Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts : Abstract : Nature

Nature 428, 664-668 (8 April 2004) | doi:10.1038/nature02446; Received 20 October 2003; Accepted 1 March 2004; Published online 21 March 2004

Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts

Charles E. Murry¹, Mark H. Soonpaa², Hans Reinecke¹, Hidehiro Nakajima², Hisako O. Nakajima², Michael Rubart², Kishore B. S. Pasumarthi^2,⁴, Jitka Ismail Virag¹, Stephen H. Bartelmez³, Veronica Poppa¹, Gillian Bradford², Joshua D. Dowell², David A. Williams^2,⁴ and Loren J. Field²

Department of Pathology, Box 357470, Room D-514 HSB, University of Washington, Seattle, Washington 98195, USA
Wells Center for Pediatric Research, Indiana University, 1044 West Walnut Street, R4 Bldg, Room W376, Indianapolis 46202-5225, USA
Department of Pathobiology, University of Washington, Seattle, Washington 98195, USA
Present addresses: Department of Pharmacology Dalhousie University, Sir Charles Tupper Medical Bldg, Room 6-F1, 5850 College Street, Halifax B3H 1X5, Canada (K.B.S.P.); Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039, USA (D.A.W.)

Correspondence to: Charles E. Murry¹ Email: murry@u.washington.edu
Email: ljfield@iupui.edu

The mammalian heart has a very limited regenerative capacity and, hence, heals by scar formation¹. Recent reports suggest that haematopoietic stem cells can transdifferentiate into unexpected phenotypes such as skeletal muscle^2,³, hepatocytes⁴, epithelial cells⁵, neurons^6,⁷, endothelial cells⁸ and cardiomyocytes^8,⁹, in response to tissue injury or placement in a new environment. Furthermore, transplanted human hearts contain myocytes derived from extra-cardiac progenitor cells^10,^11,¹², which may have originated from bone marrow^8,^13,^14,¹⁵. Although most studies suggest that transdifferentiation is extremely rare under physiological conditions, extensive regeneration of myocardial infarcts was reported recently after direct stem cell injection⁹, prompting several clinical trials^16,¹⁷. Here, we used both cardiomyocyte-restricted and ubiquitously expressed reporter transgenes to track the fate of haematopoietic stem cells after 145 transplants into normal and injured adult mouse hearts. No transdifferentiation into cardiomyocytes was detectable when using these genetic techniques to follow cell fate, and stem-cell-engrafted hearts showed no overt increase in cardiomyocytes compared to sham-engrafted hearts. These results indicate that haematopoietic stem cells do not readily acquire a cardiac phenotype, and raise a cautionary note for clinical studies of infarct repair.

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