BBS Faculty Member - Bernhard Kühn

Bernhard Kühn

Department of Pediatrics

Boston Children's Hospital
300 Longwood Avenue
Enders Building 1212
Boston, MA 02115
Tel: 617-919-4773
Fax: 617-731-0787
Email: bkuhn@enders.tch.harvard.edu
Visit my lab page here.



Stimulating myocardial growth and regeneration to treat heart disease

My laboratory is addressing the century-old problem of whether differentiated mammalian heart muscle cells, cardiomyocytes, can proliferate. Although cardiac regeneration has been studied for more than a century, little progress has been made in characterizing the mechanisms that control the cell cycle in cardiomyocytes. Our approach is multidisciplinary and involves basic and translational research. Over the past six years, we have advanced the understanding of these mechanisms in the normal and abnormal vertebrate heart, as well as the mechanisms of myocardial regeneration. This research has led us to develop a new strategy for treating heart failure, including the identification of two factors that promote myocardial regeneration.

Molecular mechanisms of cardiomyocyte proliferation

My laboratory has pioneered the use of peptide factors for stimulating cardiomyocyte proliferation to promote myocardial regeneration. We have extensively studied two factors that induce proliferation of differentiated cardiomyocytes and promote myocardial regeneration: periostin, a component of the extracellular matrix, and neuregulin1, a growth factor. Periostin and neuregulin1 are extracellular factors and thus require cell surface receptors to induce cardiomyocyte proliferation. We have demonstrated that periostin peptide requires integrins, while neuregulin1 interacts with receptor tyrosine kinases to activate intracellular signaling cascades. Although periostin and neuregulin1 activate different membranous receptors, we have demonstrated that the intracellular signaling pathways converge at phosphatidyl-inositol-3-OH kinase (PI3-kinase), a master switch controlling cell proliferation and growth.

Cellular mechanisms of cardiomyocyte proliferation

We have demonstrated that a subpopulation of mononucleated cardiomyocytes can proliferate. We have shown that approximately 50% of cardiomyocytes that entered cytokinesis finished cytokinesis with abscission, whereas the other half underwent cleavage furrow regression and became binucleated. We have shown that differentiated cardiomyocytes disassemble their sarcomeres during mitosis and cytokinesis. Thus, the presence of the differentiated contractile apparatus does not prohibit cytokinesis, as was commonly thought.

We have formulated a cellular model of cardiomyocyte proliferation: a subpopulation of mononucleated, differentiated cardiomyocytes is quiescent, i.e. they do not proliferate under resting conditions. This subpopulation can be stimulated to proliferate by administering periostin peptide and neuregulin1, suggesting that it may be possible to use controlled proliferation to regenerate damaged heart tissue in patients with heart failure.

Translational application

We have shown that periostin peptide and neuregulin1 stimulate myocardial regeneration in animal models of myocardial infarction. Stimulating cardiomyocyte proliferation with exogenous compounds would transform heart failure therapy. However, it is unknown to what extent cardiomyocyte proliferation contributes to the growth of the human heart to adult size. To address this problem, we are currently developing a cellular growth chart of the human heart, using unique samples from normal human hearts covering a broad age range.



Last Update: 8/22/2013



Publications

Bersell K, Arab S, Haring B, Kühn B. Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury. Cell 2009;138:257-70.

Kühn B, del Monte F, Hajjar RJ, Chang YS, Lebeche D, Arab S, Keating MT. Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. Nat. Med. 2007;13:962-969.



© 2013 by the President and Fellows of Harvard College