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

Charles E. Murry; Mark H. Soonpaa; Hans Reinecke; Hidehiro Nakajima; Hisako O. Nakajima; Michael Rubart; Kishore B.S. Pasumarthi; Jiika Ismail Virag; Stephen H. Bartelmez; Veronica Poppa; Gillian Bradford; Joshua D. Dowell; David A. Williams; Loren J. Field

doi:10.1038/nature02446

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

Charles E. Murry, Mark H. Soonpaa, Hans Reinecke, Hidehiro Nakajima, Hisako O. Nakajima, Michael Rubart, Kishore B.S. Pasumarthi, Jiika Ismail Virag, Stephen H. Bartelmez, Veronica Poppa, Gillian Bradford, Joshua D. Dowell, David A. Williams, Loren J. Field

Medicine

Research output: Contribution to journal › Article › peer-review

1953 Citations (Scopus)

Abstract

The mammalian heart has a very limited regenerative capacity and, hence, heals by scar formation. Recent reports suggest that haematopoietic stem cells can transdifferentiate into unexpected phenotypes such as skeletal muscle, hepatocytes, epithelial cells, neurons, endothelial cells and cardiomyocytes, in response to tissue injury or placement in a new environment. Furthermore, transplanted human hearts contain myocytes derived from extra-cardiac progenitor cells, which may have originated from bone marrow. Although most studies suggest that transdifferentiation is extremely rare under physiological conditions, extensive regeneration of myocardial infarcts was reported recently after direct stem cell injection, prompting several clinical trials. 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.

Original language	English
Pages (from-to)	664-668
Number of pages	5
Journal	Nature
Volume	428
Issue number	6983
DOIs	https://doi.org/10.1038/nature02446
Publication status	Published - Apr 8 2004

Bibliographical note

Funding Information:
Acknowledgements We thank A. Ullrich for the FGF receptor inhibitor (SU5402), T. Kato, M. Delhase and S. Roy for technical assistance and discussions, and M. Ellisman and M. Mackey for the election microscopy performed at the National Center for Microscopy and Imaging Research. Work was supported by grants from the National Institutes of Health, and Superfund Basic Research Program and CERIES research awards.

Funding Information:
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.).

ASJC Scopus Subject Areas

General

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

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Murry, C. E., Soonpaa, M. H., Reinecke, H., Nakajima, H., Nakajima, H. O., Rubart, M., Pasumarthi, K. B. S., Virag, J. I., Bartelmez, S. H., Poppa, V., Bradford, G., Dowell, J. D., Williams, D. A., & Field, L. J. (2004). Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature, 428(6983), 664-668. https://doi.org/10.1038/nature02446

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title = "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 formation. Recent reports suggest that haematopoietic stem cells can transdifferentiate into unexpected phenotypes such as skeletal muscle, hepatocytes, epithelial cells, neurons, endothelial cells and cardiomyocytes, in response to tissue injury or placement in a new environment. Furthermore, transplanted human hearts contain myocytes derived from extra-cardiac progenitor cells, which may have originated from bone marrow. Although most studies suggest that transdifferentiation is extremely rare under physiological conditions, extensive regeneration of myocardial infarcts was reported recently after direct stem cell injection, prompting several clinical trials. 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.",

author = "Murry, {Charles E.} and Soonpaa, {Mark H.} and Hans Reinecke and Hidehiro Nakajima and Nakajima, {Hisako O.} and Michael Rubart and Pasumarthi, {Kishore B.S.} and Virag, {Jiika Ismail} and Bartelmez, {Stephen H.} and Veronica Poppa and Gillian Bradford and Dowell, {Joshua D.} and Williams, {David A.} and Field, {Loren J.}",

note = "Funding Information: Acknowledgements We thank A. Ullrich for the FGF receptor inhibitor (SU5402), T. Kato, M. Delhase and S. Roy for technical assistance and discussions, and M. Ellisman and M. Mackey for the election microscopy performed at the National Center for Microscopy and Imaging Research. Work was supported by grants from the National Institutes of Health, and Superfund Basic Research Program and CERIES research awards. Funding Information: 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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T1 - Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts

AU - Murry, Charles E.

AU - Soonpaa, Mark H.

AU - Reinecke, Hans

AU - Nakajima, Hidehiro

AU - Nakajima, Hisako O.

AU - Rubart, Michael

AU - Pasumarthi, Kishore B.S.

AU - Virag, Jiika Ismail

AU - Bartelmez, Stephen H.

AU - Poppa, Veronica

AU - Bradford, Gillian

AU - Dowell, Joshua D.

AU - Williams, David A.

AU - Field, Loren J.

N1 - Funding Information: Acknowledgements We thank A. Ullrich for the FGF receptor inhibitor (SU5402), T. Kato, M. Delhase and S. Roy for technical assistance and discussions, and M. Ellisman and M. Mackey for the election microscopy performed at the National Center for Microscopy and Imaging Research. Work was supported by grants from the National Institutes of Health, and Superfund Basic Research Program and CERIES research awards. Funding Information: 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.).

PY - 2004/4/8

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N2 - The mammalian heart has a very limited regenerative capacity and, hence, heals by scar formation. Recent reports suggest that haematopoietic stem cells can transdifferentiate into unexpected phenotypes such as skeletal muscle, hepatocytes, epithelial cells, neurons, endothelial cells and cardiomyocytes, in response to tissue injury or placement in a new environment. Furthermore, transplanted human hearts contain myocytes derived from extra-cardiac progenitor cells, which may have originated from bone marrow. Although most studies suggest that transdifferentiation is extremely rare under physiological conditions, extensive regeneration of myocardial infarcts was reported recently after direct stem cell injection, prompting several clinical trials. 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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Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts

Abstract

Bibliographical note

ASJC Scopus Subject Areas

PubMed: MeSH publication types

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