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Cardiac Cell Therapy 3.0

2017; Lippincott Williams & Wilkins; Volume: 121; Issue: 2 Linguagem: Inglês

10.1161/circresaha.117.311293

1524-4571

Konstantinos E. Hatzistergos, Anastasia Vedenko,

Tissue Engineering and Regenerative Medicine

HomeCirculation ResearchVol. 121, No. 2Cardiac Cell Therapy 3.0 Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCardiac Cell Therapy 3.0The Beginning of the End or the End of the Beginning? Konstantinos E. Hatzistergos and Anastasia Vedenko Konstantinos E. HatzistergosKonstantinos E. Hatzistergos From the Interdisciplinary Stem Cell Institute, Leonard M. Miller School of Medicine, University of Miami, FL. and Anastasia VedenkoAnastasia Vedenko From the Interdisciplinary Stem Cell Institute, Leonard M. Miller School of Medicine, University of Miami, FL. Originally published7 Jul 2017https://doi.org/10.1161/CIRCRESAHA.117.311293Circulation Research. 2017;121:95–97Cardiac cell therapy (CCT) holds great promise as a regenerative medicine approach for the treatment of cardiovascular diseases (CVDs).1 The first generation of CCTs tested various adult cell types, including skeletal myoblasts, bone marrow (BM)–derived mesenchymal stem cells (MSCs), and cardiac progenitor cells (CPCs). More recently, the advent of induced pluripotent stem cells (PSCs) led to the much-anticipated second generation of CCTs with bona fide, PSC-derived CPCs and cardiomyocytes.1 The bad news is that, to date, both adult and PSC-based CCTs have failed to meet their promise of directly remuscularizing and repairing the heart to a therapeutically meaningful extent.2,3 The good news is that some cell types clearly demonstrate encouraging results in terms of efficacy and safety and, more importantly, reveal a previously underestimated key role of CCT, to indirectly promote repair by regulating mechanisms of endogenous cardiac regeneration in the host.1,4Article, see p 113The increasingly high burden of CVDs, coupled with the limited efficacy seen in both adult and PSC-based CCTs, and incomplete mechanistic understanding of adult human heart regeneration, have fueled disappointment, skepticism, and polarized the field.5 This schism has been particularly apparent in the area of adult CCTs, which also faces a current crisis of scientific distrust.5 However, the interpretation that a possible stumble in research progress is proof that CCT is broken would be unscientific. As Daniel Wegner noted, "…tipping the balance toward skepticism can eradicate ideas faster than we can generate them. Eventually, we arrive at a vacuous chasm, with no theory standing and no idea left without serious wounds."6Under this prism, it is worth exploring how the field of adult CCTs fares, compared with other regenerative medicine approaches. PSC-based CCTs offer perhaps the strongest argument against adult CCTs because of their unsurpassed ability to proliferate and differentiate into cardiomyocytes.5 The idea that such a trait is the premise of CCT is based on experiments in zebrafish and newborn mice, both of which retain full capacity to regenerate a resected heart, possibly via cardiomyocyte amplification-based remuscularization mechanisms.1 However, experiments in more clinically relevant CVD models indicate that PSC-based direct remuscularization approaches exert effects that are more cosmetic than regenerative in nature because cardiomyocyte engraftment is not accompanied by scar resorption and regeneration.3,4 Moreover, both adult and PSC-based CCTs produce comparable improvements in cardiac function,7 likely indirectly, via paracrine stimulation of endogenous repair mechanisms in the host.4 Similarly, although gene-editing approaches offer hope for elucidating the genetic basis of CVDs, their potential application as regenerative therapy is currently limited. In addition to the technical challenges with safely and efficiently gene-editing billions of cardiomyocytes in vivo, CVDs are molecularly complex, rather than of monogenic cause.8 Likewise, the molecular mechanisms of cardiomyogenesis entail precise, spatiotemporal modulation of multiple signaling gradients in both cardiomyogenic and noncardiomyogenic cells, and, therefore, the possibility of developing cell-free, drug-based approaches to recapitulate such complex and dynamic processes in vivo is currently limited.1In this issue of Circulation Research, Monsanto et al9 lend support to a promising strategy to address the limitations of cardiac regenerative approaches by engineering combinatorial CCTs. This idea stands on 2 pillars: (1) no single-cell population can produce all cell types that make up the human heart; and (2) both cardiomyogenic and noncardiomyogenic cells are essential for heart development and repair. Thus, engineering adult and PSC-derived cell combinations with complementary roles may more efficiently regulate endogenous regenerative pathways, compared with conventional CCT (Figure).1 For example, the observation that BM-MSC therapy stimulates endogenous CPCs10,11 led to the idea of combining the 2 adult cell types for greater, synergistic effects. Indeed, this hypothesis has produced encouraging results in several large and small animal studies of CVD1 and is currently in a phase II, randomized, placebo-controlled trial in ischemic cardiomyopathy patients (NCT02501811). Similarly, the combination of human PSC-derived cardiomyocytes with vascular cells12 or MSCs13 produces further improvements in heart repair compared with cardiomyocytes alone, likely because of enhanced stimulation of endogenous repair mechanisms. The new method by Monsanto et al,9 to derive 3 distinct cardiac stem cell types from within the adult human heart, could potentially foster such applications.Download figureDownload PowerPointFigure. Combinatorial cardiac cell therapies (CCTs) for heart regeneration. Although regeneration and remuscularization are thought of as synonymous in cardiac regenerative medicine, adult and pluripotent stem cell (PSC)–based CCT trials unveil regenerative barriers unlikely to be circumvented by remuscularization alone. Synergism between complementary cell types, in the form of combinatorial CCTs, is a promising strategy for therapeutically targeting endogenous cardiac regeneration roadblocks. CM indicates cardiomyogenic cells; CPCs, cardiac progenitors; ECM, extracellular matrix; EPC, endothelial progenitor cell; MSCs, mesenchymal stem cells; NC, neurogenic cells; and VC, vasculogenic cells.Using the cell-surface receptor cKit, both as a positive and negative selection marker, the authors devised a strategy to purify concurrently MSCs, CPCs, and endothelial progenitor cells from adult heart biopsies obtained during cardiac surgery.9 MSCs are the most abundant derivative, comprising ≈90% to 95% of the cardiac stem cell pool, and are purified as the CD105+/CD90+ fraction of cKit-negative cardiac cells. Consistent with previous reports,14 cardiac MSCs exhibit a fibroblastoid morphology, produce colony-forming units-fibroblast, and exhibit multilineage differentiation into adipocytes, chondrocytes, and osteocytes.9 However, compared with BM-MSCs, cardiac MSCs exhibit slow in vitro growth kinetics and express cardiac lineage markers, such as the zinc finger transcription factor GATA4 and smooth muscle actin. Immunologically, expression of MHC (major histocompatibility complexes) classes I and II and costimulatory molecules CD80 and CD86 are similar to BM-MSCs, but cardiac MSCs express higher levels of the costimulatory molecule CD40. It is, therefore, unclear whether cardiac MSCs are as immunoprivileged as BM-MSCs. Such differences, however, are not surprising because mouse studies indicate distinct identities for BM and cardiac MSCs, with the latter possibly representing postnatal epicardial progenitors.14The use of cKit as a CPC marker has been controversial.5 Recent studies identify at least 2 distinct cell types expressing cKit in the heart: a rare, cardiomyogenic cell likely of neural crest lineage, and a more abundant vasculogenic cell, possibly of mesodermal lineage.15 The work by Monsanto et al9 further supports these findings. Positive selection for cKit yields 2 stem cell types with distinct immunophenotypic and gene expression profiles. cKit+ endothelial progenitor cells are morphologically round and committed to vascular fates, as indicated by high angiogenic potential in a Matrigel-based ex vivo angiogenesis assay and expression of CD133 and PECAM1 (platelet and endothelial cell adhesion molecule 1). cKit+ CPCs exhibit spindle-like morphology and a more myogenic profile, as indicated by lack of PECAM1 and relatively higher expression of GATA4 and smooth muscle actin. However, whether CPCs retain cardiomyogenic capacity is not demonstrated. Importantly, gene expression profiling reveals striking differences between the 3 cardiac stem cell types in cytokines and extracellular matrix genes, such as SDF1, NRG1, FGF2, TIMP1, and MMP1.The study by Monsanto et al9 is an important advance in cardiac regenerative medicine. First, it is a bold demonstration of cellular plasticity retained in the human heart, regardless of age, sex or health condition. Stem cells were isolated from patients ≤84 years old and experienced a range of diseases, including diabetes mellitus and coronary artery disease. Second, the ability to isolate 3 stem cell types from a single heart biopsy allows us to gain insight into the cellular composition in the adult human heart and the potential role of these unique cell types in CVD and regeneration. Because ≈70% of human heart cells are noncardiomyocytes, thorough research of their nature should be at the forefront of cardiac regenerative medicine.1 For example, Monsanto et al9 noted that some cultures failed to yield all 3 stem cell types, a finding which merits further investigation for any potential relationship to disease mechanisms. Last, the method of Monsanto et al9 enables the isolation and expansion of therapeutic volumes of cardiac MSCs, CPCs, and endothelial progenitor cells from a single biopsy with 80% to 90% success (≈100 million cells of each type could be manufactured in ≈10 passages). Such technology is expected to be important for engineering combinatorial CCTs, using adult and PSC-based combinations,1,12,13 in a manner that effectively eliminates barriers to endogenous cardiac regeneration and may eventually lead to a much-needed scientific breakthrough for the treatment of CVDs.Sources of FundingA. Vedenko is supported by a National Eye Institute (NEI) T32 Training Grant T32 EY023194.DisclosuresK.E. Hatzistergos discloses a relationship with Vestion Inc that includes equity. Vestion did not contribute funding to this study. The other author reports no conflict.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Konstantinos E. Hatzistergos, Biomedical Research Bldg, Room 832, 1501 NW 10th Ave, Miami, FL 33136. E-mail [email protected]References1. Golpanian S, Wolf A, Hatzistergos KE, Hare JM. Rebuilding the damaged heart: mesenchymal stem cells, cell-based therapy, and engineered heart tissue.Physiol Rev. 2016; 96:1127–1168. doi: 10.1152/physrev.00019.2015.CrossrefMedlineGoogle Scholar2. Nguyen PK, Rhee JW, Wu JC. Adult stem cell therapy and heart failure, 2000 to 2016: a systematic review.JAMA Cardiol. 2016; 1:831–841. doi: 10.1001/jamacardio.2016.2225.CrossrefMedlineGoogle Scholar3. Shiba Y, Gomibuchi T, Seto T, et al. Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts.Nature. 2016; 538:388–391. doi: 10.1038/nature19815.CrossrefMedlineGoogle Scholar4. 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Stimulatory effects of mesenchymal stem cells on cKit+ cardiac stem cells are mediated by SDF1/CXCR4 and SCF/cKit signaling pathways.Circ Res. 2016; 119:921–930. doi: 10.1161/CIRCRESAHA.116.309281.LinkGoogle Scholar12. Ye L, Chang YH, Xiong Q, et al. Cardiac repair in a porcine model of acute myocardial infarction with human induced pluripotent stem cell-derived cardiovascular cells.Cell Stem Cell. 2014; 15:750–761. doi: 10.1016/j.stem.2014.11.009.CrossrefMedlineGoogle Scholar13. Puymirat E, Geha R, Tomescot A, Bellamy V, Larghero J, Trinquart L, Bruneval P, Desnos M, Hagège A, Pucéat M, Menasché P. Can mesenchymal stem cells induce tolerance to cotransplanted human embryonic stem cells?Mol Ther. 2009; 17:176–182. doi: 10.1038/mt.2008.208.CrossrefMedlineGoogle Scholar14. Chong JJ, Chandrakanthan V, Xaymardan M, et al. Adult cardiac-resident MSC-like stem cells with a proepicardial origin.Cell Stem Cell. 2011; 9:527–540. doi: 10.1016/j.stem.2011.10.002.CrossrefMedlineGoogle Scholar15. Hatzistergos KE, Takeuchi LM, Saur D, Seidler B, Dymecki SM, Mai JJ, White IA, Balkan W, Kanashiro-Takeuchi RM, Schally AV, Hare JM. cKit+ cardiac progenitors of neural crest origin.Proc Natl Acad Sci USA. 2015; 112:13051–13056.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Basara G, Bahcecioglu G, Ozcebe S, Ellis B, Ronan G and Zorlutuna P (2022) Myocardial infarction from a tissue engineering and regenerative medicine point of view: A comprehensive review on models and treatments, Biophysics Reviews, 10.1063/5.0093399, 3:3, (031305), Online publication date: 1-Sep-2022. Fang G, Yang X, Chen S, Wang Q, Zhang A and Tang B (2022) Cyclodextrin-based host–guest supramolecular hydrogels for local drug delivery, Coordination Chemistry Reviews, 10.1016/j.ccr.2021.214352, 454, (214352), Online publication date: 1-Mar-2022. Zhou W, Ma T and Ding S (2022) Non-viral approaches for somatic cell reprogramming into cardiomyocytes, Seminars in Cell & Developmental Biology, 10.1016/j.semcdb.2021.06.021, 122, (28-36), Online publication date: 1-Feb-2022. Ahmad Shiekh P, Anwar Mohammed S, Gupta S, Das A, Meghwani H, Kumar Maulik S, Kumar Banerjee S and Kumar A (2022) Oxygen releasing and antioxidant breathing cardiac patch delivering exosomes promotes heart repair after myocardial infarction, Chemical Engineering Journal, 10.1016/j.cej.2021.132490, 428, (132490), Online publication date: 1-Jan-2022. Monsanto M, Wang B, Ehrenberg Z, Echeagaray O, White K, Alvarez R, Fisher K, Sengphanith S, Muliono A, Gude N and Sussman M (2020) Enhancing myocardial repair with CardioClusters, Nature Communications, 10.1038/s41467-020-17742-z, 11:1 Gude N and Sussman M (2020) Cardiac regenerative therapy: Many paths to repair, Trends in Cardiovascular Medicine, 10.1016/j.tcm.2019.08.009, 30:6, (338-343), Online publication date: 1-Aug-2020. Witman N, Zhou C, Grote Beverborg N, Sahara M and Chien K (2020) Cardiac progenitors and paracrine mediators in cardiogenesis and heart regeneration, Seminars in Cell & Developmental Biology, 10.1016/j.semcdb.2019.10.011, 100, (29-51), Online publication date: 1-Apr-2020. Balkan W, Banerjee M, Trapana J and Hare J (2020) Marrow-derived stromal cells for cardiac regeneration Emerging Technologies for Heart Diseases, 10.1016/B978-0-12-813706-2.00010-5, (193-216), . 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Chen H, Zhang A and Wu J (2018) Harnessing cell pluripotency for cardiovascular regenerative medicine, Nature Biomedical Engineering, 10.1038/s41551-018-0244-8, 2:6, (392-398) July 7, 2017Vol 121, Issue 2 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.117.311293PMID: 28684618 Originally publishedJuly 7, 2017 Keywordsmesenchymal stromal cellscell- and tissue-based therapyendothelial progenitor cellsEditorialscardiovascular diseasescardiac precursorsPDF download Advertisement