Transplantation of human iPSC-derived muscle stem cells in the diaphragm of Duchenne muscular dystrophy model mice

PLoS One. 2022 Apr 4;17(4):e0266391. doi: 10.1371/journal.pone.0266391. eCollection 2022.

Abstract

Duchenne muscular dystrophy (DMD) is an intractable genetic muscular disorder characterized by the loss of DYSTROPHIN. The restoration of DYSTROPHIN is expected to be a curative therapy for DMD. Because muscle stem cells (MuSCs) can regenerate damaged myofibers with full-length DYSTROPHIN in vivo, their transplantation is being explored as such a therapy. As for the transplanted cells, primary satellite cells have been considered, but donor shortage limits their clinical application. We previously developed a protocol that differentiates induced pluripotent stem cells (iPSCs) to MuSCs (iMuSCs). To ameliorate the respiratory function of DMD patients, cell transplantation to the diaphragm is necessary but difficult, because the diaphragm is thin and rapidly moves. In the present study, we explored the transplantation of iMuSCs into the diaphragm. First, we show direct cell injection into the diaphragm of mouse was feasible. Then, to enhance the engraftment of the transplanted cells in a rapidly moving diaphragm, we mixed polymer solutions of hyaluronic acid, alginate and gelatin to the cell suspension, finding a solution of 20% dissolved hyaluronic acid and 80% dissolved gelatin improved the engraftment. Thus, we established a method for cell transplantation into mouse diaphragm and show that an injectable hyaluronic acid-gelatin solution enables the engraftment of iMuSCs in the diaphragm.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diaphragm
  • Dystrophin / genetics
  • Gelatin
  • Humans
  • Hyaluronic Acid
  • Induced Pluripotent Stem Cells*
  • Mice
  • Mice, Inbred mdx
  • Muscle, Skeletal
  • Muscular Dystrophy, Duchenne*

Substances

  • Dystrophin
  • Gelatin
  • Hyaluronic Acid

Grants and funding

This work was supported by a grant from the Core Center for iPS Cell Research (JP21bm0104001), Research Center Network for Realization of Regenerative Medicine from the Japan Agency for Medical Research and Development (AMED) to H.S. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.