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Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair

Nature Medicine volume 13, pages 962–969 (2007)Cite this article

Abstract

Adult mammalian hearts respond to injury with scar formation and not with cardiomyocyte proliferation, the cellular basis of regeneration. Although cardiogenic progenitor cells may maintain myocardial turnover, they do not give rise to a robust regenerative response. Here we show that extracellular periostin induced reentry of differentiated mammalian cardiomyocytes into the cell cycle. Periostin stimulated mononucleated cardiomyocytes to go through the full mitotic cell cycle. Periostin activated αV, β1, β3 and β5 integrins located in the cardiomyocyte cell membrane. Activation of phosphatidylinositol-3-OH kinase was required for periostin-induced reentry of cardiomyocytes into the cell cycle and was sufficient for cell-cycle reentry in the absence of periostin. After myocardial infarction, periostin-induced cardiomyocyte cell-cycle reentry and mitosis were associated with improved ventricular remodeling and myocardial function, reduced fibrosis and infarct size, and increased angiogenesis. Thus, periostin and the pathway that it regulates may provide a target for innovative strategies to treat heart failure.

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Figure 1: Periostin stimulates DNA synthesis and cytokinesis of differentiated mononucleated cardiomyocytes.
Figure 2: Periostin-stimulated cell-cycle reentry of differentiated cardiomyocytes requires integrins and PI3K.
Figure 3: Periostin stimulates cardiomyocyte DNA synthesis and cytokinesis in vivo.
Figure 4: Periostin improves ventricular remodeling and function after myocardial infarction.
Figure 5: Periostin reduces scar formation and attenuates post-infarct remodeling.
Figure 6: Periostin promotes cardiomyocyte proliferation after myocardial infarction.

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References

  1. Soonpaa, M.H. & Field, L.J. Survey of studies examining mammalian cardiomyocyte DNA synthesis. Circ. Res. 83, 15–26 (1998).

    Article  CAS  Google Scholar 

  2. Laflamme, M.A. & Murry, C.E. Regenerating the heart. Nat. Biotechnol. 23, 845–856 (2005).

    Article  CAS  Google Scholar 

  3. Pasumarthi, K.B. & Field, L.J. Cardiomyocyte cell cycle regulation. Circ. Res. 90, 1044–1054 (2002).

    Article  CAS  Google Scholar 

  4. Engel, F.B. et al. p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes. Genes Dev. 19, 1175–1187 (2005).

    Article  CAS  Google Scholar 

  5. Katz, E.B. et al. Cardiomyocyte proliferation in mice expressing α-cardiac myosin heavy chain-SV40 T-antigen transgenes. Am. J. Physiol. 262, H1867–H1876 (1992).

    CAS  PubMed  Google Scholar 

  6. Pasumarthi, K.B., Nakajima, H., Nakajima, H.O., Soonpaa, M.H. & Field, L.J. Targeted expression of cyclin D2 results in cardiomyocyte DNA synthesis and infarct regression in transgenic mice. Circ. Res. 96, 110–118 (2005).

    Article  CAS  Google Scholar 

  7. Nakajima, H., Nakajima, H.O., Tsai, S.C. & Field, L.J. Expression of mutant p193 and p53 permits cardiomyocyte cell cycle reentry after myocardial infarction in transgenic mice. Circ. Res. 94, 1606–1614 (2004).

    Article  CAS  Google Scholar 

  8. Takeshita, S., Kikuno, R., Tezuka, K. & Amann, E. Osteoblast-specific factor 2: cloning of a putative bone adhesion protein with homology with the insect protein fasciclin I. Biochem. J. 294, 271–278 (1993).

    Article  CAS  Google Scholar 

  9. Litvin, J., Zhu, S., Norris, R. & Markwald, R. Periostin family of proteins: therapeutic targets for heart disease. Anat. Rec. A Discov. Mol. Cell. Evol. Biol. 287, 1205–1212 (2005).

    Article  Google Scholar 

  10. Butcher, J.T., Norris, R.A., Hoffman, S., Mjaatvedt, C.H. & Markwald, R.R. Periostin promotes atrioventricular mesenchyme matrix invasion and remodeling mediated by integrin signaling through Rho/PI 3-kinase. Dev. Biol. 302, 256–266 (2007).

    Article  CAS  Google Scholar 

  11. Stanton, L.W. et al. Altered patterns of gene expression in response to myocardial infarction. Circ. Res. 86, 939–945 (2000).

    Article  CAS  Google Scholar 

  12. Wang, D. et al. Effects of pressure overload on extracellular matrix expression in the heart of the atrial natriuretic peptide-null mouse. Hypertension 42, 88–95 (2003).

    Article  CAS  Google Scholar 

  13. Lindner, V., Wang, Q., Conley, B.A., Friesel, R.E. & Vary, C.P. Vascular injury induces expression of periostin: implications for vascular cell differentiation and migration. Arterioscler. Thromb. Vasc. Biol. 25, 77–83 (2005).

    Article  CAS  Google Scholar 

  14. Goetsch, S.C., Hawke, T.J., Gallardo, T.D., Richardson, J.A. & Garry, D.J. Transcriptional profiling and regulation of the extracellular matrix during muscle regeneration. Physiol. Genomics 14, 261–271 (2003).

    Article  CAS  Google Scholar 

  15. Nakazawa, T. et al. Gene expression of periostin in the early stage of fracture healing detected by cDNA microarray analysis. J. Orthop. Res. 22, 520–525 (2004).

    Article  CAS  Google Scholar 

  16. Litvin, J. et al. Periostin and periostin-like factor in the human heart: possible therapeutic targets. Cardiovasc. Pathol. 15, 24–32 (2006).

    Article  CAS  Google Scholar 

  17. Katsuragi, N. et al. Periostin as a novel factor responsible for ventricular dilation. Circulation 110, 1806–1813 (2004).

    Article  CAS  Google Scholar 

  18. Tai, I.T., Dai, M. & Chen, L.B. Periostin induction in tumor cell line explants and inhibition of in vitro cell growth by anti-periostin antibodies. Carcinogenesis 26, 908–915 (2005).

    Article  CAS  Google Scholar 

  19. Tatsuka, M. et al. Multinuclearity and increased ploidy caused by overexpression of the aurora- and Ipl1-like midbody-associated protein mitotic kinase in human cancer cells. Cancer Res. 58, 4811–4816 (1998).

    CAS  PubMed  Google Scholar 

  20. Soonpaa, M.H., Kim, K.K., Pajak, L., Franklin, M. & Field, L.J. Cardiomyocyte DNA synthesis and binucleation during murine development. Am. J. Physiol. 271, H2183–H2189 (1996).

    CAS  PubMed  Google Scholar 

  21. Rubinson, D.A. et al. A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference. Nat. Genet. 33, 401–406 (2003).

    Article  CAS  Google Scholar 

  22. Katzberg, A.A., Farmer, B.B. & Harris, R.A. The predominance of binucleation in isolated rat heart myocytes. Am. J. Anat. 149, 489–499 (1977).

    Article  CAS  Google Scholar 

  23. Chen, X. et al. Adolescent feline heart contains a population of small, proliferative ventricular myocytes with immature physiological properties. Circ. Res. 100, 536–544 (2007).

    Article  CAS  Google Scholar 

  24. Miranti, C.K. & Brugge, J.S. Sensing the environment: a historical perspective on integrin signal transduction. Nat. Cell Biol. 4, E83–E90 (2002).

    Article  CAS  Google Scholar 

  25. Shiojima, I. & Walsh, K. Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway. Genes Dev. 20, 3347–3365 (2006).

    Article  CAS  Google Scholar 

  26. Crackower, M.A. et al. Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 110, 737–749 (2002).

    Article  CAS  Google Scholar 

  27. Matsui, T. et al. Adenoviral gene transfer of activated phosphatidylinositol 3′-kinase and Akt inhibits apoptosis of hypoxic cardiomyocytes in vitro. Circulation 100, 2373–2379 (1999).

    Article  CAS  Google Scholar 

  28. Rota, M. et al. Nuclear targeting of Akt enhances ventricular function and myocyte contractility. Circ. Res. 97, 1332–1341 (2005).

    Article  CAS  Google Scholar 

  29. Zarain-Herzberg, A., Afzal, N., Elimban, V. & Dhalla, N.S. Decreased expression of cardiac sarcoplasmic reticulum Ca2+-pump ATPase in congestive heart failure due to myocardial infarction. Mol. Cell. Biochem. 163–164, 285–290 (1996).

  30. Gilbert, M.E., Kelly, M.E., Samsam, T.E. & Goodman, J.H. Chronic developmental lead exposure reduces neurogenesis in adult rat hippocampus but does not impair spatial learning. Toxicol. Sci. 86, 365–374 (2005).

    Article  CAS  Google Scholar 

  31. Woo, Y.J. et al. Therapeutic delivery of cyclin A2 induces myocardial regeneration and enhances cardiac function in ischemic heart failure. Circulation 114, I206–I213 (2006).

    Article  Google Scholar 

  32. Engel, F.B., Hsieh, P.C., Lee, R.T. & Keating, M.T. FGF1/p38 MAP kinase inhibitor therapy induces cardiomyocyte mitosis, reduces scarring, and rescues function after myocardial infarction. Proc. Natl. Acad. Sci. USA 103, 15546–15551 (2006).

    Article  CAS  Google Scholar 

  33. Shai, S.Y. et al. Cardiac myocyte-specific excision of the β1 integrin gene results in myocardial fibrosis and cardiac failure. Circ. Res. 90, 458–464 (2002).

    Article  CAS  Google Scholar 

  34. Ren, J. β3 Integrin deficiency promotes cardiac hypertrophy and inflammation. J. Mol. Cell. Cardiol. 42, 367–377 (2007).

    Article  CAS  Google Scholar 

  35. Fazel, S. et al. Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines. J. Clin. Invest. 116, 1865–1877 (2006).

    Article  CAS  Google Scholar 

  36. Sun, M. et al. Temporal response and localization of integrins β1 and β3 in the heart after myocardial infarction: regulation by cytokines. Circulation 107, 1046–1052 (2003).

    Article  CAS  Google Scholar 

  37. Rios, H. et al. Periostin null mice exhibit dwarfism, incisor enamel defects, and an early-onset periodontal disease-like phenotype. Mol. Cell. Biol. 25, 11131–11144 (2005).

    Article  CAS  Google Scholar 

  38. Yoshioka, N. et al. Suppression of anchorage-independent growth of human cancer cell lines by the TRIF52/periostin/OSF-2 gene. Exp. Cell Res. 279, 91–99 (2002).

    Article  CAS  Google Scholar 

  39. Litvin, J. et al. Expression and function of periostin-isoforms in bone. J. Cell. Biochem. 92, 1044–1061 (2004).

    Article  CAS  Google Scholar 

  40. Shioi, T. et al. The conserved phosphoinositide 3-kinase pathway determines heart size in mice. EMBO J. 19, 2537–2548 (2000).

    Article  CAS  Google Scholar 

  41. Srivastava, D. Making or breaking the heart: from lineage determination to morphogenesis. Cell 126, 1037–1048 (2006).

    Article  CAS  Google Scholar 

  42. Shi, Q. & King, R.W. Chromosome nondisjunction yields tetraploid rather than aneuploid cells in human cell lines. Nature 437, 1038–1042 (2005).

    Article  CAS  Google Scholar 

  43. Ma, H., Sumbilla, C.M., Farrance, I.K., Klein, M.G. & Inesi, G. Cell-specific expression of SERCA, the exogenous Ca2+ transport ATPase, in cardiac myocytes. Am. J. Physiol. Cell Physiol. 286, C556–C564 (2004).

    Article  CAS  Google Scholar 

  44. He, T.C. et al. A simplified system for generating recombinant adenoviruses. Proc. Natl. Acad. Sci. USA 95, 2509–2514 (1998).

    Article  CAS  Google Scholar 

  45. Shiraishi, I. et al. Nuclear targeting of Akt enhances kinase activity and survival of cardiomyocytes. Circ. Res. 94, 884–891 (2004).

    Article  CAS  Google Scholar 

  46. Lebeche, D., Kang, Z.B. & Hajjar, R. Candesartan abrogates G protein-coupled receptor agonist-induced MAPK activation and cardiac myocyte hypertrophy. J. Renin Angiotensin Aldosterone Syst. 2, 154–161 (2001).

    Article  Google Scholar 

  47. del Monte, F. et al. Abrogation of ventricular arrhythmias in a model of ischemia and reperfusion by targeting myocardial calcium cycling. Proc. Natl. Acad. Sci. USA 101, 5622–5627 (2004).

    Article  CAS  Google Scholar 

  48. Prunier, F. et al. Delayed erythropoietin therapy reduces post-MI cardiac remodeling only at a dose that mobilizes endothelial progenitor cells. Am. J. Physiol. Heart Circ. Physiol. 292, H522–H529 (2007).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank M. Dai and L.-B. Chen (Dana Farber Cancer Institute, Boston, Massachusetts, USA) for recombinant human periostin; members of the Clapham, del Monte, Hajjar, Keating, McGowan, and Pu laboratories for discussions and sharing reagents; S.P. Sardi (Children's Hospital Boston, Boston, Massachusetts, USA) for lentivirus constructs; and R. Breitbart for suggestions and critical review of the manuscript. This study was supported in part by grants from the US National Institutes of Health (R01 HL078691, HL057263, HL071763, HL080498 and HL083156 to R.J.H.; K08 HL069842 to F.d.M.; and K01 HL076659 to D.L.) and the Leducq Transatlantic Network (to R.J.H.).

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  1. Roger J Hajjar, Djamel Lebeche & Mark T Keating

    Present address: Present addresses: Cardiovascular Research Center, Mount Sinai School of Medicine, One Gustave Levy Place, New York, New York 10029, USA (R.J.H., D.L.); Novartis Institutes for BioMedical Research, Inc., 500 Technology Square, Cambridge, Massachusetts 02139, USA (M.T.K.).,

Authors and Affiliations

  1. Department of Cardiology, Children's Hospital Boston, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Bernhard Kühn, Shima Arab & Mark T Keating

  2. Cardiovascular Research Center, Massachusetts General Hospital, 149 13th Street, Charlestown, Massachusetts, 02129, USA

    Federica del Monte, Roger J Hajjar & Djamel Lebeche

  3. Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, 02114, Massachusetts, USA

    Yuh-Shin Chang

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Contributions

B.K. supervised research; B.K., F.d.M., R.J.H., Y.-S.C., D.L., S.A. and M.T.K. designed experiments; B.K., F.d.M., Y.-S.C. and S.A. performed and analyzed experiments; F.d.M., Y.-S.C., and D.L. provided plasmids and adenovirus constructs; B.K. and S.A. wrote the manuscript.

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Correspondence to Bernhard Kühn or Mark T Keating.

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Competing interests

B.K. and M.T.K. filed a patent application relevant to this work on January 22, 2007 (US Provisional Patent Application Serial No. 60/881,938).

R.J.H. is the scientific founder of Celladon Inc. and Nanocor, two biotechnology companies, which are commercializing AAV gene therapy for heart failure.

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Kühn, B., del Monte, F., Hajjar, R. et al. Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. Nat Med 13, 962–969 (2007). https://doi.org/10.1038/nm1619

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