vessel CABG was performed using left internal thoracic artery to left anterior descending artery graft. During CABG, an epicardial patch was applied to the hibernating myocardium region consisting either of MSCs grown onto a polyglactin mesh (n = 6), or sham polyglactin mesh without MSCs (n = 6). Four weeks after CABG and patch placement, cardiac magnetic resonance imaging was performed and cardiac tissue was examined by gross inspection, including coronary dilators for vessel stenosis and patency, electron microscopy, protein assays, and proteomic analysis. RESULTS CABG + MSC myocardium showed improvement in contractile function (78.24% ± 19.6%) compared with sham patch (39.17% ± 5.57%) during inotropic stimulation (P < .05). Compared with sham patch control, electron microscopy of CABG + MSC myocardium showed improvement in mitochondrial size, number, and morphology; protein analysis similarly showed increases in expression of the mitochondrial biogenesis marker peroxisome proliferator-activated receptor gamma coactivator 1-alpha (0.0022 ± 0.0009 vs 0.023 ± 0.009) (P < .01) along with key components of the electron transport chain, including succinate dehydrogenase (complex II) (0.06 ± 0.02 vs 0.14 ± 0.03) (P < .05) and adenosine triphosphate synthase (complex V) (2.7 ± 0.4 vs 4.2 ± 0.26) (P < .05). CONCLUSIONS In hibernating myocardium, placement of a stem cell patch during CABG shows promise in improving myocardial function by improving mitochondrial morphology and function.
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Affiliation(s)
- Laura L Hocum Stone
- Minneapolis VA Health Care System, Minneapolis, Minn; Department of Surgery, University of Minnesota, Minneapolis, Minn.
| | - Cory Swingen
- Department of Surgery, University of Minnesota, Minneapolis, Minn
| | - Christin Wright
- Minneapolis VA Health Care System, Minneapolis, Minn; Department of Surgery, University of Minnesota, Minneapolis, Minn
| | - Steven S Qi
- Department of Surgery, University of Minnesota, Minneapolis, Minn
| | - Matt Rassette
- Minneapolis VA Health Care System, Minneapolis, Minn
| | - Edward O McFalls
- Minneapolis VA Health Care System, Minneapolis, Minn; Department of Medicine, University of Minnesota, Minneapolis, Minn
| | - Rosemary F Kelly
- Department of Surgery, University of Minnesota, Minneapolis, Minn
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49
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Leppik L, Sielatycka K, Henrich D, Han Z, Wang H, Eischen-Loges MJ, Oliveira KMC, Bhavsar MB, Ratajczak MZ, Barker JH. Role of Adult Tissue-Derived Pluripotent Stem Cells in Bone Regeneration. Stem Cell Rev Rep 2019; 16:198-211. [PMID: 31828580 PMCID: PMC6987071 DOI: 10.1007/s12015-019-09943-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Background Bone marrow-derived mononuclear cells (BM-MNC) consist of a heterogeneous mix of mesenchymal stem cells (MSC), hematopoietic progenitor cells (HPC), endothelial progenitor cells (EPC), monocytes, lymphocytes and pluripotent stem cells. Whereas the importance of MSC and EPC has been well documented in bone healing and regeneration studies, the role of pluripotent stem cells is still poorly understood. In the present study we evaluated if and how Very Small Embryonic Like cells (VSEL), isolated from rat BM-MNC, contribute to bone healing. Methods Large bone defects were made in the femurs of 38 Sprague Dawley female rats and treated with β-TCP scaffold granules seeded with male VSEL; BM-MNC, VSEL-depleted BM-MNC or scaffold alone, and bone healing was evaluated at 8 weeks post-surgery. Results Bone healing was significantly increased in defects treated with VSEL and BM-MNC, compared to defects treated with VSEL-depleted BM-MNC. Donor cells were detected in new bone tissue, in all the defects treated with cells, and in fibrous tissue only in defects treated with VSEL-depleted BM-MNC. The number of CD68+ cells was the highest in the VSEL-depleted group, whereas the number of TRAP positive cells was the lowest in this group. Conclusions Based on the results, we can conclude that VSEL play a role in BM-MNC induced bone formation. In our rat femur defect model, in defects treated with VSEL-depleted BM-MNC, osteoclastogenesis and bone formation were decreased, and foreign body reaction was increased.
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Affiliation(s)
- Liudmila Leppik
- Frankfurt Initiative for Regenerative Medicine, Experimental Orthopedics & Trauma Surgery, J.W. Goethe University, Frankfurt am Main, Germany.
| | - K Sielatycka
- Institute of Biology, Faculty of Exact and Natural Science, University of Szczecin, Szczecin, Poland
| | - D Henrich
- Department of Trauma, Hand & Reconstructive Surgery, J.W. Goethe University, Frankfurt/Main, Germany
| | - Z Han
- Frankfurt Initiative for Regenerative Medicine, Experimental Orthopedics & Trauma Surgery, J.W. Goethe University, Frankfurt am Main, Germany
| | - H Wang
- Frankfurt Initiative for Regenerative Medicine, Experimental Orthopedics & Trauma Surgery, J.W. Goethe University, Frankfurt am Main, Germany
| | - M J Eischen-Loges
- Frankfurt Initiative for Regenerative Medicine, Experimental Orthopedics & Trauma Surgery, J.W. Goethe University, Frankfurt am Main, Germany
| | - K M C Oliveira
- Frankfurt Initiative for Regenerative Medicine, Experimental Orthopedics & Trauma Surgery, J.W. Goethe University, Frankfurt am Main, Germany
| | - M B Bhavsar
- Frankfurt Initiative for Regenerative Medicine, Experimental Orthopedics & Trauma Surgery, J.W. Goethe University, Frankfurt am Main, Germany
| | - M Z Ratajczak
- Stem Cell Institute at the James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - J H Barker
- Frankfurt Initiative for Regenerative Medicine, Experimental Orthopedics & Trauma Surgery, J.W. Goethe University, Frankfurt am Main, Germany
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Abstract
The investment of nearly 2 decades of clinical investigation into cardiac cell therapy has yet to change cardiovascular practice. Recent insights into the mechanism of cardiac regeneration help explain these results and provide important context in which we can develop next-generation therapies. Non-contractile cells such as bone marrow or adult heart derivatives neither engraft long-term nor induce new muscle formation. Correspondingly, these cells offer little functional benefit to infarct patients. In contrast, preclinical data indicate that transplantation of bona fide cardiomyocytes derived from pluripotent stem cells induces direct remuscularization. This new myocardium beats synchronously with the host heart and induces substantial contractile benefits in macaque monkeys, suggesting that regeneration of contractile myocardium is required to fully recover function. Through a review of the preclinical and clinical trials of cardiac cell therapy, distinguishing the primary mechanism of benefit as either contractile or non-contractile helps appreciate the barriers to cardiac repair and establishes a rational path to optimizing therapeutic benefit.
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Affiliation(s)
- Kenta Nakamura
- Institute for Stem Cell and Regenerative Medicine, University of Washington
- Center for Cardiovascular Biology, University of Washington
- Department of Medicine/Cardiology, University of Washington
| | - Charles E Murry
- Institute for Stem Cell and Regenerative Medicine, University of Washington
- Center for Cardiovascular Biology, University of Washington
- Department of Medicine/Cardiology, University of Washington
- Department of Pathology, University of Washington
- Department of Bioengineering, University of Washington
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