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.
Highlights
A number of novel approaches for regenerative therapies based on mesenchymal stem cells (MSCs) are currently under development.[1]
We addressed and verified the possibility that S1P signals across the plasma membrane of CMSCs to mitogen-activated protein kinase (MAPKs) and other kinases central to the regulation of cell proliferation, differentiation and motility
In CMSCs we observed a parallel transient increase of extracellular-signal-regulated kinase 1/2 (ERK1/2) and p38 phosphorylation operated by S1P via a Gi-dependent signaling branch that diverges from the pertussis toxin (PTX) insensitive branch oriented on protein kinase D 1 (PKD1)
Summary
A number of novel approaches for regenerative therapies based on mesenchymal stem cells (MSCs) are currently under development.[1] Among tissues of fetal origin, placenta appears to be an untapped supply of multipotent cells.[2,3,4] Collecting placenta MSCs presents minimal ethical and legal concerns and warrants high yields of precursor cells endowed of expanded plasticity, low immunogenicity and immunomodulatory properties.[3,5] To preserve intact these valuable properties, ideally MSC expansion and differentiation should be controlled in vitro by mimicking physiological stimuli as close as possible.
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