CCN1-Induced Cellular Senescence Promotes Heart Regeneration

HomeCirculationVol. 139, No. 21CCN1-Induced Cellular Senescence Promotes Heart Regeneration Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBCCN1-Induced Cellular Senescence Promotes Heart Regeneration Teng Feng, BS, Jufeng Meng, MD, Shan Kou, BS, Zhen Jiang, BS, Xinyan Huang, BS, Zhengkai Lu, BS, Huan Zhao, BS, Lester F. Lau, PhD, Bin Zhou, MD, PhD and Hui Zhang, PhD Teng FengTeng Feng School of Life Science and Technology, ShanghaiTech University, China (T.F., J.M., S.K., Z.J., X.H., Z.L., B.Z., H. Zhang). University of Chinese Academy of Sciences, Beijing (T.F., S.K., Z.J., X.H., Z.L., H. Zhao, B.Z.). , Jufeng MengJufeng Meng School of Life Science and Technology, ShanghaiTech University, China (T.F., J.M., S.K., Z.J., X.H., Z.L., B.Z., H. Zhang). , Shan KouShan Kou School of Life Science and Technology, ShanghaiTech University, China (T.F., J.M., S.K., Z.J., X.H., Z.L., B.Z., H. Zhang). University of Chinese Academy of Sciences, Beijing (T.F., S.K., Z.J., X.H., Z.L., H. Zhao, B.Z.). , Zhen JiangZhen Jiang School of Life Science and Technology, ShanghaiTech University, China (T.F., J.M., S.K., Z.J., X.H., Z.L., B.Z., H. Zhang). University of Chinese Academy of Sciences, Beijing (T.F., S.K., Z.J., X.H., Z.L., H. Zhao, B.Z.). , Xinyan HuangXinyan Huang School of Life Science and Technology, ShanghaiTech University, China (T.F., J.M., S.K., Z.J., X.H., Z.L., B.Z., H. Zhang). University of Chinese Academy of Sciences, Beijing (T.F., S.K., Z.J., X.H., Z.L., H. Zhao, B.Z.). , Zhengkai LuZhengkai Lu School of Life Science and Technology, ShanghaiTech University, China (T.F., J.M., S.K., Z.J., X.H., Z.L., B.Z., H. Zhang). University of Chinese Academy of Sciences, Beijing (T.F., S.K., Z.J., X.H., Z.L., H. Zhao, B.Z.). , Huan ZhaoHuan Zhao University of Chinese Academy of Sciences, Beijing (T.F., S.K., Z.J., X.H., Z.L., H. Zhao, B.Z.). State Key Laboratory of Cell Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (H. Zhao, B.Z.). , Lester F. LauLester F. Lau Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago College of Medicine (L.F.L.). , Bin ZhouBin Zhou Bin Zhou, MD, PhD, 320 Yueyang Rd, A2112, Shanghai, 200031, China. Email E-mail Address: [email protected] School of Life Science and Technology, ShanghaiTech University, China (T.F., J.M., S.K., Z.J., X.H., Z.L., B.Z., H. Zhang). University of Chinese Academy of Sciences, Beijing (T.F., S.K., Z.J., X.H., Z.L., H. Zhao, B.Z.). State Key Laboratory of Cell Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (H. Zhao, B.Z.). Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China (B.Z.). and Hui ZhangHui Zhang Hui Zhang, PhD, 393 Middle Huaxia Rd, B328, Shanghai, 201210, China. Email E-mail Address: [email protected] School of Life Science and Technology, ShanghaiTech University, China (T.F., J.M., S.K., Z.J., X.H., Z.L., B.Z., H. Zhang). Originally published20 May 2019https://doi.org/10.1161/CIRCULATIONAHA.119.039530Circulation. 2019;139:2495–2498Cellular senescence plays important roles in a variety of physiological and pathological processes.1 However, whether it is associated with neonatal heart regeneration2 remains unknown. We performed apical resection (AR) at postnatal day (P) 1 and collected hearts for senescence-associated β-galactosidase staining at different time points after AR (Figure [A]). Senescent cells (SCs) were identified in the periresected regions at P3, P7, and P14, whereas no SCs were detected in the fully restored hearts at P21 (Figure [A]). Because β-galactosidase is not exclusively expressed in SCs, we also collected apices and periresected regions from sham and injured hearts, respectively, at P7 and examined the mRNA levels of Trp53, Cdkn1a, p16INK4a, and several genes associated with the senescence-associated secretory phenotype including IL-1a, IL-6, Ccl2, PAI1, Vegfc, and Mmp2. All these genes were upregulated in the periresected regions at P7 (data not shown). Taken together, AR induced senescence in neonatal hearts, and these SCs disappeared when the hearts were fully restored.Download figureDownload PowerPointFigure. CCN1-induced cellular senescence promotes heart regeneration.A, Top, Schematic diagram shows the experimental strategy. The hearts subjected with sham or AR at P1 were collected for SAβ staining at P3, P7, P14, and P21. The middle and bottom show the results of SAβ staining on the apical/periresected regions at different time points. Scale bars, 100 µm. B, Schematic diagram shows the strategy for ABT263 treatment. AR was performed at P1, and the hearts were harvested for analysis at P8 or P22 indicated by the red arrows. C, SAβ staining on vehicle- or ABT263-treated hearts at P8. Scale bars, 100 µm. D, Sirius red staining on vehicle- or ABT263-treated hearts at P22. The dotted line indicates incision. Scale bars, 200 µm. E, The percentage of proliferating cardiomyocytes in the periresected regions of vehicle- or ABT263-treated hearts at P8. ***P<0.001; n=4 mice for each group. F, Immunostaining for PDGFRa and Ki67 on vehicle- or ABT263-treated hearts at P8. The arrows indicate PDGFRa+Ki67+ fibroblasts. Scale bars, 100 µm. G, SAβ staining on Trp53+/– or Trp53–/– hearts at P7 post-AR. Scale bars, 100 µm. H, Sirius red staining on Trp53+/– or Trp53–/– hearts at P22 post-AR. The dotted line indicates incision. Scale bars, 200 µm. I, The percentage of proliferating cardiomyocytes in the periresected regions of Trp53+/– or Trp53–/– hearts at P8. ***P<0.001; n=4 mice for each group. J, Immunostaining for PDGFRa and Ki67 on hearts from Trp53+/– or Trp53–/– mice at P8 post-AR. The arrows indicate PDGFRa+Ki67+ fibroblasts in the periresected regions. Scale bars, 100 µm. K, Immunostaining for tdTomato and CDKN1A on hearts of Postn-CreER;R26-tdTomato mice, which were subjected with AR at P1, administered with tamoxifen at P6, and harvested at P8. The arrows indicate tdTomato+CDKN1A+ myofibroblasts in the periresected region. Scale bars, 100 µm. L, SAβ staining on hearts of control or mutant mice at P7 that were subjected with AR at P1 and treated with tamoxifen at P3 and P6. Scale bars, 100 µm. M, Sirius red staining on control or mutant hearts at P22 post-AR. The dotted line indicates incision. Scale bars, 200 µm. N, The percentage of proliferating cardiomyocytes in the periresected regions of control or mutant hearts at P8. ***P<0.001; n=4 mice for each group. O, Immunostaining for PDGFRa and Ki67 on control or mutant hearts at P8. The arrows indicate PDGFRa+Ki67+ fibroblasts in the periresected regions. Scale bars, 100 µm. P, In situ hybridization for Ccn1 on hearts at P4 with or without AR. Scale bars, 200 µm. Q, Immunostaining for TNNI3 and CCN1 on hearts at P7 post-AR. The arrows indicate TNNI3+CCN1+ cardiomyocytes in the periresected region. The boxed region on the left is split into channels in the top right and bottom right. Scale bar, 100 µm. R, SAβ staining on scramble- or shCcn1-treated hearts that were injected with AAV9 at P0, subjected to AR at P1, and harvested at P7. Scale bars, 100 µm. S, Sirius red staining on scramble- or shCcn1-treated hearts at P22 post-AR. The dotted line indicates incision. Scale bars, 500 µm. T, The percentage of proliferating cardiomyocytes in the periresected regions of scramble or shCcn1 hearts at P7. ***P<0.001; n=4 mice for each group. U, Immunostaining for PDGFRa and Ki67 on scramble- or shCcn1-treated hearts at P7. The arrows indicate PDGFRa+Ki67+ fibroblasts in the periresected regions. Scale bars, 100 µm. V and W, The adult mice were injected with vehicle/CCN1 at 1 day and 3 days post-MI, and harvested at 4 days post-MI for analysis. V, SAβ staining on vehicle- or CCN1-treated adult hearts. Scale bars, 100 µm. W, Immunostaining for PDGFRa and Ki67 on vehicle- or CCN1-treated adult hearts. The arrows indicate PDGFRa+Ki67+ fibroblasts in ischemic regions. Few proliferating fibroblasts were identified in the remote regions of both groups. Scale bars, 100 µm. X and Y, The mice were injected with vehicle/CCN1 at 1, 3, 5, and 7 days post-MI and harvested at 8 days post-MI for analysis. X, Sirius red staining on vehicle- or CCN1-treated adult hearts at 8 days post-MI. Scale bars, 1000 µm. n=6 mice for each group. Y, Left ventricular ejection fraction (EF), end-systolic volume (ESV), and end-diastolic volume (EDV) of vehicle- or CCN1-treated adult hearts at 8 days post-MI. *P<0.05; ***P<0.001; NS, nonsignificant; n=6 mice for each group. Z, Schematic figure shows the mechanisms by which cellular senescence promotes neonatal heart regeneration. Each image showing the result of immunostaining, SAβ staining, Sirius red staining, or in situ hybridization is representative of 3 individual mouse samples at least. MI was induced by permanent coronary artery ligation. All data are presented as mean values±SEM and were analyzed using unpaired Student t test. Significance was accepted when P<0.05. AR indicates apical resection; DAPI, 4′,6-diamidino-2-phenylindole; MI, myocardial infarction; P, postnatal day; SAβ, senescence-associated β-galactosidase; and TAM, tamoxifen.To investigate the role of SCs in neonatal heart regeneration, we administered neonatal mice with the senolytic drug ABT263 after AR (Figure [B]).3 The ABT263-treated hearts had fewer SCs in the periresected regions at P8 and were not fully restored at P22, showing evidence of fibrotic scars (Figure [C and D]). Immunostaining revealed that the percentage of proliferating cardiomyocytes was decreased and fibroblast proliferation was increased in the periresected regions of ABT263-treated hearts at P8 (Figure [E and F] and data not shown). Next, we performed AR on Trp53 knockout mice that are deficient in SCs. The Trp53–/– hearts had fewer SCs in the periresected regions at P7 and were not fully regenerated at P22, showing apparent scars (Figure [G and H]). Cardiomyocyte proliferation was impaired and fibroblast expansion was enhanced in the periresected regions of Trp53–/– hearts at P8 (Figure [I and J] and data not shown). Thus, clearance of SCs by ABT263 or inactivation of senescence by Trp53 knockout significantly inhibited neonatal heart regeneration after AR, indicating critical roles of senescence in neonatal heart regeneration.Activated fibroblasts (myofibroblasts) highly express periostin (POSTN). We used Postn-CreER;R26-loxp-stop-loxp-tdTomato (R26-tdTomato) to label myofibroblasts after AR and found CDKN1A+ myofibroblasts in the periresected regions at P8 (Figure [K]). Senescence-associated β-galactosidase activity was also detected in PDGFRa+ fibroblasts isolated from AR-treated hearts (data not shown). These results suggest that some fibroblasts are senescent post-AR. Therefore, we crossed Postn-CreER;Trp53fl/+ with Trp53fl/fl, performed AR at P1, and injected tamoxifen at P3 and P6 to delete Trp53 in myofibroblasts. The mutant hearts had fewer SCs at P7 and were not fully restored at P22 (Figure [L and M]). Cardiomyocyte proliferation was inhibited, and fibroblast proliferation was increased in the periresected regions of mutants at P8 (Figure [N and O] and data not shown). These data show that fibroblast senescence is required for neonatal heart regeneration after AR.The matricellular protein CCN1 has been reported to induce fibroblast senescence and restrict fibrosis in cutaneous wound healing through the activation of Trp53 and p16INK4a pathways.4 We found that Ccn1 was highly expressed in the periresected regions at P4 post-AR (Figure [P]). Immunostaining showed that CCN1 was expressed in cardiomyocytes in the injured sites (Figure [Q]). To knock down Ccn1, we injected AAV9-shCcn1-eGFP at P0 and performed AR at P1. The shCcn1-treated hearts had fewer SCs at P7 and were not fully restored at P22 (Figure [R and S]). Meanwhile, cardiomyocyte proliferation was decreased and fibroblast proliferation was enhanced in the periresected regions of shCcn1-treated hearts at P7 (Figure [T and U] and data not shown). Collectively, CCN1 is required for senescence after AR and neonatal heart regeneration.We found that CCN1 treatment induced fibroblast senescence and triggered the expression of senescence-associated secretory phenotype factors including IL-1a and IL-6 in vitro (data not shown). In addition, interleukin-6 or interleukin-1a treatment both promoted neonatal cardiomyocyte proliferation in culture (data not shown). Therefore, we examined whether CCN1 had therapeutic effects on adult hearts after myocardial infarction (MI). Fibroblast senescence occurs in adult hearts after MI, and inactivation of Trp53 enhances cardiac fibrosis after MI.5 We administered the infarcted adult mice with recombinant CCN1 and found that CCN1-treated hearts had more SCs and fewer proliferating fibroblasts in the ischemic regions (Figure [V and W]). However, we did not find any difference in cardiomyocyte proliferation between vehicle- and CCN1-treated groups. In CCN1-treated hearts, the infarcted size was attenuated and the cardiac function, including left ventricular ejection fraction, was improved compared with controls (Figure [X and Y]).Our study suggests that AR-induced CCN1 secretion from cardiomyocytes results in fibroblast senescence, which promotes neonatal heart regeneration by enhancing cardiomyocyte proliferation and reducing cardiac fibrosis (Figure [Z]). Although the role of endogenous CCN1 in adult hearts after MI is not yet fully understood, CCN1 treatment has potential therapeutic effects on MI by inhibiting myofibroblast proliferation to prevent adverse cardiac remodeling and improving cardiac function.All animal procedures complied with and were approved by the Institutional Animal Care and Use Committee.AcknowledgmentsWe thank L. Hui, PhD, for providing the Trp53flox mouse line. We thank the research platforms at the School of Life Science and Technology, ShanghaiTech University. We thank H. Chen, C. Zheng, and H. Feng for the animal husbandry. We appreciate the valuable suggestions from Z. Lin, PhD.Sources of FundingThis work was sponsored by grants from the National Key R&D Program of China (No. 2018YFA0108100), the National Science Foundation of China (No. 31822034, No. 31871474, No. 81861128023, No. 91849202, and No. 31625019), the “Shuguang Program” supported by Shanghai Education Development Foundation and Shanghai Municipal Commission (No. 17SG54), and the ShanghaiTech University start-up fund.DisclosuresNone.Footnoteshttps://www.ahajournals.org/journal/circData 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 authors on reasonable request.Bin Zhou, MD, PhD, 320 Yueyang Rd, A2112, Shanghai, 200031, China. Email [email protected]ac.cnHui Zhang, PhD, 393 Middle Huaxia Rd, B328, Shanghai, 201210, China. Email [email protected]edu.cnReferences1. He S, Sharpless NE. 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May 21, 2019Vol 139, Issue 21 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.119.039530PMID: 31107624 Originally publishedMay 20, 2019 Keywordsfibroblastscellular senescencemyocardial infarctionregenerationCCN1 proteinPDF download Advertisement SubjectsMyocardial InfarctionMyocardial Regeneration