EphA7+ perivascular cells as myogenic and angiogenic precursors improving skeletal muscle regeneration in a muscular dystrophic mouse model

Kohei Kano; Kiwamu Horiuchi; Yuri Yoshida; Taiki Hayasaka; Maki Kabara; Yui Tomita; Takamitsu Tatsukawa; Risa Matsuo; Jun Sawada; Naoki Nakagawa; Naofumi Takehara; Naoyuki Hasebe; Jun-Ichi Kawabe

doi:10.1016/j.scr.2020.101914

EphA7⁺ perivascular cells as myogenic and angiogenic precursors improving skeletal muscle regeneration in a muscular dystrophic mouse model

Stem Cell Res. 2020 Jul 21:47:101914. doi: 10.1016/j.scr.2020.101914. Online ahead of print.

Authors

Affiliations

¹ Department of Cardiovascular Regeneration and Innovation, Asahikawa Medical University, Asahikawa, 2-1-1 Midorigaoka-higashi, Asahikawa 078-8510, Japan; Department of Medicine, Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University, Asahikawa, 2-1-1 Midorigaoka-higashi, Asahikawa 078-8510, Japan.
² Department of Biochemistry, Asahikawa Medical University, Asahikawa, 2-1-1 Midorigaoka-higashi, Asahikawa 078-8510, Japan; Department of Vascular Surgery, Asahikawa Medical University, Asahikawa, 2-1-1 Midorigaoka-higashi, Asahikawa 078-8510, Japan.
³ Department of Cardiovascular Regeneration and Innovation, Asahikawa Medical University, Asahikawa, 2-1-1 Midorigaoka-higashi, Asahikawa 078-8510, Japan.
⁴ Department of Biochemistry, Asahikawa Medical University, Asahikawa, 2-1-1 Midorigaoka-higashi, Asahikawa 078-8510, Japan; Department of Radiology, Asahikawa Medical University, Asahikawa, 2-1-1 Midorigaoka-higashi, Asahikawa 078-8510, Japan.
⁵ Department of Biochemistry, Asahikawa Medical University, Asahikawa, 2-1-1 Midorigaoka-higashi, Asahikawa 078-8510, Japan; Department of Dermatology, Asahikawa Medical University, Asahikawa, 2-1-1 Midorigaoka-higashi, Asahikawa 078-8510, Japan.
⁶ Department of Medicine, Division of Cardiovascular, Respiratory and Neurology, Asahikawa Medical University, Asahikawa, 2-1-1 Midorigaoka-higashi, Asahikawa 078-8510, Japan.
⁷ Department of Cardiovascular Regeneration and Innovation, Asahikawa Medical University, Asahikawa, 2-1-1 Midorigaoka-higashi, Asahikawa 078-8510, Japan; Department of Biochemistry, Asahikawa Medical University, Asahikawa, 2-1-1 Midorigaoka-higashi, Asahikawa 078-8510, Japan. Electronic address: kawabeju@asahikawa-med.ac.jp.

PMID: 32738632
DOI: 10.1016/j.scr.2020.101914

Abstract

Skeletal muscle has a capacity for muscular regeneration mediated by satellite cells (SCs) and non-SCs. Although it is proposed that non-SCs are attractive therapeutic targets for dystrophies, the biological properties of these cells remain unclear. We have recently identified novel multipotent pericytes (PCs), capillary stem cells (CapSCs) derived from the microvasculature. In the present study, we determined if CapSCs contributed to myogenic regeneration using muscular dystrophy mouse model. CapSCs were isolated as EphA7⁺NG2⁺PCs from the subcutaneous adipose tissues of GFP-transgenic mice. Co-culture with C2C12 myoblast cells showed that CapSCs effectively enhanced myogenesis as compared to controls including EphA7^- PCs and adipose stromal cells (ASCs). CapSCs transplanted in cardiotoxin-injured gastrocnemius muscles were well differentiated into both muscle fibers and microvessels, as compared to controls. At three weeks after cell-transplantation into the limbs of the mdx/utrn^-/-mouse, CapSCs increased the number of GFP⁺myofibers along with dystrophin expression and the area size of myofibers, and also enhanced the muscular mass and its performance, assessed by treadmill test as compared to controls. In conclusion, CapSCs have potent myogenic regeneration capacity and improved the pathological condition in a muscular dystrophy mouse. Thus, CapSCs are an attractive cellular source in regenerative therapy for muscular dystrophy.

Keywords: Capillary; Muscular dystrophy; Myogenesis; Pericytes; Skeletal muscle; Stem cells.