CXCL12 and osteopontin from bone marrow-derived mesenchymal stromal cells improve muscle regeneration

Abstract

Muscle satellite cells are essential for muscle regeneration. However, efficient regeneration does not occur without muscle-resident mesenchymal progenitor cells. We show here that bone marrow-derived mesenchymal stromal cells (Bm-MSCs) also facilitate muscle regeneration in Duchenne muscular dystrophy (DMD) model mice. Bm-MSCs transplanted into peritoneal cavities of DMD model mice with severe muscle degeneration strongly suppressed dystrophic pathology and improved death-related symptoms, which resulted in dramatic lifespan extension. Isolated single myofibers from Bm-MSC-transplanted mice manifested considerably less myofiber splitting compared with myofibers from non-transplanted mice, which indicated that transplantation significantly ameliorated abnormal regeneration. With regard to the number of satellite cells, several cells remained on myofibers from Bm-MSC-transplanted model mice, but satellite cells rarely occurred on myofibers from non-transplanted mice. Also, CXCL12 was crucial for muscle regeneration. CXCL12 facilitated muscle regeneration and paired box protein–7 (PAX7) expression after cardiotoxin-related muscle injury in vivo. The majority of primary muscle satellite cells sorted by integrin-α7 and CD34 expressed CXCR4, a receptor specific for CXCL12. CXCL12 strongly suppressed p-STAT3 expression in these sorted cells in vitro. CXCL12 may therefore influence muscle regeneration through STAT3 signaling in satellite cells. Targeting these proteins in or on muscle satellite cells may improve many degenerative muscle diseases.

Muscle Stem/Progenitor Cells and Mesenchymal Stem Cells of Bone Marrow Origin for Skeletal Muscle Regeneration in Muscular Dystrophies

“…Our hypothesis on the regenerative potential of MSCs of BM origin in muscular dystrophies is also supported by very recent studies by Maeda et al ( 2017 ). The authors documented that transplantation of MSCs of BM origin into peritoneal cavities of a mdx mouse model strongly suppressed dystrophic pathology in diaphragms of mdx deficient mice, which resulted in significant lifespan extension.…”

“…Biological properties of MSCs provide an even wider tool with regenerative potential, as previously documented by their well-predicted therapeutic application in tissue regeneration of post-infarct heart (Jung et al 2017 ; van den Akker et al 2013 ). The immunomodulatory potential of MSCs is not only desired in the well-known therapy of graft-versus-host disease, and serious complications in patients after hematopoietic stem cell transplantation (Copland et al 2015 ; Le Blanc et al 2004 ; Lin and Hogan 2011 ), but also proved to be beneficial in therapy for skeletal, muscular (Maeda et al 2017 ) and neural regeneration (Mokarram et al 2012 ).…”

Perfect chronic skeletal muscle regeneration in adult spiny mice, Acomys cahirinus

“…Since we saw decreased levels of inflammation in the A . cahirinus TA during regeneration we looked at levels of Cxcl12 , a chemokine that has been shown to have a novel anti-inflammatory role 33 , as well as a role in positively regulating muscle regeneration 34 , 35 . The change in expression of Cxcl12 was greater in A .…”

“…musculus because of the lack of induction of inflammation and fibrosis pathways and in support of this we found that A . cahirinus expressed higher levels of Cxcl12 , a cytokine with a known anti-inflammatory role 33 and a role in positively regulating muscle regeneration 34 , 35 . Identifying cytokines such as this may well provide the molecular explanation for the improved muscle regenerative capacities of A .…”

Making Skeletal Muscle from Human Pluripotent Stem Cells

“…Mesenshymal stem/progenitor cells (MSC/MPC) are also expected to be a tool for regenerative medicine. They themselves do not differentiate into myofibers, but support muscle regeneration by paracrine effects [11]. The history of direct reprogramming in the muscle field is long, starting with the discovery of MyoD by Weintraub and his colleagues [12,13].…”