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Periostin Induces Proliferation of Differentiated Cardiomyocytes and Promotes Cardiac Repair

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Periostin Induces Proliferation of Differentiated Cardiomyocytes and Promotes Cardiac Repair ARTICLES Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair Bernhard Ku¨hn1, Federica del Monte2, Roger J Hajjar2,4, Yuh-Shin Chang3, Djamel Lebeche2,4, Shima Arab1 & Mark T Keating1,4 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 aV, b1, b3 and b5 integrins located in the cardiomyocyte cell membrane. Activation of phosphatidylinositol-3-OH kinase was required for periostin- http://www.nature.com/naturemedicine 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. Differentiated cardiomyocytes carry the pump function of the heart. hypertrophic cardiomyopathy16. By contrast, liposomal gene delivery Loss of cardiomyocytes, which occurs, for example, after a large of periostin leads to dilative cardiomyopathy without hypertrophy17. myocardial infarction, typically results in heart failure. Observations Here we have investigated whether recombinant periostin, delivered spanning the twentieth century show that some cardiomyocytes in the through the cardiac extracellular matrix, can increase cardiomyocyte adult heart undergo DNA synthesis and mitosis1,2. Cell-cycle activity proliferation. We show that periostin induced reentry of differentiated Nature Publishing Group Group Nature Publishing 7 in the region bordering a myocardial infarction transiently increases mononucleated cardiomyocytes into the cell cycle. Periostin-induced tenfold to 0.004% (ref. 1). Although this increase is not sufficient for cardiomyocyte cell-cycle reentry required integrins and the phos- 200 regeneration, it suggests that some cardiomyocytes have the potential phatidylinositol-3-OH kinase (PI3K) pathway. After experimental © to reenter the cell cycle in response to extracellular signals in the myocardial infarction, periostin reduced infarct size and fibrosis infarct border zone. It may be possible to apply specific extracellular and improved cardiac function. These results suggest that peri- factors to induce cardiomyocyte proliferation with the aim of enhan- ostin treatment may enhance the regenerative capacity of adult cing cardiac regeneration. mammalian hearts. In contrast to most adult cardiomyocytes, fetal cardiomyocytes do proliferate. After birth, cardiomyocytes become binucleated, down- RESULTS regulate cell-cycle activators, upregulate cell-cycle inhibitors, and Periostin induces cycling of differentiated cardiomyocytes withdraw from the cell cycle3. Although modification of intrinsic The presence of periostin in the developing myocardium9 and its cell-cycle regulation can increase cell-cycle activity of differentiated ability to induce proliferation of neonatal cardiomyocytes (Supple- cardiomyocytes4–7, few extrinsic factors that induce cardiomyocyte mentary Fig. 1 online) prompted us to investigate whether periostin proliferation are known. can induce cell cycle reentry of differentiated cardiomyocytes. Isolated Periostin comprises a signal peptide and four fasciclin-1 (fas1) adult rat ventricular cardiomyocytes with the characteristic rod shape domains. Alternative splicing of the carboxy terminus gives rise to (Fig. 1a,b) provided an in vitro assay platform. Recombinant human periostin-like factor. Periostin, a component of the extracellular periostin18 (500 ng/ml) was added for 9 d. After labeling with matrix8, is associated with epithelial-mesenchymal transition during 5-bromodeoxyuridine (BrdU) for the last 3 d, DNA synthesis was cardiac development9,10. Periostin is reexpressed in adult life after determined. Tracking the fate of individual rod-shaped cardiomyocytes myocardial11,12, vascular13 and skeletal muscle14 injury and after bone showed that they undergo DNA synthesis while expressing the cardiac fracture15. Adenoviral gene delivery of periostin-like factor causes contractile protein tropomyosin (Fig. 1a). Periostin induced a 14-fold 1Department of Cardiology, Children’s Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115, USA. 2Cardiovascular Research Center, Massachusetts General Hospital, 149 13th Street, Charlestown, Massachusetts 02129, USA. 3Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA). 4Present 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.). Correspondence should be addressed to B.K. ([email protected]) or M.T.K. ([email protected]). Received 13 January; accepted 13 June; published online 15 July 2007; doi:10.1038/nm1619 962 VOLUME 13 [ NUMBER 8 [ AUGUST 2007 NATURE MEDICINE ARTICLES abBrdU, Aurora B kinase, c Phase DAPI, tropomyosin Phase DAPI, troponin I 3 1 DNA synthesis Cytokinesis P < 0.005 DNA P < 0.05 100 synthesis 2 75 0.5 Cytokinesis 1 50 cytokinesis 25 Cardiomyocyte Cardiomyocyte cytokinesis (%) (% of maximal) DNA synthesis, DNA synthesis (%) 0 0 0 No PN FGF No PN FGF 0 3 6 9 12 stim. stim. Day 1 Day 9 Day 1 Day 9 Duration of stimulation (d) BrdU, Aurora B kinase, BrdU, d aurora B kinase DAPI, troponin I e DAPI, tropomyosin H2B-GFP DNA synthesis Day 3 Day 9 Figure 1 Periostin stimulates DNA synthesis and cytokinesis of differentiated mononucleated cardiomyocytes. (a,b) Primary adult rat ventricular cardio- myocytes were photographed in phase contrast after attachment; they were then stimulated with periostin, labeled with BrdU for the last 3 d, and cell cycle activity was determined by immunofluorescence microscopy after 9 days. Examples of corresponding phase contrast images (left micrographs) and immuno- fluorescent images (right micrographs) and results of quantification are shown. (a) Cardiomyocyte in S phase retaining expression of tropomyosin. (b)Cardio- myocyte in cytokinesis expressing troponin I. (c) Cardiomyocytes were stimulated with periostin, BrdU was added for the last 3 d, and DNA synthesis and cytokinesis were analyzed at the indicated times. (d) BrdU-labeled cardiomyocyte in cytokinesis. (e) Cardiomyocyte nuclei visualized by troponin T–controlled http://www.nature.com/naturemedicine expression of H2B-GFP. DNA synthesis was visualized 9 d after addition of BrdU for the last 3 d. Color codes for antibody staining are indicated. Scale bars, 50 mm. No stim., no stimulation; PN, periostin. Data are mean ± s.e.m. of 8 (a), 6 (b)and3(c) experiments. Statistical significance was tested by ANOVA. increase in cardiomyocyte DNA synthesis to 1.1 ± 0.2%, similar to the Cardiomyocyte cycling requires integrins and PI3K effect of fibroblast growth factor (FGF), which is known to promote Periostin-induced cardiomyocyte cell-cycle reentry was concentration- cell-cycle reentry of differentiated cardiomyocytes4 (Fig. 1a). dependent (Supplementary Fig. 3 online) and did not correlate with We detected cytokinesis, the final step of the mitotic cell cycle, by the abundance of cardiac fibroblasts (Supplementary Fig. 4 online), visualizing aurora B kinase, a component of the contractile ring at the suggesting that periostin has a direct effect on cardiomyocytes. site of cytoplasmic separation that is required for cytokinesis19. Non- Integrins may function as periostin receptors in cardiomyocytes10. stimulated cardiomyocytes did not progress into cytokinesis. In We therefore determined whether blocking specific integrin subunits Nature Publishing Group Group Nature Publishing 7 cardiomyocytes stimulated with periostin, aurora B kinase was would inhibit periostin-stimulated cardiomyocyte cell-cycle activity. detected after dissociation from the midbody, characteristic of the Antibodies specific to aV, b1, b3 and b5 integrins inhibited periostin- 200 completion of cytokinesis (Fig. 1b). Periostin stimulated cytokinesis in stimulated DNA synthesis in differentiated cardiomyocytes, whereas © 0.5 ± 0.2% of cardiomyocytes, similar to the effect of FGF (Fig. 1b). blocking a7 integrin had no effect (Fig. 2a). Reducing the expression 20 Because most adult mammalian cardiomyocytes are binucleated ,a of integrin aV or b1 by RNA-mediated interference (RNAi) inhibited possible origin of cardiomyocyte cytokinesis is breakdown of binu- periostin-induced cell-cycle reentry in neonatal cardiomyocytes (Sup- cleated cardiomyocytes into mononucleated cardiomyocytes, without plementary Fig. 5 online). We conclude that periostin requires prior DNA synthesis. Periostin-induced cardiomyocyte DNA synthesis integrin aV and a b1, b3 or b5 subunit to induce cardiomyocyte cell- began after 3 d; however, cytokinesis was not detected before 6 d cycle reentry. (Fig. 1c). If periostin-stimulated DNA synthesis preceded cytokinesis,
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