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(Circulation Research. 2008;102:e107.)
© 2008 American Heart Association, Inc.

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Cell-Free Embryonic Stem Cell Extract–Mediated Derivation of Multipotent Stem Cells From NIH3T3 Fibroblasts for Functional and Anatomical Ischemic Tissue Repair

Johnson Rajasingh, Erin Lambers, Hiromichi Hamada, Evelyn Bord, Tina Thorne, Ilona Goukassian, Prasanna Krishnamurthy, Kenneth M. Rosen, Deepali Ahluwalia, Yan Zhu, Gangjian Qin, Douglas W. Losordo, Raj Kishore

From the Feinberg Cardiovascular Research Institute (J.R., E.L., H.H., E.B., T.T., I.G., P.K., D.A., G.Q., D.W.L., R.K.), Feinberg School of Medicine, Northwestern University, Chicago, Ill; and Division of Neurology Research (K.M.R.) and Cardiovascular Research (Y.Z.), Caritas St. Elizabeth’s Medical Center. Tufts University School of Medicine, Boston, Mass.

Correspondence to Raj Kishore, PhD, Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, 303 E Chicago Ave, Chicago IL 60611. E-mail r-kishore{at}northwestern.edu

The oocyte-independent source for the generation of pluripotent stem cells is among the ultimate goals in regenerative medicine. We report that on exposure to mouse embryonic stem cell (mESC) extracts, reversibly permeabilized NIH3T3 cells undergo dedifferentiation followed by stimulus-induced redifferentiation into multiple lineage cell types. Genome-wide expression profiling revealed significant differences between NIH3T3 control and ESC extract–treated NIH3T3 cells including the reactivation of ESC-specific transcripts. Epigenetically, ESC extracts induced CpG demethylation of Oct4 promoter, hyperacetylation of histones 3 and 4, and decreased lysine 9 (K-9) dimethylation of histone 3. In mouse models of surgically induced hindlimb ischemia or acute myocardial infarction transplantation of reprogrammed NIH3T3 cells significantly improved postinjury physiological functions and showed anatomic evidence of engraftment and transdifferentiation into skeletal muscle, endothelial cell, and cardiomyocytes. These data provide evidence for the generation of functional multipotent stem-like cells from terminally differentiated somatic cells without the introduction of retroviral mediated transgenes or ESC fusion.

Key Words: Somatic Cell Dedifferentiation • ES cells • Nuclear reprogramming • Epigenetics • Tissue Repair • Myocardial infarction

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