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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 2008-0033v1 26/6/1537    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 Google Scholar Articles by Schenke-Layland, K. Articles by MacLellan, W. R. PubMed PubMed Citation Articles by Schenke-Layland, K. Articles by MacLellan, W. R.

EMBRYONIC STEM CELLS

Reprogrammed Mouse Fibroblasts Differentiate into Cells of the Cardiovascular and Hematopoietic Lineages

^aDepartment of Medicine and Physiology, Cardiovascular Research Laboratory,
^cDepartment of Surgery, Regenerative Bioengineering and Repair Laboratory,
^dDepartment of Biological Chemistry, and
^eMolecular Biology Institute, Johnson Comprehensive Cancer Center and Institute for Stem Cell Biology and Medicine, David Geffen School of Medicine, and
^bDepartment of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, California, USA

Key Words. Induced pluripotent stem cells • Embryonic stem cells • Reprogramming • Extracellular matrix • Collagen IV • Cardiovascular • Hematopoietic

Correspondence: W. Robb MacLellan, M.D., Cardiovascular Research Laboratory, University of California Los Angeles School of Medicine, 675 C.E. Young Drive, MRL 3-645, Los Angeles, California 90095-1760, USA. Telephone: 310-825-2556; Fax: 310-206-5777; e-mail: rmaclellan{at}mednet.ucla.edu

Received January 14, 2008; accepted for publication April 9, 2008.
First published online in STEM CELLS EXPRESS   May 1, 2008.

Forced expression of the four transcription factors Oct4, Sox2, c-Myc, and Klf4 is sufficient to confer a pluripotent state upon the murine fibroblast genome, generating induced pluripotent stem (iPS) cells. Although the differentiation potential of these cells is thought to be equivalent to that of embryonic stem (ES) cells, it has not been rigorously determined. In this study, we sought to identify the capacity of iPS cells to differentiate into Flk1-positive progenitors and their mesodermal progeny, including cells of the cardiovascular and hematopoietic lineages. Immunostaining of tissues from iPS cell-derived chimeric mice demonstrated that iPS cells could contribute in vivo to cardiomyocytes, smooth muscle cells, endothelial cells, and hematopoietic cells. To compare the in vitro differentiation potential of murine ES and iPS cells, we either induced embryoid body (EB) formation of each cell type or cultured the cells on collagen type IV (ColIV), an extracellular matrix protein that had been reported to direct murine ES cell differentiation to mesodermal lineages. EB formation and exposure to ColIV both induced iPS cell differentiation into cells that expressed cardiovascular and hematopoietic markers. To determine whether ColIV-differentiated iPS cells contained a progenitor cell with cardiovascular and hematopoietic differentiation potential, Flk1-positive cells were isolated by magnetic cell sorting and exposed to specific differentiation conditions, which induced differentiation into functional cardiomyocytes, smooth muscle cells, endothelial cells, and hematopoietic cells. Our data demonstrate that murine iPS cells, like ES cells, can differentiate into cells of the cardiovascular and hematopoietic lineages and therefore may represent a valuable cell source for applications in regenerative medicine.

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