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

Abstract

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 muscle2,3, hepatocytes4, epithelial cells5, neurons6,7, endothelial cells8 and cardiomyocytes8,9, in response to tissue injury or placement in a new environment. Furthermore, transplanted human hearts contain myocytes derived from extra-cardiac progenitor cells10,11,12, which may have originated from bone marrow8,13,14,15. 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 trials16,17. 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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Figure 1: Failure of HSCs from MHC–nLAC mice to activate cardiac reporter genes or express endogenous myosin heavy chain.
Figure 2: Absence of cardiac differentiation of HSCs after direct injection into infarcts, contrasted with rare transdifferentiation after bone marrow transplantation. β-Act–EGFP mice were cell donors.

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Acknowledgements

C.E.M. and L.J.F. thank L. Reinlib for his longstanding support of this collaboration. We thank C. Storey for assistance in sorting HSCs and in bone marrow transplantation, and L. Fernando Santana for assistance with enzymatic dissociation of mouse hearts. These studies were supported in part by NIH grants to C.E.M. and L.J.F., and by the HHMI (G.B., D.A.W.).

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Correspondence to Charles E. Murry.

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The laboratory of C.E.M. receives partial research funding from Geron. L.J.F. is a consultant for Cardion.

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Includes supplementary table showing methodological comparison of Orlic et al. vs. Murry et al. and supplementary methods. (DOC 50 kb)

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Murry, C., Soonpaa, M., Reinecke, H. et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 428, 664–668 (2004). https://doi.org/10.1038/nature02446

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