Reassessment of c-Kit in Cardiac Cells
2018; Lippincott Williams & Wilkins; Volume: 123; Issue: 1 Linguagem: Inglês
10.1161/circresaha.118.313215
ISSN1524-4571
Autores Tópico(s)Pluripotent Stem Cells Research
ResumoHomeCirculation ResearchVol. 123, No. 1Reassessment of c-Kit in Cardiac Cells Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBReassessment of c-Kit in Cardiac CellsA Complex Interplay Between Expression, Fate, and Function Bin Zhou and Sean M. Wu Bin ZhouBin Zhou From the State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China (B.Z.) and Sean M. WuSean M. Wu Division of Cardiovascular Medicine, Department of Medicine, Cardiovascular Institute, Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, CA (S.M.W.). Originally published22 Jun 2018https://doi.org/10.1161/CIRCRESAHA.118.313215Circulation Research. 2018;123:9–11c-Kit (CD117) is a type III receptor tyrosine kinase that activates a downstream signaling cascade on binding to stem cell factor. Studies from the past 3 decades have demonstrated the expression of c-Kit in various cell types including embryonic, spermatogonial, and hematopoietic stem cells as well as differentiated cells such as melanocytes, neurons, Leydig cells in the testis, and mast cells.1 The expression of c-Kit to mark a stem cell population in the adult heart was initially reported by Beltrami et al2 and subsequent studies to validate or extend this work has led to tremendous conflicts and controversies. Much of the disagreements involve inconsistent results and discrepant conclusions that stem from the use of distinct tools and models that each carries its own advantages and disadvantages. In general, studies that used single allele knockin replacement of the endogenous C-KIT locus have demonstrated fewer labeled cells than studies that utilized transgenic reporters (discussed below). Furthermore, a functional role for c-Kit signaling in cardiac cells has been raised but not convincingly demonstrated.Article, see p 57c-Kit+ Cells in Cardiac Development and RegenerationAfter the initial report of c-Kit as a marker for adult cardiac stem cell (CSC),2 numerous studies describe the isolation, expansion, and in vitro differentiation of adult c-Kit+ cardiac cell into multiple cardiovascular cell lineages (for a review see Hesse et al1). The expression of c-Kit in cardiac cells declines from embryonic stages and is nearly completely absent in the adult heart. In developing embryos, a population of cardiomyogenic c-Kit+ cardiac progenitors is present in the neural crest.3 The ability of a rare number of neonatal c-Kit+ nonmyocytes to differentiate in vitro into beating cardiomyocytes were shown by 2 independent groups.4,5 Interestingly, neither group was able to demonstrate cardiomyogenic differentiation from adult c-Kit+ nonmyocytes either in vitro or in vivo. These studies raised an interesting possibility that both the downregulation of c-Kit expression in cardiac cells and the loss of cardiomyogenic potential in resident nonmyocytes (of which some may be c-Kit+ CSCs) may account for the decline in cardiomyogenesis in adult hearts compared with neonatal hearts. Although the discrepancy in the cardiomyogenic potential of adult c-Kit+ cells between various studies remains to be clarified, human c-Kit+ cardiac cells were isolated, ex vivo expanded, and transplanted into myocardial infarction patients in phase I/IIa studies (SCIPIO6 [Cardiac Stem Cell Infusion in Patients With Ischemic Cardiomyopathy] and CADEUCES [Cardiosphere-Derived Autologous Stem Cells to Reverse Ventricular Dysfunction]7). Although the patient numbers were relatively small, both studies demonstrated safety and hints of cardiac functional improvement in patients injected with either ex vivo expanded c-Kit+ cells (SCIPIO)6 or cardiosphere-derived cells that contains c-Kit+ cells (CADEUCES).7 Because c-Kit+ cells were delivered by intracoronary infusion in both studies, it is likely that the reported benefit is because of paracrine mechanisms given the difficulty in demonstrating long-term cell engraftment after transplantation in human.8 The interest in further validating the benefit of adult c-Kit+ cells in a larger patient population from the clinical community contrasts sharply with the ongoing debate surrounding the cardiomyogenic capacity of adult c-Kit+ cardiac cell in the basic research community. Although clinical studies in human may be argued as the most relevant model for investigation, the contribution from mouse models that offers precise targeting of specific gene for an improved mechanistic understanding of the biology at work is critical and necessary to guide future clinical studies. A series of recent studies from multiple laboratories to lineage trace c-Kit expressing cells in mice using direct or inducible Cre/LoxP-based strategy have attempted to address the ability of c-Kit+ cells to give rise to cardiomyocytes in the heart in vivo throughout the entire lifespan from fetal to adult stages.Lineage Tracing Studies to Address the Contribution of c-Kit+ Cells to CardiomyocytesThe effort to lineage trace c-Kit+ CSCs in vivo was first performed by injection of lentivirus expressing Cre recombinase under c-Kit promoter.9 Ellison et al9 showed the Cre-labeled c-Kit+ cells contributed to a substantial number of cardiomyocytes after isoproterenol-induced heart injury. Because the transgenic c-Kit promoter used to drive Cre expression may exhibit off-target labeling, given the short promoter used and the unexpectedly large number of cardiomyocytes labeled, the strategy to target Cre recombinase into endogenous gene locus (knockin) was recently used for tracing c-Kit+ cells. Using similar approaches, 3 independent groups found that c-Kit-Cre labeled very few, if any, cardiomyocytes in the adult heart,10–12 raising concerns over the previously reported claim that c-Kit+ CSCs give rise to new cardiomyocytes. Interestingly, the c-Kit-Cre and inducible Cre generated by independent laboratories all resulted in the loss of c-Kit expression in one allele,10–12 raising the possibility of under-reporting of cells that express a low level of c-Kit and a defect in the differentiation of endogenous c-Kit+ CSCs into cardiomyocytes. The haploinsufficiency of c-Kit in all published knockin studies begs the question of whether there is a role for c-Kit protein to regulate cardiac cell function (eg, proliferation, survival, and differentiation). In this regard, a new transgenic mouse line that uses a longer regulatory element from the C-KIT locus and leaves the endogenous c-Kit gene unperturbed would be very helpful to reassess the labeling of c-Kit+ cells in the adult heart and examine the functional requirement of c-Kit.Comparison of a New c-Kit Transgenic Reporter With the Previous Knockin ModelIn this issue, Gude et al13 generated a new transgenic c-Kit reporter system to study Kit+ cell function and biology in vivo and in vitro. In this new system, the cDNA expressing reverse tetracycline transactivator was driven by a longer 14 kb fragment of mouse c-Kit promoter and activates H2BEGFP (histone 2B enhanced green fluorescent protein) reporter driven by a tetracycline response element. This transgenic reporter system, named as CKH2B, labeled ≈80% of c-Kit+ noncardiomyocytes,13 indicating a high efficiency of c-Kit+ cell labeling by the transgene. Gude et al13 then compared the labeling of c-Kit+ cells between c-Kit-MerCreMer (CKmCm) lineage tracing model and the CKH2B transgene model. Although there was no significant difference in the expression level of the reporter between these 2 strategies, the frequency of c-Kit+ cell detected on heart sections and by flow cytometry analysis in CKH2B model was over 2 folds higher than that in the CKmCm model.13 The substantial increase in labeled cell population among nonmyocytes in the CKH2B model over CKmCm model could be explained by the differences in the reporter strategy (eg, direct reporter versus lineage tracing) and expression level of c-Kit (and Cre), given that the efficiency of Cre-mediated excision of the LoxP-flanked sequence vary significantly between cell types. In this regard, the haploinsufficiency of c-Kit in the knockin models may result in incomplete labeling of cells that express c-Kit at a lower level.To explore whether c-Kit signaling has any biological function in cardiac cells, the authors isolated the presumed CSCs population from the adult heart and examined the dynamics of c-Kit expression under normal and stress conditions. Both c-Kit mRNA and protein were upregulated in isolated cells under stress such as serum starvation.13 Treatment of stem cell factor on these cells significantly enhanced their proliferation and survival with reduced apoptosis and necrosis,13 supporting the proproliferative and antiapoptotic activities of c-Kit signaling in CSCs and consistent with results from an independent study showing that c-Kit+ CSCs isolated from c-Kit-Cre knockin mice showed a defect in differentiation into cardiomyocytes.14 Taken together, these studies provided new functional evidence, albeit, in vitro, that c-Kit may serve not only as a marker but also an important receptor in the biology of cardiac cells.Interestingly, Gude et al13 also reported that CKH2B transgene tagged a subpopulation of adult cardiomyocytes, a finding consistent with previous studies.4,12 Similar to CSCs, adult cardiomyocytes also express increased c-Kit mRNA and protein after isoproterenol treatment,13 suggesting a potential role for c-Kit signaling in the cardiomyocyte injury response. The finding of c-Kit expression in adult cardiomyocytes requires a reinterpretation of the previous c-Kit-Cre lineage tracing data regardless of whether there was minimal or significant labeling of cardiomyocytes.10,11 This finding suggests that the direct but rare expression of c-Kit in cardiomyocytes might account for the labeled cardiomyocytes observed in the adult heart, adding another layer of complexity to the ongoing discussion about the contribution of a stem/progenitor-like cell population in the adult heart. By using dual recombinases (Cre and Dre) that only labels c-Kit+ nonmyocytes, He et al15 demonstrate the lack of contribution by c-Kit+ nonmyocytes to new cardiomyocytes in both adult cardiac homeostasis and after injury. Future studies that compare c-Kit+ from c-Kit– cardiomyocytes in vivo may provide new knowledge about whether there are myocyte subpopulations that exhibit a greater propensity for cardiac repair and regeneration.ConclusionsBoth transgene and knockin alleles have inherent strengths and weaknesses in fate mapping of endogenous CSCs. Interpretation of the fate mapping data from different genetic tools needs to consider its caveats and limitations. Although knockin strategy keeps all regulatory elements intact, current c-Kit-Cre knockin alleles all have reduced c-Kit expression. Transgenic approach avoids disruption of the endogenous allele but whether the selected fragment of promoter faithfully recapitulates the in vivo c-Kit gene expression can be difficult to ascertain. The creation of a new knockin mouse line that introduces Cre into the C-KIT locus without disrupting c-Kit gene expression (eg, by P2A self-cleaving peptide after coding element of the endogenous c-Kit gene) may help to resolve this issue. Aside from the strength of labeling problem, the expression of c-Kit in both cardiomyocytes and nonmyocytes clearly confound any interpretation of fate mapping using c-Kit as a marker. The use of a more precise lineage tracing tool such as the dual recombinases system may alleviate this issue.15 Questions such as what are the in vivo functions of c-Kit gene in CSCs and cardiomyocytes during cardiac homeostasis and regeneration and what is responsible for the downregulation of the expression of c-Kit in the heart and the decline in cardiomyogenic capacity of c-Kit+ cells with age will require further investigation. With the advent of more powerful tools, we think the confusion surrounding c-Kit cardiac biology can be clarified in the near future.AcknowledgmentsWe thank Michael Hesse, Bernd Fleischmann, and Joseph Wu for their critique and apologize for the inability to discuss a majority of articles published in this research area. This study was supported by National Key Research and Development Program of China (2016YFC1300600, 2017YFC1001303, SQ2018YFA010021, and SQ2018YFA010113) and National Science Foundation of China (31730112, 91639302, 31625019, and 81761138040) to Dr Zhou and National Institutes of Health Director's Pioneer Award (DP1 LM012179-02), the National Heart, Lung, and Blood Institute Progenitor Cell Biology Consortium (U01 HL099776), an American Heart Association Established Investigator Award (17EIA33410923), the Hoffmann Foundation, and an Endowed Faculty Scholar Award of the Lucile Packard Foundation for Children and Child Health Research Institute at Stanford to Dr Wu.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Bin Zhou, MD, PhD, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, A2112, 320 Yueyang Rd, Shanghai 200031, China, E-mail [email protected]; or Sean M. 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June 22, 2018Vol 123, Issue 1 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.118.313215PMID: 29929968 Originally publishedJune 22, 2018 Keywordsgene targetingregenerationEditorialshaploinsufficiencystem cell factorLeydig cellsPDF download Advertisement SubjectsMyocardial Regeneration
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