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• W3209076737 abstract "Central MessageSuccessful transplantation of induced autologous pluripotent stem cells requires many challenging technical steps.See Article page 359. Successful transplantation of induced autologous pluripotent stem cells requires many challenging technical steps. See Article page 359. It should be simple in theory: if a treatment fails, one only needs to add a missing element, and voilà, recovery continues as ever before. However, it seems that biology is complex and molecular pathways interdependent, and several interventions are often needed to initiate successful healing. Stem cell research aims at manufacturing products that compensate devitalized myocardium caused by infarction and heart failure. Stem cells are applied to tissue injury, but several risks persist, such as allogeneic tissue rejection, poor cell sustainability, and harmful interaction on vital paracrine functions. Induced autologous pluripotent stem cells (iPSCs) may solve tissue rejection but not necessarily tissue adherence, consequences of genetic mutations, or harmful chemical and molecular mechanisms.1Pelacho B. Mazo M. Gavira J.J. Prósper F. Adult stem cells: from new cell sources to changes in methodology.J Cardiovasc Transl Res. 2011; 4: 154-160Crossref PubMed Scopus (11) Google Scholar The study by Osada and colleagues2Osada H. Kawatou M. Fujita D. Tabata Y. Minatoya K. Yamashita J.K. et al.Therapeutic potential of clinical-grade human induced pluripotent stem cell-derived cardiac tissues.J Thorac Cardiovasc Surg Open. 2021; 8: 359-374Scopus (2) Google Scholar investigated whether piles of cardiac cell sheets created from iPSCs together with gelatin hydrogel microspheres would add to cardiomyocyte regeneration, cardiac function, and recovery after experimental myocardial infarction. iPSCs were first differentiated to create potent cells for transplantation using inhibition of the canonical Wnt/β-catenin signaling pathway. Thereafter, gelatin hydrogen microspheres were added to create layers of cell sheets, since relatively poor cell engraftment without a carrying media is evident.1Pelacho B. Mazo M. Gavira J.J. Prósper F. Adult stem cells: from new cell sources to changes in methodology.J Cardiovasc Transl Res. 2011; 4: 154-160Crossref PubMed Scopus (11) Google Scholar The resulting treat was applied to experimentally induced myocardial infarction of rats without a thymus. In conclusion, transplantation of the differentiated iPSCs together with gelatin hydrogen microspheres was feasible and showed signs of functional cardiac recovery and healed myocardial scar area. The study by Osada and colleagues2Osada H. Kawatou M. Fujita D. Tabata Y. Minatoya K. Yamashita J.K. et al.Therapeutic potential of clinical-grade human induced pluripotent stem cell-derived cardiac tissues.J Thorac Cardiovasc Surg Open. 2021; 8: 359-374Scopus (2) Google Scholar is technically outstanding and thought-provoking. Exciting details of the study necessitate discussion to plan subsequent research. Wnt/β-catenin signaling is fundamental to many processes, including cell differentiation, proliferation, and tissue regeneration.3Naito A.T. Shiojima I. Akazawa H. Hidaka K. Morisaki T. Kikuchi A. et al.Developmental stage-specific biphasic roles of Wnt/beta-catenin signaling in cardiomyogenesis and hematopoiesis.Proc Natl Acad Sci U S A. 2006; 103: 19812-19817Crossref PubMed Scopus (365) Google Scholar While the upregulation of Wnt/β-catenin signal is required for mesoderm differentiation, the cardiac specification process requires its inhibition,3Naito A.T. Shiojima I. Akazawa H. Hidaka K. Morisaki T. Kikuchi A. et al.Developmental stage-specific biphasic roles of Wnt/beta-catenin signaling in cardiomyogenesis and hematopoiesis.Proc Natl Acad Sci U S A. 2006; 103: 19812-19817Crossref PubMed Scopus (365) Google Scholar but only at a specific time window; otherwise, the procedure may be inefficient or even harmful.3Naito A.T. Shiojima I. Akazawa H. Hidaka K. Morisaki T. Kikuchi A. et al.Developmental stage-specific biphasic roles of Wnt/beta-catenin signaling in cardiomyogenesis and hematopoiesis.Proc Natl Acad Sci U S A. 2006; 103: 19812-19817Crossref PubMed Scopus (365) Google Scholar,4Kahn M. Can we safely target the Wnt pathway?.Nat Rev Drug Discov. 2014; 13: 513-532Crossref PubMed Scopus (648) Google Scholar Can manipulation of the cell proliferation pathway exacerbate the risk of cancer and arrhythmia?4Kahn M. Can we safely target the Wnt pathway?.Nat Rev Drug Discov. 2014; 13: 513-532Crossref PubMed Scopus (648) Google Scholar The transplanted graft may provide a reservoir of therapeutic cytokines and growth factors that enable the transplanted cells to survive on the hypoxic infarcted area while development of angiogenesis would ensue.1Pelacho B. Mazo M. Gavira J.J. Prósper F. Adult stem cells: from new cell sources to changes in methodology.J Cardiovasc Transl Res. 2011; 4: 154-160Crossref PubMed Scopus (11) Google Scholar,2Osada H. Kawatou M. Fujita D. Tabata Y. Minatoya K. Yamashita J.K. et al.Therapeutic potential of clinical-grade human induced pluripotent stem cell-derived cardiac tissues.J Thorac Cardiovasc Surg Open. 2021; 8: 359-374Scopus (2) Google Scholar However, angiogenesis is assumed to initiate from the outer border of the infarction, and the center of the infarction is left without vascular supply for some time. Thick layers of supportive cell sheets may in themselves limit cell oxygenation.1Pelacho B. Mazo M. Gavira J.J. Prósper F. Adult stem cells: from new cell sources to changes in methodology.J Cardiovasc Transl Res. 2011; 4: 154-160Crossref PubMed Scopus (11) Google Scholar The use of athymic nude rats as recipients may partly simulate the concept of clinical autologous transplantation, but the use of immunosuppressants is anticipated during any allogeneic transplantation.5Kawamura T. Miyagawa S. Fukushima S. Maeda A. Kashiyama N. Kawamura A. et al.Cardiomyocytes derived from MHC-homozygous induced pluripotent stem cells exhibit reduced allogeneic immunogenicity in MHC-matched non-human primates.Stem Cell Reports. 2016; 6: 312-320Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar Would even a graft-versus-host type of disease be possible while using patient cells with genetic mutations?6Frick M. Chan W. Arends C.M. Hablesreiter R. Halik A. Heuser M. et al.Role of donor clonal hematopoiesis in allogeneic hematopoietic stem-cell transplantation.J Clin Oncol. 2019; 10: 375-385Crossref Scopus (96) Google Scholar The combination of preparing all elements of a successful graft is indeed challenging. Many different phases of a manufacturing recipe may increase the risk of undesired outcome; the more cooks, the more complex the output becomes. How much functional cardiac recovery with limited scar and vascular density is required for sufficient clinical recovery after myocardial infarction? When would translational research provide enough technical and ethical evidence to launch stem cell technology into efficient clinical practice?7Walley J. Khan M.A. Shah S.K. Witter S. Wei X. How to get research into practice: first get practice into research.Bull World Health Org. 2007; 85: 424-425Crossref PubMed Scopus (51) Google Scholar Therapeutic potential of clinical-grade human induced pluripotent stem cell-derived cardiac tissuesJTCVS OpenVol. 8PreviewTo establish a protocol to prepare and transplant clinical-grade human induced pluripotent stem cell (hiPSC)-derived cardiac tissues (HiCTs) and to evaluate the therapeutic potential in an animal myocardial infarction (MI) model. Full-Text PDF Open Access" @default.
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• W3209076737 title "Commentary: A pile of vital cells is needed to treat myocardial infarction" @default.
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• W3209076737 doi "https://doi.org/10.1016/j.xjon.2021.10.034" @default.
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