Sulfs are regulators of growth factor signaling for satellite cell differentiation and muscle regeneration

Abstract

Heparan sulfate proteoglycans (HSPGs) are required during muscle regeneration for regulating extracellular signaling pathways. HSPGs interact with growth factors and receptors through heparan sulfate (HS) chains. However, the regulatory mechanisms that control HS sulfation to affect the growth factor-dependent proliferation and differentiation of satellite cells are yet unknown. Here we report the essential functions of extracellular HS 6-O-endosulfatases (Sulfs) during muscle regeneration. We show that quiescent and activated satellite cells differentially express mouse Sulf1 (MSulf1) and MSulf2. MSulfs are not required for the formation of skeletal muscles and satellite cells, but they have redundant, essential roles to promote muscle regeneration, as MSulf double mutant mice exhibit delayed myogenic differentiation and prolonged Pax7 expression after cardiotoxin-induced skeletal muscle injury, while single MSulf knockouts regenerate normally. HS structural analysis demonstrates that Sulfs are regulatory HS-modifying enzymes that control HS 6-O-desulfation of activated satellite cells. Mechanistically, we show that MSulfs repress FGF2 signaling in activated satellite cells, leading us to propose that MSulfs are growth factor signaling sensors to control the proliferation to differentiation switch of satellite cells to initiate differentiation during regeneration. Our results establish Sulfs as essential regulators of HS-dependent growth factor signaling in the adult muscle stem cell niche.

Organ-specific Sulfation Patterns of Heparan Sulfate Generated by Extracellular Sulfatases Sulf1 and Sulf2 in Mice

“…In contrast, double knock-out mice showed neonatal lethality associated with subtle skeletal abnormalities and kidney hypoplasia (20,28,29). Defects in esophageal innervation, muscle regeneration, and spermatogenesis were also reported in Sulf1/2 double knock-out mice (20,30,31). Recently, by using Sulf1/2 double knock-out mice that survived to adulthood (probably due to differences in genetic background), it was reported that aged double knockout mice developed proteinuria and showed abnormal renal morphology (32).…”

Roles of Heparan Sulfate Sulfation in Dentinogenesis

“…Both Sulf1 and Sulf2 are endosulfatases that act extracellularly and generate structural heterogeneity along HS chains by modifying the sulfation pattern of HS postsynthetically. Sulf1/ Sulf2 double null mutant mice show numerous distinct phenotypes (31)(32)(33)(34)(35)(36)(37). In skeletal structures, malformations, including reduced bone length, premature vertebrae ossification, and fusion of sternebrae and tail vertebrae, are observed (35).…”

The association of arylendosulfatase 1 (SULF1) gene polymorphism with recurrent miscarriage

“…As mentioned, previous studies have investigated the effects of reduction of SULF1 and SULF2 in abnormal embryonic development [15][16][17]. Therefore, we hypotheses that SULFs polymorphism may have an effect on recurrent pregnancy losses in RM patients.…”

“…It was shown that genetically deficient mice for these sulfatases, show some abnormal phenotypes such as brain malformations, skeletal malformations, abnormal innervations of smooth muscle and embryonic lethality [15][16][17]. In one study mice were generated carrying loss of function alleles for the secreted Sulf1 and Sulf2.…”