Skip to main content

Advertisement

SpringerLink
Log in

Epigenetically modified cardiac mesenchymal stromal cells limit myocardial fibrosis and promote functional recovery in a model of chronic ischemic cardiomyopathy

  • Original Contribution
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Preclinical investigations support the concept that donor cells more oriented towards a cardiovascular phenotype favor repair. In light of this philosophy, we previously identified HDAC1 as a mediator of cardiac mesenchymal cell (CMC) cardiomyogenic lineage commitment and paracrine signaling potency in vitro—suggesting HDAC1 as a potential therapeutically exploitable target to enhance CMC cardiac reparative capacity. In the current study, we examined the effects of pharmacologic HDAC1 inhibition, using the benzamide class 1 isoform-selective HDAC inhibitor entinostat (MS-275), on CMC cardiomyogenic lineage commitment and CMC-mediated myocardial repair in vivo. Human CMCs pre-treated with entinostat or DMSO diluent control were delivered intramyocardially in an athymic nude rat model of chronic ischemic cardiomyopathy 30 days after a reperfused myocardial infarction. Indices of cardiac function were assessed by echocardiography and left ventricular (LV) Millar conductance catheterization 35 days after treatment. Compared with naïve CMCs, entinostat-treated CMCs exhibited heightened capacity for myocyte-like differentiation in vitro and superior ability to attenuate LV remodeling and systolic dysfunction in vivo. The improvement in CMC therapeutic efficacy observed with entinostat pre-treatment was not associated with enhanced donor cell engraftment, cardiomyogenesis, or vasculogenesis, but instead with more efficient inhibition of myocardial fibrosis and greater increase in myocyte size. These results suggest that HDAC inhibition enhances the reparative capacity of CMCs, likely via a paracrine mechanism that improves ventricular compliance and contraction and augments myocyte growth and function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Avolio E, Meloni M, Spencer HL, Riu F, Katare R, Mangialardi G, Oikawa A, Rodriguez-Arabaolaza I, Dang ZX, Mitchell K, Reni C, Alvino VV, Rowlinson J, Livi U, Cesselli D, Angelini G, Emanueli C, Beltrami AP, Madeddu P (2015) Combined intramyocardial delivery of human pericytes and cardiac stem cells additively improves the healing of mouse infarcted hearts through stimulation of vascular and muscular repair. Circ Res 116:E81–E94. https://doi.org/10.1161/Circresaha.115.306146

    Article  CAS  PubMed  Google Scholar 

  2. Behfar A, Yamada S, Crespo-Diaz R, Nesbitt JJ, Rowe LA, Perez-Terzic C, Gaussin V, Homsy C, Bartunek J, Terzic A (2010) Guided cardiopoiesis enhances therapeutic benefit of bone marrow human mesenchymal stem cells in chronic myocardial infarction. J Am Coll Cardiol 56:721–734. https://doi.org/10.1016/j.jacc.2010.03.066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Charoenviriyakul C, Takahashi Y, Morishita M, Matsumoto A, Nishikawa M, Takakura Y (2017) Cell type-specific and common characteristics of exosomes derived from mouse cell lines: yield, physicochemical properties, and pharmacokinetics. Eur J Pharm Sci 96:316–322. https://doi.org/10.1016/j.ejps.2016.10.009

    Article  CAS  PubMed  Google Scholar 

  4. Gnecchi M, Zhang ZP, Ni AG, Dzau VJ (2008) Paracrine Mechanisms in Adult Stem Cell Signaling and Therapy. Circ Res 103:1204–1219. https://doi.org/10.1161/Circresaha.108.176826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Granger A, Abdullah I, Huebner F, Stout A, Wang T, Huebner T, Epstein JA, Gruber PJ (2008) Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice. FASEB J 22:3549–3560. https://doi.org/10.1096/fj.08-108548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Guo YR, Wysoczynski M, Nong YB, Tomlin A, Zhu XP, Gumpert AM, Nasr M, Muthusamy S, Li H, Book M, Khan A, Hong KU, Li QH, Bolli R (2017) Repeated doses of cardiac mesenchymal cells are therapeutically superior to a single dose in mice with old myocardial infarction. Basic Res Cardiol 112:18. https://doi.org/10.1007/s00395-017-0606-5

    Article  PubMed  PubMed Central  Google Scholar 

  7. Hadjal Y, Hadadeh O, Yazidi CEI, Barruet E, Binetruy B (2013) A p38mapk-p53 cascade regulates mesodermal differentiation and neurogenesis of embryonic stem cells. Cell Death Dis 4:e737. https://doi.org/10.1038/cddis.2013.246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Halevy O (1993) P53 Gene Is up-Regulated during Skeletal-Muscle Cell-Differentiation. Biochem Bioph Res Co 192:714–719. https://doi.org/10.1006/bbrc.1993.1473

    Article  CAS  Google Scholar 

  9. Hodgkinson CP, Bareja A, Gomez JA, Dzau VJ (2016) emerging concepts in paracrine mechanisms in regenerative cardiovascular medicine and biology. Circ Res 118:95–107. https://doi.org/10.1161/Circresaha.115.305373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hong KU, Guo Y, Li QH, Cao P, Al-Maqtari T, Vajravelu BN, Du J, Book MJ, Zhu X, Nong Y, Bhatnagar A, Bolli R (2014) c-kit + cardiac stem cells alleviate post-myocardial infarction left ventricular dysfunction despite poor engraftment and negligible retention in the recipient heart. PLoS One 9:e96725. https://doi.org/10.1371/journal.pone.0096725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hong KU, Li QH, Guo Y, Patton NS, Moktar A, Bhatnagar A, Bolli R (2013) A highly sensitive and accurate method to quantify absolute numbers of c-kit + cardiac stem cells following transplantation in mice. Basic Res Cardiol 108:346. https://doi.org/10.1007/s00395-013-0346-0

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ieda M, Fu JD, Delgado-Olguin P, Vedantham V, Hayashi Y, Bruneau BG, Srivastava D (2010) Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142:375–386. https://doi.org/10.1016/j.cell.2010.07.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ahn SY, Chang YS, Sung DK, Yoo HS, Sung SI, Choi SJ, Park WS, J Pharmacol Exp TherJ Am Heart Assoc (2015) Cell type-dependent variation in paracrine potency determines therapeutic efficacy against neonatal hyperoxic lung injury. Cytotherapy 17:1025–1035. https://doi.org/10.1016/j.jcyt.2015.03.008

    Article  CAS  PubMed  Google Scholar 

  14. Kanazawa H, Tseliou E, Dawkins JF, De Couto G, Gallet R, Malliaras K, Yee K, Kreke M, Valle I, Smith RR, Middleton RC, Ho CS, Dharmakumar R, Li D, Makkar RR, Fukuda K, Marban L, Marban E (2016) Durable benefits of cellular postconditioning: long-term effects of allogeneic cardiosphere-derived cells infused after reperfusion in pigs with acute myocardial infarction. J Am Heart Assoc 5:e002796. https://doi.org/10.1161/jaha.115.002796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lee TM, Lin MS, Chang NC (2007) Inhibition of histone deacetylase on ventricular remodeling in infarcted rats. Am J Physiol Heart Circ Physiol 293:H968–977. https://doi.org/10.1152/ajpheart.00891.2006

    Article  CAS  PubMed  Google Scholar 

  16. Litwin SE, Katz SE, Morgan JP, Douglas PS (1994) Serial echocardiographic assessment of left ventricular geometry and function after large myocardial infarction in the rat. Circulation 89:345–354

    Article  CAS  Google Scholar 

  17. Makino S, Fukuda K, Miyoshi S, Konishi F, Kodama H, Pan J, Sano M, Takahashi T, Hori S, Abe H, Hata J, Umezawa A, Ogawa S (1999) Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest 103:697–705. https://doi.org/10.1172/Jci5298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Martire A, Bedada FB, Uchida S, Poling J, Kruger M, Warnecke H, Richter M, Kubin T, Herold S, Braun T (2016) Mesenchymal stem cells attenuate inflammatory processes in the heart and lung via inhibition of TNF signaling. Basic Res Cardiol 111:54. https://doi.org/10.1007/s00395-016-0573-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mayourian J, Cashman TJ, Ceholski DK, Johnson BV, Sachs D, Kaji DA, Sahoo S, Hare JM, Hajjar RJ, Sobie EA, Costa KD (2017) Experimental and computational insight into human mesenchymal stem cell paracrine signaling and heterocellular coupling effects on cardiac contractility and arrhythmogenicity. Circ Res 121:411–423. https://doi.org/10.1161/Circresaha.117.310796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mayourian J, Ceholski DK, Gorski PA, Mathiyalagan P, Murphy JF, Salazar SI, Stillitano F, Hare JM, Sahoo S, Hajjar RJ, Costa KD (2018) Exosomal microRNA-21-5p mediates mesenchymal stem cell paracrine effects on human cardiac tissue contractility. Circ Res 122:933–944. https://doi.org/10.1161/Circresaha.118.312420

    Article  CAS  PubMed  Google Scholar 

  21. Mazzaro G, Bossi G, Coen S, Sacchi A, Soddu S (1999) The role of wild-type p53 in the differentiation of primary hemopoietic and muscle cells. Oncogene 18:5831–5835. https://doi.org/10.1038/sj.onc.1202962

    Article  CAS  PubMed  Google Scholar 

  22. Moore JB 4th, Zhao J, Fischer AG, Keith MCL, Hagan D, Wysoczynski M, Bolli R (2017) Histone deacetylase 1 depletion activates human cardiac mesenchymal stromal cell proangiogenic paracrine signaling through a mechanism requiring enhanced basic fibroblast growth factor synthesis and secretion. J Am Heart Assoc 6:e006183. https://doi.org/10.1161/jaha.117.006183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Moore JB 4th, Zhao J, Keith MC, Amraotkar AR, Wysoczynski M, Hong KU, Bolli R (2016) The Epigenetic regulator HDAC1 modulates transcription of a core cardiogenic program in human cardiac mesenchymal stromal cells through a p53-dependent mechanism. Stem cells 34:2916–2929. https://doi.org/10.1002/stem.2471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Moscoso I, Centeno A, Lopez E, Rodriguez-Barbosa JI, Santamarina I, Filgueira P, Sanchez MJ, Dominguez-Perles R, Penuelas-Rivas GP, Domenech N (2005) Differentiation “in vitro” of primary and immortalized porcine mesenchymal stem cells into cardiomyocytes for cell transplantation. Transpl P 37:481–482. https://doi.org/10.1016/j.transproceed.2004.12.247

    Article  CAS  Google Scholar 

  25. Oyama T, Nagai T, Wada H, Naito AT, Matsuura K, Iwanaga K, Takahashi T, Goto M, Mikami Y, Yasuda N, Akazawa H, Uezumi A, Takeda S, Komuro I (2007) Cardiac side population cells have a potential to migrate and differentiate into cardiomyocytes in vitro and in vivo. J Cell Biol 176:329–341. https://doi.org/10.1083/jcb.200603014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Preibisch S, Saalfeld S, Tomancak P (2009) Globally optimal stitching of tiled 3D microscopic image acquisitions. Bioinformatics 25:1463–1465. https://doi.org/10.1093/bioinformatics/btp184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Qian Q, Qian H, Zhang X, Zhu W, Yan YM, Ye SQ, Peng XJ, Li W, Xu Z, Sun LY, Xu WR (2012) 5-azacytidine induces cardiac differentiation of human umbilical cord-derived mesenchymal stem cells by activating extracellular regulated kinase. Stem Cells Dev 21:67–75. https://doi.org/10.1089/scd.2010.0519

    Article  CAS  PubMed  Google Scholar 

  28. Rossini A, Frati C, Lagrasta C, Graiani G, Scopece A, Cavalli S, Musso E, Baccarin M, Di Segni M, Fagnoni F, Germani A, Quaini E, Mayr M, Xu QB, Barbuti A, DiFrancesco D, Pompilio G, Quaini F, Gaetano C, Capogrossi MC (2011) Human cardiac and bone marrow stromal cells exhibit distinctive properties related to their origin. Cardiovasc Res 89:650–660. https://doi.org/10.1093/cvr/cvq290

    Article  CAS  PubMed  Google Scholar 

  29. Ruau D, Ensenat-Waser R, Dinger TC, Vallabhapurapu DS, Rolletschek A, Hacker C, Hieronymus T, Wobus AM, Muller AM, Zenke M (2008) Pluripotency associated genes are reactivated by chromatin-modifying agents in neurosphere cells. Stem cells 26:920–926. https://doi.org/10.1634/stemcells.2007-0649

    Article  CAS  PubMed  Google Scholar 

  30. Sanganalmath SK, Bolli R (2013) Cell therapy for heart failure a comprehensive overview of experimental and clinical studies, current challenges, and future directions. Circ Res 113:810–834. https://doi.org/10.1161/Circresaha.113.300219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Segura AM, Frazier OH, Buja LM (2014) Fibrosis and heart failure. Heart Fail Rev 19:173–185. https://doi.org/10.1007/s10741-012-9365-4

    Article  CAS  PubMed  Google Scholar 

  32. Soddu S, Blandino G, Scardigli R, Coen S, Marchetti A, Rizzo MG, Bossi G, Cimino L, Crescenzi M, Sacchi A (1996) Interference with p53 protein inhibits hematopoietic and muscle differentiation. J Cell Biol 134:193–204. https://doi.org/10.1083/jcb.134.1.193

    Article  CAS  PubMed  Google Scholar 

  33. Stein AB, Tiwari S, Thomas P, Hunt G, Levent C, Stoddard MF, Tang XL, Bolli R, Dawn B (2007) Effects of anesthesia on echocardiographic assessment of left ventricular structure and function in rats. Basic Res Cardiol 102:28–41. https://doi.org/10.1007/s00395-006-0627-y

    Article  CAS  PubMed  Google Scholar 

  34. Subramanian S, Bates SE, Wright JJ, Espinoza-Delgado I, Piekarz RL (2010) Clinical toxicities of histone deacetylase inhibitors. Pharmaceuticals 3:2751–2767. https://doi.org/10.3390/ph3092751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Suzuki G, Weil BR, Leiker MM, Ribbeck AE, Young RF, Cimato TR, Canty JM (2014) global intracoronary infusion of allogeneic cardiosphere-derived cells improves ventricular function and stimulates endogenous myocyte regeneration throughout the heart in swine with hibernating myocardium. PloS one 9:e113009. https://doi.org/10.1371/journal.pone.0113009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Tang XL, Li Q, Rokosh G, Sanganalmath SK, Chen N, Ou Q, Stowers H, Hunt G, Bolli R (2016) Long-term outcome of administration of c-kit(POS) cardiac progenitor cells after acute myocardial infarction: transplanted cells do not become cardiomyocytes, but structural and functional improvement and proliferation of endogenous cells persist for at least 1 year. Circ Res 118:1091–1105. https://doi.org/10.1161/CIRCRESAHA.115.307647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Tang XL, Rokosh G, Sanganalmath SK, Tokita Y, Keith MC, Shirk G, Stowers H, Hunt GN, Wu W, Dawn B, Bolli R (2015) Effects of intracoronary infusion of escalating doses of cardiac stem cells in rats with acute myocardial infarction. Circ Heart Fail 8:757–765. https://doi.org/10.1161/CIRCHEARTFAILURE.115.002210

    Article  PubMed  PubMed Central  Google Scholar 

  38. Tang XL, Rokosh G, Sanganalmath SK, Yuan F, Sato H, Mu J, Dai S, Li C, Chen N, Peng Y, Dawn B, Hunt G, Leri A, Kajstura J, Tiwari S, Shirk G, Anversa P, Bolli R (2010) Intracoronary administration of cardiac progenitor cells alleviates left ventricular dysfunction in rats with a 30-day-old infarction. Circulation 121:293–305. https://doi.org/10.1161/CIRCULATIONAHA.109.871905

    Article  PubMed  PubMed Central  Google Scholar 

  39. Weil BR, Suzuki G, Leiker MM, Fallavollita JA, Canty JM Jr (2015) Comparative efficacy of intracoronary allogeneic mesenchymal stem cells and cardiosphere-derived cells in swine with hibernating myocardium. Circ Res 117:634–644. https://doi.org/10.1161/CIRCRESAHA.115.306850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wysoczynski M, Dassanayaka S, Zafir A, Ghafghazi S, Long BW, Noble C, DeMartino AM, Brittian KR, Bolli R, Jones SP (2016) A new method to stabilize C-Kit expression in reparative cardiac mesenchymal cells. Front Cell Dev Biol 4:78. https://doi.org/10.3389/fcell.2016.00078

    Article  PubMed  PubMed Central  Google Scholar 

  41. Wysoczynski M, Guo Y, Moore JB 4th, Muthusamy S, Li Q, Nasr M, Li H, Nong Y, Wu W, Tomlin AA, Zhu X, Hunt G, Gumpert AM, Book MJ, Khan A, Tang XL, Bolli R (2017) Myocardial reparative properties of cardiac mesenchymal cells isolated on the basis of adherence. J Am Coll Cardiol 69:1824–1838. https://doi.org/10.1016/j.jacc.2017.01.048

    Article  PubMed  PubMed Central  Google Scholar 

  42. Xie M, Kong YL, Tan W, May H, Battiprolu PK, Pedrozo Z, Wang ZV, Morales C, Luo X, Cho G, Jiang N, Jessen ME, Warner JJ, Lavandero S, Gillette TG, Turer AT, Hill JA (2014) Histone deacetylase inhibition blunts ischemia/reperfusion injury by inducing cardiomyocyte autophagy. Circulation 129:1139–U1170. https://doi.org/10.1161/Circulationaha.113.002416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yang G, Tian J, Feng C, Zhao LL, Liu Z, Zhu J (2012) Trichostatin a promotes cardiomyocyte differentiation of rat mesenchymal stem cells after 5-azacytidine induction or during coculture with neonatal cardiomyocytes via a mechanism independent of histone deacetylase inhibition. Cell Transpl 21:985–996. https://doi.org/10.3727/096368911X593145

    Article  Google Scholar 

  44. Yang G, Tian J, Feng C, Zhao LL, Liu ZG, Zhu J (2012) Trichostatin A promotes cardiomyocyte differentiation of rat mesenchymal stem cells after 5-azacytidine induction or during coculture with neonatal cardiomyocytes via a mechanism independent of histone deacetylase inhibition. Cell Transpl 21:985–996. https://doi.org/10.3727/096368911X593145

    Article  Google Scholar 

  45. Yoon CH, Koyanagi M, Iekushi K, Seeger F, Urbich C, Zeiher AM, Dimmeler S (2010) Mechanism of improved cardiac function after bone marrow mononuclear cell therapy: role of cardiovascular lineage commitment. Circulation 121:2001–2011. https://doi.org/10.1161/CIRCULATIONAHA.109.909291

    Article  PubMed  Google Scholar 

  46. Zhang L, Qin X, Zhao Y, Fast L, Zhuang S, Liu P, Cheng G, Zhao TC (2012) Inhibition of histone deacetylases preserves myocardial performance and prevents cardiac remodeling through stimulation of endogenous angiomyogenesis. J Pharmacol Exp Ther 341:285–293. https://doi.org/10.1124/jpet.111.189910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhang LX, Zhao Y, Cheng G, Guo TL, Chin YE, Liu PY, Zhao TC (2010) Targeted deletion of NF-kappaB p50 diminishes the cardioprotection of histone deacetylase inhibition. Am J Physiol Heart Circ Physiol 298:H2154–2163. https://doi.org/10.1152/ajpheart.01015.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhao J, Ghafghazi S, Khan AR, Farid TA, Moore JB 4th (2016) Recent developments in stem and progenitor cell therapy for cardiac repair. Circ Res 119:e152–e159. https://doi.org/10.1161/CIRCRESAHA.116.310257

    Article  CAS  PubMed  Google Scholar 

  49. Zhao Y, Lu SL, Wu LP, Chai GL, Wang HY, Chen YQ, Sun J, Yu Y, Zhou W, Zheng QH, Wu M, Otterson GA, Zhu WG (2006) Acetylation of p53 at lysine 373/382 by the histone deacetylase inhibitor depsipeptide induces expression of p21(Waf1/Cip1). Mol Cell Biol 26:2782–2790. https://doi.org/10.1128/Mcb.26.7.2782-2790.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by National Institutes of Health grants R01 HL141081 (JBM), P01 HL078825 (RB), and UM1 HL113530 (RB). Additional funding was provided by the University of Louisville’s School of Medicine Basic Grant Program (JBM).

Author information

Authors and Affiliations

  1. Institute of Molecular Cardiology, Division of Cardiovascular Medicine, University of Louisville, 580 S. Preston Street, Louisville, KY, 40292, USA

    Joseph B. Moore IV, Xian-Liang Tang, John Zhao, Annalara G. Fischer, Wen-Jian Wu, Anna M. Gumpert, Heather Stowers, Marcin Wysoczynski & Roberto Bolli

  2. Department of Medicine, Cardiovascular Innovation Institute, University of Louisville, Louisville, KY, USA

    Shizuka Uchida

Authors
  1. Joseph B. Moore IV
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xian-Liang Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Annalara G. Fischer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wen-Jian Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shizuka Uchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anna M. Gumpert
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Heather Stowers
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marcin Wysoczynski
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Roberto Bolli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joseph B. Moore IV.

Ethics declarations

Conflict of interest

The authors indicate no potential conflicts of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Moore, J.B., Tang, XL., Zhao, J. et al. Epigenetically modified cardiac mesenchymal stromal cells limit myocardial fibrosis and promote functional recovery in a model of chronic ischemic cardiomyopathy. Basic Res Cardiol 114, 3 (2019). https://doi.org/10.1007/s00395-018-0710-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00395-018-0710-1

Keywords

Search

Navigation