Heart Factory or Fiction?
2013; Lippincott Williams & Wilkins; Volume: 128; Issue: 20 Linguagem: Inglês
10.1161/circulationaha.113.006262
ISSN1524-4539
AutoresBrian C. Jensen, Cam Patterson,
Tópico(s)Tissue Engineering and Regenerative Medicine
ResumoHomeCirculationVol. 128, No. 20Heart Factory or Fiction? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBHeart Factory or Fiction?Cardiac Progenitor Cells and Regeneration Brian C. Jensen, MD and Cam Patterson, MD, MBA Brian C. JensenBrian C. Jensen From the McAllister Heart Institute and Division of Cardiology, University of North Carolina School of Medicine, Chapel Hill. and Cam PattersonCam Patterson From the McAllister Heart Institute and Division of Cardiology, University of North Carolina School of Medicine, Chapel Hill. Originally published18 Oct 2013https://doi.org/10.1161/CIRCULATIONAHA.113.006262Circulation. 2013;128:2181–2182Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2013: Previous Version 1 "Create in me a clean heart, O God." Psalm 51:10In the Christian tradition, the doctrine of regeneration considers the "deceitful…and wicked" heart a vessel for accepting God and thereby being born again. Indeed, many cultures have invested the heart with powers well beyond its biological role in maintaining systemic perfusion. However, the capacity of the heart for renewal was limited to metaphor until relatively recently, when science revealed a very literal interpretation of cardiac regeneration. Contrary to long-standing belief, it now appears that new cardiomyocytes are created after birth and that cardiomyocyte renewal continues in the aging human heart. Most studies estimate that the annual rate of myocyte renewal is roughly 1%,1,2 although other groups suggest that up to 40% of a heart's cardiomyocytes might be regenerated each year.3 These new cells may arise from resident cardiac progenitor cells (CPCs), from proliferation of preexisting cardiomyocytes, or from migratory populations of epicardial cells. Regardless of their origin, their number and inherent function seem insufficient to heal the profoundly injured heart because roughly 300 000 Americans die every year of heart failure. Of course, the more sanguine among us view this striking burden of disease as a therapeutic opportunity, and clinical trials of myocardial regeneration using various cell types and preparations already have been conducted. Early trials in the field used bone marrow–derived stem cells with mixed results.4 More recently, 2 trials have investigated the use of CPCs, and their findings have been somewhat promising.5,6 Although treatment with stem cells appears safe, enthusiasm for their expanded use is restrained by the acknowledgment that both evidence of meaningful clinical benefit and clear mechanisms of benefit are lacking. Thus, rigorous ongoing investigation of stem cell biology in the heart is essential in clarifying whether therapeutic cardiac regeneration could indeed become a reality.Article see p 2211In the current issue of Circulation, Goichberg and colleagues7 provide new explication of the mechanisms underlying human CPCs (hCPC) aging. The group has contributed substantially to the extant literature on hCPCs, including seminal observations on the number and function of CPCs in the aging and failing human heart.3 Here, they explore the role of ephrins in the trafficking of hCPCs, specifically focusing on the interaction between the ligand ephrin A1 and its receptor, EphA2. Using a variety of in vitro approaches, the authors demonstrate reduced motility of hCPCs with senescence induced by serial passaging. This impairment is associated with diminished responsiveness to ephrin A1, likely resulting from failure of EphA2-mediated endocytosis and subcellular transport of its ligand. These defects are rescued by lentiviral infection with exogenous EphA2, which restores the migratory capacity of experimentally aged hCPCs. The authors implicate oxidative stress as an underlying mechanism for the blunted response of EphA2 to its ligand and ultimately suggest that defects in EphA2 activity level might be useful in distinguishing "young" from "old" hCPCs for therapeutic purposes.The present work builds on previous observations by this group and others. Aging and heart failure are thought to impair the reparative capacity of rodent CPCs,8,9 but the authors' identification of functional defects in senescent hCPCs is novel. The present article also is the first to describe a role for ephrins in the motility of hCPCs. Ephrins are known to mediate regenerative processes involving other stem cell niches, including skeletal muscle satellite cells,10 and other members of the ephrin family directly regulate migration and cell cycle reentry of intestinal progenitor cells.11 The Leri laboratory first identified the contribution of ephrin A1-EphA2 signaling to CPC motility in the setting of a mouse model of myocardial infarction,12 and here their findings are extended to cultured senescent human heart cells. The authors rightly suggest that an expanded understanding of the mechanisms underlying the regenerative capacity of hCPCs is biologically important, although they and others13 acknowledge that purifying highly functional hCPCs is required to achieve clinically meaningful myocardial regeneration. Their proposed strategy for sorting hCPCs based on the potency of ephrin A1-EphA2 interactions is novel and could be explored further with in vivo approaches.Although the authors are to be congratulated for making further contributions to the rapidly expanding literature on myocardial regeneration, their article subtextually reinforces how much remains to be learned about stem cells in the heart. In this article, the authors used antibody-coated immunomagnetic beads to select cKit+ cells for initial culture, although further cell sorting and typing methods were not specified.14 Importantly, it is clear that the adult heart contains multiple populations of CPCs, and recent work demonstrates that these populations activate distinct transcriptional programs.15 In mice, cKit+ CPCs are 2- to 3-fold less abundant than Sca1+ CPCs, and the cKit+ population may also contain CD45+ cells, suggestive of bone marrow origin.15 Thus, it seems possible that the hCPCs used for these experiments may be a somewhat mixed population and nearly certain that the biology of these cells is not fully representative of all hCPC populations. Thus, the authors' demonstration of the role of ephrin signaling is well supported in the cultured cells that they studied, but it is less clear that their findings are broadly applicable to hCPC populations in vivo.The fidelity of the induced senescence model of cultured cKit+ hCPCs to aged hCPCs in the human heart also is unclear. More specifically, the serial in vitro passaging of human heart cells should not be conflated with the biological process of aging. Furthermore, it is conceivable that the pathophysiological consequences of the putative age-related loss of hCPC function might well be offset by the more rapid turnover of hCPCs in older patients' hearts.3 Indeed, the authors' previous report of rapid in vivo cardiomyogenesis in aged hearts seems somewhat at odds with the effects of experimentally induced cellular senescence reported in the present article.Taken in the broader context, this article is the most recent contribution of a productive and influential laboratory to a deeply conflicted field. On one hand, a recent publication concludes that cKit+ CPCs are necessary and sufficient for myocardial regeneration in the mouse heart.16 However, other leading myocardial biologists identify very little regenerative capacity from CPCs in the adult mammalian heart,17 finding that new cardiomyocytes are created instead by the division of preexisting cardiomyocytes.18 The lack of scientific consensus notwithstanding, our most prestigious academic medical centers are actively recruiting patients for participation in further clinical trials using hCPCs. Although the degree of enthusiasm for the stem cell enterprise among scientists, clinicians, and patients alike may simply be commensurate with the desperate need for new heart failure therapies, one cannot help but wonder whether its enduring metaphoric appeal also exerts some influence. Regardless of motivation, it is indisputably true that our current knowledge of cardiac stem cell biology is incomplete and that further study is required to understand its therapeutic potential. It remains to be seen whether the biology of the heart will match the very human desire for regeneration and rebirth.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Cam Patterson, MD, MBA, Chief, Division of Cardiology, University of North Carolina School of Medicine, 8200 Medical Biomolecular Research Bldg, Chapel Hill, NC 27599-7126. E-mail [email protected]References1. Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabé-Heider F, Walsh S, Zupicich J, Alkass K, Buchholz BA, Druid H, Jovinge S, Frisén J. Evidence for cardiomyocyte renewal in humans.Science. 2009; 324:98–102.CrossrefMedlineGoogle Scholar2. 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Di Scipio F, Sprio A, Folino A, Carere M, Salamone P, Yang Z, Berrone M, Prat M, Losano G, Rastaldo R and Berta G (2014) Injured cardiomyocytes promote dental pulp mesenchymal stem cell homing, Biochimica et Biophysica Acta (BBA) - General Subjects, 10.1016/j.bbagen.2014.03.005, 1840:7, (2152-2161), Online publication date: 1-Jul-2014. Altmann P, Mildner M, Haider T, Traxler D, Beer L, Ristl R, Golabi B, Gabriel C, Leutmezer F and Ankersmit H (2014) Secretomes of apoptotic mononuclear cells ameliorate neurological damage in rats with focal ischemia, F1000Research, 10.12688/f1000research.4219.2, 3, (131) November 12, 2013Vol 128, Issue 20 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.113.006262PMID: 24141257 Originally publishedOctober 18, 2013 Keywordsstem cellsheart failureregenerationEditorialscell agingPDF download Advertisement
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