Sphingosine 1-Phosphate (S1P)/ S1P Receptor Signaling and Mechanotransduction: Implications for Intrinsic Tissue Repair/Regeneration

Abstract

Tissue damage, irrespective from the underlying etiology, destroys tissue structure and, eventually, function. In attempt to achieve a morpho-functional recover of the damaged tissue, reparative/regenerative processes start in those tissues endowed with regenerative potential, mainly mediated by activated resident stem cells. These cells reside in a specialized niche that includes different components, cells and surrounding extracellular matrix (ECM), which, reciprocally interacting with stem cells, direct their cell behavior. Evidence suggests that ECM stiffness represents an instructive signal for the activation of stem cells sensing it by various mechanosensors, able to transduce mechanical cues into gene/protein expression responses. The actin cytoskeleton network dynamic acts as key mechanotransducer of ECM signal. The identification of signaling pathways influencing stem cell mechanobiology may offer therapeutic perspectives in the regenerative medicine field. Sphingosine 1-phosphate (S1P)/S1P receptor (S1PR) signaling, acting as modulator of ECM, ECM-cytoskeleton linking proteins and cytoskeleton dynamics appears a promising candidate. This review focuses on the current knowledge on the contribution of S1P/S1PR signaling in the control of mechanotransduction in stem/progenitor cells. The potential contribution of S1P/S1PR signaling in the mechanobiology of skeletal muscle stem cells will be argued based on the intriguing findings on S1P/S1PR action in this mechanically dynamic tissue.

Interactions between Muscle and Bone—Where Physics Meets Biology

“…Prominent examples involved in tissue regeneration and mechanosensing/mechanotransduction in bone and muscle are prostaglandins, NO, sphingosines, and ATP, and its dephosphorylation-related products that fuel into purinergic signaling. Physical forces through muscular activity or vibration induce the cellular secretion of ATP and sphingosines, which are tightly involved in osteoblast, osteoclast, and osteocyte activity [2,[63][64][65].…”

“…Finally, besides SLIT3, also other axon-guided molecules such as semaphorin-4D (SEMA4D), SEMA3A, and netrin-1 were described to couple osteoblast and osteoclast activity in the remodeling process (coupling reviewed in [119]). While the role of such coupling systems in bone remodeling becomes more and more evident, systems such as sphingosine 1-phosphate and its receptor appear to be involved in mechanotransduction not only in development but also in adult life [65,120]. Bone remodeling involves the removal of gratuitous or old and damaged bone by osteoclasts ahead of tissue restoration according to (new) physical strain conditions [118].…”

Role of Ceramidases in Sphingolipid Metabolism and Human Diseases

“…In physical conditions, they play contrasting roles within cellular metabolism. Ceramide has been shown to be involved in stress-related cellular responses and apoptosis, whereas S1P stimulates cell survival, proliferation, and tissue regeneration [1][2][3][4]. Hence, maintaining the balance between ceramide and S1P is crucial for cells, as these bioactive lipids substantially contribute to cell fate decisions [5,6].…”

S1P/S1P Receptor Signaling in Neuromuscolar Disorders

“…The down-regulation of S1PR1 and S1PR3 also occurs after denervation confirming the trophic action of S1P/S1PR [126]. In an ex-vivo murine model of muscle damage induced by eccentric contraction, the bioactive lipid is able to reduce the deposition of collagen and promote the expression of metalloprotease-9, indicating the ability of S1P to affect the stiffness of the extracellular matrix and then satellite cell behavior [12,127]. In addition, Bondì et al [128] observed that S1P/S1PR3 axis plays a negative role in muscle mass maintenance and force in soleus during aging and extracellular S1P exerts a protective effect during muscle fatigue development [129].…”

“…In addition, Bondì et al [128] observed that S1P/S1PR3 axis plays a negative role in muscle mass maintenance and force in soleus during aging and extracellular S1P exerts a protective effect during muscle fatigue development [129]. S1P/S1PR3 signaling also modulates excitation-contraction coupling and intracellular calcium mobilization [121][122][123][124][125][126][127][128][129][130].…”