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First published online May 1, 2008
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Submitted on February 20, 2008
Accepted on April 21, 2008

EMBRYONIC STEM CELLS

Paraxial Mesodermal Progenitors Derived from Mouse Embryonic Stem Cells Contribute Muscle Regeneration via Differentiation into Muscle Satellite Cells

Hidetoshi Sakurai 1, Yayoi Okawa 2, Yuta Inami 1, Naomi Nishio 1, Ken Ichi Isobe 1*

1 Department of Immunology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan
2 Department of Functioning Activation, National Institute for Longevity Sciences, 35 Gengo, Morioka-cho, Obu-shi, Aichi, 474-8511, Japan

* To whom correspondence should be addressed. E-mail: kisobe{at}med.nagoya-u.ac.jp.


  Abstract

Pluripotent embryonic stem (ES) cells hold great potentials for cell-based therapies. Although several recent studies have reported the potential of ES cell-derived progenitors for skeletal muscle regeneration, how the cells contribute to reconstitute the damaged myofibers has remained elusive. Here, we demonstrated the process of injured muscle regeneration by the engraftment of ES cell-derived mesodermal progenitors. Mesodermal progenitor cells were induced by conventional differentiation system and isolated by cell sorter monitoring marker expression of platelet-derived growth factor receptor-{alpha} (PDGFR-{alpha}), a marker of paraxial mesoderm, and vascular endothelial growth factor receptor-2 (VEGFR-2), a marker of lateral mesoderm. The PDGFR-{alpha}+ population which represented the paraxial mesodermal character demonstrated significant engraftment when transplanted into injured muscle of immunodeficient mouse. Moreover, they could differentiate into the muscle satellite cells which were the stem cells of adult muscle and characterized by the expression of Pax7 and CD34. These ES cell-derived satellite cells could form the functional mature myofibers in vitro, and generate the myofibers fused with the damaged host myofibers in vivo. On the other hand, the PDGFR-{alpha}-VEGFR-2+ population which showed lateral mesodermal character exhibited restricted potential to differentiate into the satellite cells in injured muscle. Our results show the potential of ES cell-derived paraxial mesodermal progenitor cells to generate functional muscle stem cells in vivo without inducing or suppressing gene manipulation. This knowledge could be used to form the foundation of the development of stem cell therapies to repair diseased and damaged muscles.

______________________________________________________________________________

Author contributions: H.S.: Conception and design, provision of study material or patients, collection and/or assembly of data, data analysis and interpretation, manuscript writing; Y.O.: Conception and design; Y.I.: Provision of study material or patients, collection and/or assembly of data; N.N.: Provision of study material or patients, collection and/or assembly of data; K.I.: Conception and design, financial support, administrative support, final approval of manuscript.

 Key Words. ES cell, mesoderm, muscle satellite cell, muscle regeneration, PDGFR-{alpha}






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