Pleiotropic effects of sphingosine-1-phosphate signaling to control human chorionic mesenchymal stem cell physiology

Abstract

Chorionic stem cells represent a promising opportunity for regenerative medicine. A deeper understanding of the stimuli that regulate their physiology, could lead to innovative clinical approaches. We revealed the presence of multiple sphingosine-1-phosphate (S1P) receptor isoforms in chorion-derived mesenchymal stem cells (CMSCs). Their activation simultaneously propagated from the plasma membrane through Gi and other heterotrimeric G proteins and further diverged toward extracellular-signal-regulated kinase 1/2 (ERK1/2), p38 and protein kinase D 1. At a functional level, S1P signaling inhibited CMSC migration, while promoting proliferation. Instead, a reduction of cell density was obtained when S1P was combined to treatments that increased cAMP intracellular concentration. Such surprising reduction of cell viability was relatively specific as it was not observed with stromal stem cells from bone marrow. Neither it was observed by activating analogous G proteins with bradykinin nor by inducing cell death via a cAMP-independent pathway. S1P could thus reveal novel keys to improve CMSC differentiation programs acting on cAMP concentration. Furthermore, S1P receptor agonists/antagonists could become instrumental in favoring CMSC engraftment by controlling cell motility.

Sgpl1 deletion elevates S1P levels, contributing to NPR2 inactivity and p21 expression that block germ cell development

“…S1P plays a vital role in regulating cell proliferation, survival, movement, and calcium homeostasis. Extracellular S1P exerts its effects by binding to its specific G protein-coupled receptors (S1PRs) to regulate downstream signals 19 , 20 . S1P can also mobilize calcium release from the endoplasmic reticulum to mediate various cellular functions 21 , 22 .…”

cAMP Response Element-Binding Protein Controls the Appearance of Neuron-Like Traits in Chorion Mesenchymal Cells

“…Albeit our initial characterization of these cells using a set of mesenchymal markers described a homogeneous population of precursors [15], we found that the morphological effect only occurred in part of the cells. Noticeably, neuron-like cells were not distributed randomly but in clusters (Fig.…”

“…Our lab previously demonstrated that S1P ac- tivates ERK1/2 in C-MSCs in a dose-dependent manner. ERK1/2 activation was transient in time and it was completely inhibited by pertussis toxin, indicating that the pathway was fully Gi-dependent [15]. Combining 10 µM S1P with 50 µM forskolin was found to prevent the effect of forskolin (Fig.…”

“…C-MSCs were enzymatically isolated from human term placenta and characterized as previously described [15]. In the experiments shown, cells were passaged 6-10 times.…”

“…C-MSCs were isolated from human placentas at term and propagated in vitro. We characterized the mesenchymal properties of these preparations in terms of immunophenotype and potency in a previous paper [15].…”