title: Endogenous mesenchymal stromal cells in bone marrow are required to preserve muscle function in mdx mice.
abstract: The physiological role of "endogenous" bone marrow (BM) mesenchymal stromal cells (MSCs) in tissue regeneration is poorly understood. Here, we show the significant contribution of unique endogenous BM-MSC populations to muscle regeneration in Duchenne muscular dystrophy (DMD) mice (mdx). Transplantation of BM cells (BMCs) from 10-week-old mdx into 3-4-week-old mdx mice increased inflammation and fibrosis and reduced muscle function compared with mdx mice that received BMCs from 10-week-old wild-type mice, suggesting that the alteration of BMC populations in mdx mice affects the progression of muscle pathology. Two distinct MSC populations in BM, that is, hematopoietic lineage (Lin)(-) /ckit(-) /CD106(+) /CD44(+) and Lin(-) /ckit(-) /CD106(+) /CD44(-) cells, were significantly reduced in 10-week-old mdx mice in disease progression. The results of a whole-transcriptome analysis indicated that these two MSC populations have distinct gene expression profiles, indicating that the Lin(-) /ckit(-) /CD106(+) /CD44(+) and Lin(-) /ckit(-) /CD106(+) /CD44(-) MSC populations are proliferative- and dormant-state populations in BM, respectively. BM-derived Lin(-) /CD106(+) /CD44(+) MSCs abundantly migrated to damaged muscles and highly expressed tumor necrosis factor-alpha-stimulated gene/protein-6 (TSG-6), an anti-inflammatory protein, in damaged muscles. We also demonstrated that TSG-6 stimulated myoblast proliferation. The injection of Lin(-) /ckit(-) /CD106(+) /CD44(+) MSCs into the muscle of mdx mice successfully ameliorated muscle dysfunction by decreasing inflammation and enhancing muscle regeneration through TSG-6-mediated activities. Thus, we propose a novel function of the unique endogenous BM-MSC population, which countered muscle pathology progression in a DMD model.
authors.affiliation: Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Fujita
authors.forename: Katsuto
authors.initials: K
authors.lastname: Tamai
authors.forename: Eriko
authors.initials: E
authors.lastname: Aikawa
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nimura
authors.forename: Saki
authors.initials: S
authors.lastname: Ishino
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kikuchi
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kaneda
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D009132:Muscles / Q000473:pathology*; D009135:Muscular Diseases / Q000378:metabolism / Q000473:pathology*
keywords: Bone marrow cells; Duchenne muscular dystrophy; Mesenchymal stromal cells; Muscle satellite cells; TNF-α-stimulated gene/protein-6; TSG-6