Fate Mapping of Sca1 + Cardiac Progenitor Cells in the Adult Mouse Heart

HomeCirculationVol. 138, No. 25Fate Mapping of Sca1+ Cardiac Progenitor Cells in the Adult Mouse Heart Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBFate Mapping of Sca1+ Cardiac Progenitor Cells in the Adult Mouse Heart Juan Tang, PhD, Yan Li, PhD, Xiuzhen Huang, BA, Lingjuan He, PhD, Libo Zhang, BS, Haixiao Wang, BS, Wei Yu, PhD, Wenjuan Pu, PhD, Xueying Tian, PhD, Yu Nie, PhD, Shengshou Hu, MD, PhD, Qing-Dong Wang, PhD, Kathy O. Lui, PhD and Bin Zhou, MD, PhD Juan TangJuan Tang 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 (J.T., Y.L., X.H., L.H., L.Z., H.W., W.Y., W.P., B.Z.). Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (J.T., Y.L., X.H., L.H., L.Z., W.Y., W.P., B.Z.). Search for more papers by this author , Yan LiYan Li 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 (J.T., Y.L., X.H., L.H., L.Z., H.W., W.Y., W.P., B.Z.). Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (J.T., Y.L., X.H., L.H., L.Z., W.Y., W.P., B.Z.). Search for more papers by this author , Xiuzhen HuangXiuzhen Huang 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 (J.T., Y.L., X.H., L.H., L.Z., H.W., W.Y., W.P., B.Z.). Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (J.T., Y.L., X.H., L.H., L.Z., W.Y., W.P., B.Z.). Search for more papers by this author , Lingjuan HeLingjuan He 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 (J.T., Y.L., X.H., L.H., L.Z., H.W., W.Y., W.P., B.Z.). Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (J.T., Y.L., X.H., L.H., L.Z., W.Y., W.P., B.Z.). Search for more papers by this author , Libo ZhangLibo Zhang 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 (J.T., Y.L., X.H., L.H., L.Z., H.W., W.Y., W.P., B.Z.). Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (J.T., Y.L., X.H., L.H., L.Z., W.Y., W.P., B.Z.). Search for more papers by this author , Haixiao WangHaixiao Wang 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 (J.T., Y.L., X.H., L.H., L.Z., H.W., W.Y., W.P., B.Z.). Search for more papers by this author , Wei YuWei Yu 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 (J.T., Y.L., X.H., L.H., L.Z., H.W., W.Y., W.P., B.Z.). Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (J.T., Y.L., X.H., L.H., L.Z., W.Y., W.P., B.Z.). Search for more papers by this author , Wenjuan PuWenjuan Pu 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 (J.T., Y.L., X.H., L.H., L.Z., H.W., W.Y., W.P., B.Z.). Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (J.T., Y.L., X.H., L.H., L.Z., W.Y., W.P., B.Z.). Search for more papers by this author , Xueying TianXueying Tian Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China (X.T., B.Z.). Search for more papers by this author , Yu NieYu Nie State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (Y.N., S.H.). Search for more papers by this author , Shengshou HuShengshou Hu State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (Y.N., S.H.). Search for more papers by this author , Qing-Dong WangQing-Dong Wang Bioscience Heart Failure, Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden (Q.-D.W.). Search for more papers by this author , Kathy O. LuiKathy O. Lui Department of Chemical Pathology; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong (K.O.L.). Search for more papers by this author and Bin ZhouBin Zhou Bin Zhou, MD, PhD, Yueyang Rd 320, A2112, Shanghai 200031, China. Email E-mail Address: [email protected] 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 (J.T., Y.L., X.H., L.H., L.Z., H.W., W.Y., W.P., B.Z.). Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (J.T., Y.L., X.H., L.H., L.Z., W.Y., W.P., B.Z.). Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China (X.T., B.Z.). School of Life Science and Technology, ShanghaiTech University, China (B.Z.). Search for more papers by this author Originally published17 Dec 2018https://doi.org/10.1161/CIRCULATIONAHA.118.036210Circulation. 2018;138:2967–2969This article is commented on by the following:Adult Cardiac Stem Cell Concept and the Process of ScienceEditorial, see p 2940Sca1+ cardiac progenitor cells have been reported as resident cardiac stem cells that can differentiate into cardiomyocytes.1,2 Whether endogenous Sca1+ cells contribute to cardiomyocytes in vivo remains unclear. To trace Sca1+ cardiac progenitor cells, we generated a Sca1-2A-CreER knockin mouse line that harbors CreER inframe with Sca1 coding region by a 2A self-cleaving peptide sequence (Figure, A). All mice protocols were approved by the Institutional Animal Care and Use Committee at the Institute for Nutritional Sciences and the Institute of Biochemistry and Cell Biology. To characterize whether Sca1-2A-CreER targets endogenous Sca1+ cells, we performed pulse tamoxifen induction and collected heart samples within 24 to 48 hours after tamoxifen induction. Flow cytometric analysis and immunostaining data showed that Sca1-2A-CreER specifically labels endogenous Sca1+ cells in the mouse heart (Figure, B through D). Z-stack confocal images showed that Sca1+ cells were VE-cad+ cells (Figure, E), and quantitatively the majority of VE-cad+ endothelial cells (67.48±2.18%) were tdTomato+, whereas almost all tdTomato+ cells (95.14±0.71%) were VE-cad+ endothelial cells. Immunostaining for tdTomato and TNNI3 showed no labeling of cardiomyocytes by Sca1-2A-CreER (Figure, F). We also did not find any tdTomato+ cells in the dissociated cardiomyocytes (Figure, G).Download figureDownload PowerPointFigure. Fate mapping of Sca1+ cells in cardiac homeostasis and after injuries. A, Schematic figure showing the knockin strategy for generation of Sca1-2A-CreER allele. B, Immunostaining for Sca1 and tdTomato on Sca1-2A-CreER;R26-tdTomato heart section collected at 24 to 48 hours after tamoxifen induction. C, Quantification of the percentage of Sca1+ cells in tdTomato+ cells. D, Flow cytometric analysis of Sca1+ cells in tdTomato+ cells, showing specificity of Sca1+ cell labeling. E and F, Immunostaining for tdTomato and VE-cad (E) or TNNI3 (F) on heart sections. Arrowheads indicate tdTomato+ endothelial cells. YZ indicates signals from dotted lines on Z-stack images. G, Bright-field and epifluorescence images of dissociated cardiomyocytes. H through N, Fate mapping of Sca1+ cells during cardiac homeostasis at 12 weeks after tamoxifen induction. H, Immunostaining for tdTomato and TNNI3 on heart sections. I, Flow cytometric analysis of RFP signal in cardiomyocytes. J, Bright-field and epifluorescence images of dissociated cardiomyocytes. K, Flow cytometric analysis of the percentage of tdTomato+ cells in CD31+ cells (left) or CD31+ cells in tdTomato+ cells (right). L, Immunostaining for tdTomato and VE-cad on heart sections. Arrowheads indicate tdTomato+ endothelial cells. M, Flow cytometric analysis of PDGFRa+ and tdTomato+ cells. N, Immunostaining for tdTomato and PDGFRa on heart section. Quantification of the percentage of PDGFRa+ cells in tdTomato+ cells or tdTomato+ cells in PDGFRa+ cells by immunostaining data. O through X, Fate mapping of Sca1+ cells after heart injuries. O and P, Immunostaining for tdTomato and TNNI3 on heart sections at 1, 4, and 6 weeks after myocardial infraction (MI). XZ or YZ indicates signals from dotted lines on Z-stack images. Q, Flow cytometric analysis of tdTomato signal in cardiomyocytes. R, Bright-field and epifluorescence images of dissociated cardiomyocytes from MI hearts. S, Immunostaining for tdTomato and VE-cad on heart sections. Arrowheads indicate tdTomato+ endothelial cells. Quantification of tdTomato+ cells in VE-cad+ cells or VE-cad+ cells in tdTomato+ cells. T and U, Immunostaining for tdTomato and PDGFRa on heart sections at 1 or 4 weeks after MI. V, Quantification of the percentage of PDGFRa+ in tdTomato+ cells in different regions of MI hearts. W and X, Immunostaining for tdTomato, TNNI3 (W), or VE-cad (X) on ischemia-reperfusion heart sections. Y, Schematic figure showing Sca1+ cell fate in the adult heart. For each quantification, data are mean±SEM (n=5, *P<0.05). Two-sided unpaired Student t test was used for comparing differences between 2 groups and ANOVA test for >2 groups. Scale bars, 100 µm. Each image is representative of 5 individual biological samples. ECs indicates endothelial cells.We next used Sca1-2A-CreER to perform fate-mapping analysis of Sca1+ cells during cardiac homeostasis. Sca1-2A-CreER;R26-tdTomato hearts were collected at 12 weeks after tamoxifen induction. Z-stack confocal images of heart sections stained with TNNI3 and tdTomato showed no tdTomato+ cardiomyocytes (Figure, H). Flow cytometric analysis showed no tdTomato+ cardiomyocytes (Figure, I). Dissociated cardiomyocytes also exhibited no tdTomato+ signal (Figure, J). By contrast, flow cytometric analysis showed that 60.88±2.38% endothelial cells expressed tdTomato (Figure, K). It is notable that 94.25±0.54% tdTomato+ cells were CD31+ endothelial cells (Figure, K), indicating that most Sca1+ cells adopted an endothelial cell fate during cardiac homeostasis. Immunostaining for tdTomato and CD31 on heart sections showed that Sca1+ cells contributed to a substantial number of endothelial cells (Figure, L). Sca1+ cells also contribute to cardiac fibroblasts. Flow cytometric analysis showed that 1.79±0.14% PDGFRa+ cells were labeled by tdTomato, whereas 0.52±0.072% tdTomato+ cells expressed PDGFRa (Figure, M). Z-stack confocal images of heart sections stained with tdTomato and PDGFRa showed that 1.82±0.11% of PDGFRa+ cells were labeled by tdTomato, whereas 0.51±0.025% of tdTomato+ cells were PDGFRa+ in the normal heart during homeostasis (Figure, N).To test whether Sca1+ cells generated new cardiomyocytes after cardiac injury, we performed myocardial infarction (MI) model at 2 weeks after tamoxifen treatment and collected hearts at 1, 4, and 6 weeks after MI. Z-stack confocal images on heart sections stained with tdTomato and TNNI3 showed no tdTomato+ cardiomyocytes in the MI heart (Figure, O). We also did not find any tdTomato+ cardiomyocytes in heart samples collected at 4 or 6 weeks after MI (Figure, P). Flow cytometric analysis exhibited no tdTomato+ cardiomyocytes (Figure, Q). Cell dissociation confirmed the absence of tdTomato+ cardiomyocytes (Figure, R). By immunostaining for tdTomato and VE-cad on MI heart sections, we detected a substantial number of tdTomato+ coronary endothelial cells in the injured region (Figure, S). Quantitatively, 64.54±1.71% VE-cad+ cells expressed tdTomato, whereas 91.77±1.12% tdTomato+ cells expressed VE-cad in the injured myocardium (Figure, S). PDGFRa+tdTomato+ cells were detected in the infarct and border regions of MI heart (Figure, T and U). Quantitatively, 7.72±0.43%, 5.32±0.31%, and 1.96±0.29% of tdTomato+ cells expressed PDGFRa in the infarct, border, and remote regions of the left ventricle of MI hearts, respectively (Figure, V). In the ischemia-reperfusion model, Sca1+ cells also contributed to cardiac endothelial cells but not cardiomyocytes (Figure, W and X).In conclusion, Sca1+ cardiac progenitor cells mainly differentiate into cardiac endothelial cells and fibroblasts but not cardiomyocytes during cardiac homeostasis and after injuries (Figure, Y). Our study raises caution on the extrapolation of previously identified myogenic potential of Sca1+ cardiac progenitor cells and the associated mechanisms of actions for cardiac regeneration. New cardiomyocytes are more likely to be derived from preexisting cardiomyocytes through proliferation rather than differentiation of cardiac stem cells or progenitor cells.3–5Sources of FundingThis work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB19000000, XDA16020204), National Key Research & Development Program of China (2018YFA0107900, 2018YFA0108100, 2016YFC1300600, 2017YFC1001303), National Science Foundation of China (31730112, 91639302, 31625019, 81761138040, 31571503, 31501172, 31601168, 31701292, 91749122, 9184920003), Astrazeneca, Royal Society-Newton Advanced Fellowship (NA170109), Research Council of Hong Kong (04110515, 14111916, C4024-16 W) and Health and Medical Research Fund (03140346, 04152566).DisclosuresNone.FootnotesData sharing: The data that support the findings of this study and study materials, as well as experimental procedures and protocols, are available from the corresponding author upon reasonable request.https://www.ahajournals.org/journal/circBin Zhou, MD, PhD, Yueyang Rd 320, A2112, Shanghai 200031, China. 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Lee,Circulation. 2018;138:2940-2942 December 18, 2018Vol 138, Issue 25 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.036210PMID: 30566021 Originally publishedDecember 17, 2018 Keywordscardiac progenitor cellSca1+cardiomyocytemyocardial infarctioncardiac regenerationPDF download Advertisement SubjectsBasic Science ResearchStem Cells