Development of therapeutic strategy for Duchenne muscular dystrophy-Based on cell fusion and myogenic transdifferentiation theory

2009 Fiscal Year Final Research Report

• Project/Area Number: 19790749
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Pediatrics
• Research Institution: National Research Institute for Child Health and Development
• Principal Investigator: SAI Syoko National Research Institute for Child Health and Development, 生殖・細胞医療研究部, 流動研究員 (80392497)
• Project Period (FY): 2007 – 2009
• Keywords: 筋ジストロフィー / 周産期幹細胞

Research Abstract

Duchenne muscular dystrophy (DMD), the most common lethal genetic disorder in children, is an X-linked recessive muscle disease characterized by the absence of dystrophin at the sarcolemma of muscle fibers. We examined a putative mesenchymal stromal cells obtained from endometrial or placenta tissue samples to determine whether these cells repair muscular degeneration in a murine mdx model of DMD. Implanted cells conferred human dystrophin in degenerated muscle of immunodeficient mdx mice. We then examined endometrial-derived cells, menstrual blood-derived cells, and placenta-derived cell to determine whether primarily cultured nontransformed cells also repair dystrophied muscle. In vivo transfer of these cells into dystrophic muscles of immunodeficient mdx mice restored sarcolemmal expression of dystrophin. Labeling of implanted cells with enhanced green fluorescent protein and differential staining of human and murine nuclei suggest that human dystrophin expression is due to cell fusion between host myocytes and implanted cells. In vitro analysis revealed that cells can efficiently transdifferentiate into myoblasts/myocytes, fuse to C2C12 murine myoblasts by in vitro coculturing, and start to express dystrophin after fusion. These results demonstrate that the endometrial-derived cells, menstrual blood-derived cells, and placenta-derived cell can transfer dystrophin into dystrophied myocytes through cell fusion and transdifferentiation in vitro and in vivo.

Research Products

• [Journal Article] Cells of extraembryonic mesodermal origin confer human dystrophin in the mdx model of Duchenne Muscular Dystrophy. (2010)
  • Author(s): Kawamichi Y, Cui CH*, Yoyoda M, Makino H, Takahashi Y, matsumoto K, Saito H, Ohta H, Saito K, Umezawa A.
  • Journal Title: J Cell Physiol. 223(3) Pages: 695-702
• [Journal Article] Novel Cardiac Precursor-Like Cells from Human Menstrual Blood-Derived Mesenchymal Cells. (2008)
  • Author(s): Hida N, Nishiyama N, Miyoshi S, Kira S, Segawa K, Uyama T, Mori T, Miyado K, Ikegami Y, Cui CH, Kiyono T, Kyo S, Shimizu T, Okano T, Sakamoto M, Ogawa S, Umezawa A.
  • Journal Title: Stem Cells. 26(7) Pages: 1695-1704
• [Journal Article] Myogenic transdifferentiation of menstrual blood-derived cells. (2007)
  • Author(s): Toyoda M, Cui CH, Umezawa A.
  • Journal Title: Acta Myol. 26(3) Pages: 176-8
• [Journal Article] Working' cardiomyocytes exhibiting plateau action potentials from human placenta-derived extraembryonic mesodermal cells. (2007)
  • Author(s): Okamoto K, Miyoshi S, Toyoda M, Hida N, Ikegami Y, Makino H, Nishiyama N, Tsuji H, Cui CH, Segawa K, Uyama T, Kami D, Miyado K, Asada H, Matsumoto K, Saito H, Yoshimura Y, Ogawa S, Aeba R, Yozu R, Umezawa A.
  • Journal Title: Exp Cell Res. 313(12) Pages: 2550-2562
• [Journal Article] Myogenesis by Endometrium derived Cells. (2007)
  • Author(s): Cui CH, Umezawa A.
  • Journal Title: Medical Technology. 35 Pages: 10-11
• [Journal Article] Menstrual blood-derived cells confer human dystrophin expression in the murine model of Duchenne muscular dystrophy via cell fusion and myogenic transdifferentiation. (2007)
  • Author(s): Cui CH, Uyama T, Miyado K, Terai M, Kyo S, Kiyono T, Umezawa A.
  • Journal Title: Mol Biol Cell. 18(5) Pages: 1586-1594