Combined Notch and PDGF Signaling Enhances Migration and Expression of Stem Cell Markers while Inducing Perivascular Cell Features in Muscle Satellite Cells

Abstract

Summary Satellite cells are responsible for skeletal muscle regeneration. Upon activation, they proliferate as transient amplifying myoblasts, most of which fuse into regenerating myofibers. Despite their remarkable differentiation potential, these cells have limited migration capacity, which curtails clinical use for widespread forms of muscular dystrophy. Conversely, skeletal muscle perivascular cells have less myogenic potential but better migration capacity than satellite cells. Here we show that modulation of Notch and PDGF pathways, involved in developmental specification of pericytes, induces perivascular cell features in adult mouse and human satellite cell-derived myoblasts. DLL4 and PDGF-BB-treated cells express markers of perivascular cells and associate with endothelial networks while also upregulating markers of satellite cell self-renewal. Moreover, treated cells acquire trans-endothelial migration ability while remaining capable of engrafting skeletal muscle upon intramuscular transplantation. These results extend our understanding of muscle stem cell fate plasticity and provide a druggable pathway with clinical relevance for muscle cell therapy.

Topography-Mediated Myotube and Endothelial Alignment, Differentiation, and Extracellular Matrix Organization for Skeletal Muscle Engineering

“…PDGFB was downregulated by the ECs, and in co-culture it was upregulated. Increase of expression of PDGFB in the co-culture means that the cell-cell interactions are leading to a pre-vascularization process where remaining satellite cells are being activated mimicking an injury process and endothelial cells express this marker to recruit pericytes [30]. We only detected that the gene expression was affected by the topography at Day 5 of culture of ECs, where the VEGFA expression was downregulated in the directional topography compared to TCP.…”

Pericytes in Muscular Dystrophies

“…In the quest for an ideal cell type for muscle cell therapy, our group also explored a different approach by taking advantage of the findings that embryonic and foetal myoblasts could be converted to the pericyte fate following activation of Notch and PDGF pathways via Dll4 and PDGF-BB . As mentioned earlier in this chapter, adult murine and human satellite cellderived myoblasts exposed to Dll4 and PDGF-BB also acquired perivascular cell features, including transendothelial migration ability, whilst maintain myogenic capacity (Gerli et al, 2019). We propose that this strategy could generate a hybrid pericyte-myoblast cell retaining the two peculiar characteristics of both cell types: the ability to generate muscle with high efficacy (myoblast) alongside transendothelial migration capacity (pericyte-derived cells).…”

“…with developing blood vessels in the muscles recruiting supporting perivascular cells from the surrounding mesoderm ( Figure 1) . Recent work in our laboratory has demonstrated that this mechanism is also conserved in adult murine and human satellite cell-derived myoblasts, and that it can be exploited to enhance migration of myoblasts when transplanted (Gerli et al, 2019). dystrophies (Partridge et al, 1989).…”

Pim1 kinase positively regulates myoblast behaviors and skeletal muscle regeneration

“…Skeletal muscle stem cells, also known as muscle satellite cells (SCs), reside between the plasma membrane and basal lamina in a quiescent state 2 . Once the skeletal muscle is damaged, the quiescent SCs are immediately activated to generate transient amplifying precursors called myoblasts 3 , which further differentiate and fuse either to form new multinucleated muscle fibers or to repair damaged parts of existing muscle fibers 1 . The regulation of these steps is closely associated with the sequential activation of a series of myogenic regulatory factors in SCs.…”