HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 2008-0187v1 26/10/2644    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yamada, S. Articles by Terzic, A. Search for Related Content PubMed PubMed Citation Articles by Yamada, S. Articles by Terzic, A.

TRANSLATIONAL AND CLINICAL RESEARCH

Embryonic Stem Cell Therapy of Heart Failure in Genetic Cardiomyopathy

^aMarriott Heart Disease Research Program, Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Medical Genetics, and
^bDepartment of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, Minnesota, USA;
^cDepartment of Autonomic Physiology, Graduate School of Medicine, Chiba University, Chiba, Japan;
^dDivision of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

Key Words. ABCC9 • ATP-sensitive K⁺ channels • Dilated cardiomyopathy • Genetics • KCNJ11 • Kir6.2

Correspondence: Correspondence: Andre Terzic, M.D., Ph.D., Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA. Telephone: 507-284-2747; Fax: 507-266-9936; e-mail: terzic.andre{at}mayo.edu

Received on February 29, 2008; accepted for publication on July 16, 2008.

First published online in STEM CELLS EXPRESS  July 31, 2008.

Pathogenic causes underlying nonischemic cardiomyopathies are increasingly being resolved, yet repair therapies for these commonly heritable forms of heart failure are lacking. A case in point is human dilated cardiomyopathy 10 (CMD10; Online Mendelian Inheritance in Man #608569), a progressive organ dysfunction syndrome refractory to conventional therapies and linked to mutations in cardiac ATP-sensitive K⁺ (K_ATP) channel subunits. Embryonic stem cell therapy demonstrates benefit in ischemic heart disease, but the reparative capacity of this allogeneic regenerative cell source has not been tested in inherited cardiomyopathy. Here, in a Kir6.2-knockout model lacking functional K_ATP channels, we recapitulated under the imposed stress of pressure overload the gene-environment substrate of CMD10. Salient features of the human malignant heart failure phenotype were reproduced, including compromised contractility, ventricular dilatation, and poor survival. Embryonic stem cells were delivered through the epicardial route into the left ventricular wall of cardiomyopathic stressed Kir6.2-null mutants. At 1 month of therapy, transplantation of 200,000 cells per heart achieved teratoma-free reversal of systolic dysfunction and electrical synchronization and halted maladaptive remodeling, thereby preventing end-stage organ failure. Tracked using the lacZ reporter transgene, stem cells engrafted into host heart. Beyond formation of cardiac tissue positive for Kir6.2, transplantation induced cell cycle activation and halved fibrotic zones, normalizing sarcomeric and gap junction organization within remuscularized hearts. Improved systemic function induced by stem cell therapy translated into increased stamina, absence of anasarca, and benefit to overall survivorship. Embryonic stem cells thus achieve functional repair in nonischemic genetic cardiomyopathy, expanding indications to the therapy of heritable heart failure.

Disclosure of potential conflicts of interest is found at the end of this article.

This article has been cited by other articles:

				K. D. Boudoulas and A. K. Hatzopoulos Cardiac repair and regeneration: the Rubik's cube of cell therapy for heart disease Dis. Model. Mech., July 1, 2009; 2(7-8): 344 - 358. [Abstract] [Full Text] [PDF]