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(Circulation. 2005;112:2857-2866.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Functional Recovery of Damaged Skeletal Muscle Through Synchronized Vasculogenesis, Myogenesis, and Neurogenesis by Muscle-Derived Stem Cells

Tetsuro Tamaki, PhD; Yoshiyasu Uchiyama, MD, PhD; Yoshinori Okada, BS; Tetsuya Ishikawa, PhD; Masahiro Sato, PhD; Akira Akatsuka, BS; Takayuki Asahara, MD, PhD

From the Department of Regenerative Medicine, Division of Basic Clinical Science (T.T., T.I., T.A.), the Department of Orthopedics (Y.U.), and the Teaching and Research Support Center (Y.O., A.A.), Tokai University School of Medicine, and the Institute of Medical Sciences, Tokai University (M.S.), Kanagawa; and the Institute of Biomedical Research and Innovation, Division of Stem Cell Translational Research (T.A.), and the RIKEN Center of Developmental Biology, Stem Cell Translational Research Team, Kobe (T.A.), Japan.

Correspondence to Tetsuro Tamaki, PhD, Muscle Physiology and Cell Biology Unit, Department of Regenerative Medicine, Division of Basic Clinical Science, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan. E-mail tamaki{at}is.icc.u-tokai.ac.jp

Received April 9, 2005; revision received August 4, 2005; accepted August 8, 2005.

Background— Recent studies have shown that skeletal muscle–derived stem cells (MDSCs) can give rise to several cell lineages after transplantation. However, the potential therapeutic uses of MDSCs, the functional significance of the transplanted tissue, and vasculogenesis, myogenesis, and reconstitution of other tissues have yet to be investigated in detail. In addition, the relationship between MDSCs and mesenchymal bone marrow cells is of interest.

Methods and Results— We developed a severe-damage model of mouse tibialis anterior muscle with a large deficit of nerve fibers, muscle fibers, and blood vessels. We investigated the potential therapeutic use of freshly isolated CD34⁺/45^– (Sk-34) cells. Results showed that, after transplantation, implanted cells give rise to myogenic, vascular (pericytes, vascular smooth muscle cells, and endothelial cells), and neural (Schwann) cells, as well as contributing to the synchronized reconstitution of blood vessels, muscle fibers, and peripheral nerves, with significant recovery of both mass and contractile function after transplantation. Investigation of Sk-34 cell transplantation to the renal capsule (nonmuscle tissue) and fluorescence in situ hybridization analysis for the transplanted muscle detecting the Y chromosome revealed the intrinsic plasticity of the Sk-34 cell population. In addition, there were no donor-derived Sk-34 cells in the muscle of lethally irradiated bone marrow–transplanted animals, indicating that the Sk-34 cells were not derived from bone marrow.

Conclusions— These findings indicate that freshly isolated skeletal muscle–derived Sk-34 cells are potentially useful for reconstitution therapy of the vascular, muscular, and peripheral nervous systems. These results provide new insights into somatic stem and/or progenitor cells with regard to vasculogenesis, myogenesis, and neurogenesis.

Key Words: angiogenesis • stem cells • endothelium • transplantation • vasculature

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