Transmembrane proteoglycans syndecan-2, 4, receptor candidates for the impact of HGF and FGF2 on semaphorin 3A expression in early-differentiated myoblasts

Abstract

Regenerative mechanisms that regulate intramuscular motor innervation are thought to reside in the spatiotemporal expression of axon-guidance molecules. Our previous studies proposed an unexplored role of resident myogenic stem cell (satellite cell)-derived myoblasts as a key presenter of a secreted neural chemorepellent semaphorin 3A (Sema3A); hepatocyte growth factor (HGF) and basic fibroblast growth factor (FGF2) triggered its expression exclusively at the early differentiation phase. In order to advance this concept, the present study described that transmembrane heparan/chondroitin sulfate proteoglycans syndecan-2, 4 may be the plausible receptor candidates for HGF and FGF2 to signal Sema3A expression. Results showed that mRNA expression of syndecan-2, 4 was abundant (two magnitudes higher than syndecan-1, 3) in early-differentiated myoblasts and their in vitro knockdown diminished the HGF/FGF2-induced expression of Sema3A down to a baseline level. Pretreatment with heparitinase and chondroitinase ABC decreased the HGF and FGF2 responses, respectively, in non–knockdown cultures, supporting a possible model that HGF and FGF2 may bind to heparan and chondroitin sulfate chains of syndecan-2, 4 to signal Sema3A expression. The findings, therefore, extend our understanding that HGF/FGF2-syndecan-2, 4 association may stimulate a burst of Sema3A secretion by myoblasts recruited to the site of muscle injury; this would ensure a coordinated delay in the attachment of motoneuron terminals onto fibers early in muscle regeneration, and thus synchronize the recovery of muscle fiber integrity and the early resolution of inflammation after injury with reinnervation toward functional recovery.

Slow-Myofiber Commitment by Semaphorin 3A Secreted from Myogenic Stem Cells

“…Notably, our previous studies demonstrated that Sema3A secretion may occur in response to a burst of HGF secretion from anti‐inflammatory macrophages (CD206‐positive M2) that infiltrate regenerating muscle and recruit myoblasts to the injury site at 3–7 days post‐CTX injury. The M2 infiltration follows the rapid invasion of phagocytic pro‐inflammatory macrophages (CD86‐positive M1) immediately post‐injury . Together with these reports, the current investigation extends our understanding of the physiological significance of M2 macrophage‐satellite cell (myoblast) coupling in myogenic regeneration to include fiber‐type commitment in early‐differentiation, illustrated in the dashed‐line box in Figure , far left.…”

The role of semaphorin3A in myogenic regeneration and the formation of functional neuromuscular junctions on new fibres

“…HGF and FGF may also induce Sema3A expression through the syndecan proteoglycan pathway, as suggested in preliminary studies of differentiating SC‐derived cultures (Do et al , , ). Pretreatment of differentiating SCs with either heparitinase or chondroitinase reduces the expression of Sema3A mRNA that is induced by HGF or FGF2, respectively.…”

“…HGF is expressed and secreted from anti‐inflammatory M2 cells (Sakaguchi et al , ). HGF stimulates Sema3A expression by myoblasts recruited to the site of injury (Sakaguchi et al , ; Do et al , ). Finally, Sema3A is a soluble (i.e.…”

“…This indicates that there is very likely an alternative receptor (i.e. not cmet) engaged in Sema3A signalling (Tatsumi et al , ; Do et al , ).…”

Emerging roles of syndecan 2 in epithelial and mesenchymal cancer progression

“…It is well established that GFs are capable of controlling cell behaviour in a manner‐dependent on their bioavailability, specific receptors status as well as downstream signalling . SDC2 has been identified as a co‐receptor for heparan‐binding GFs like fibroblast GF (FGF), epidermal GF (EGF), granulocyte macrophage colony‐stimulating factor (GM‐CSF), Wnt proteins and vascular endothelial GF (VEGF) as well as hepatocyte GF (HGF) . Consequently, we can characterize SDC2 as an important mediator of tyrosine kinase receptor activities .…”