The Adipose Mesenchymal Stem Cell Secretome Inhibits Inflammatory Responses of Microglia: Evidence for an Involvement of Sphingosine-1-Phosphate Signalling

Abstract

Central nervous system (CNS) inflammation is primarily driven by microglial cells which secrete proinflammatory cytokines and undergo proliferation upon activation, as it occurs in neurodegenerative diseases. Uncontrolled or prolonged CNS inflammation is potentially harmful and can result in cellular damage. Recently, many studies have focused on human adipose tissue as an attractive source of cytokines with immunosuppressive properties that potentially modulate inflammation. Our study aimed to evaluate if different methods of human tissue collection could affect adipose mesenchymal stem cell (ADSC)-derived cytokine secretion and investigate the effects of ADSC secretome in modulating microglia activation and the possible implication of sphingosine-1-phosphate (S1P) in these effects. Our results demonstrate that the conditioned medium (CM) of ADSCs isolated by two different processing methods (lipoaspirate and Lipogems) significantly inhibited the lipopolysaccharide (LPS)-induced effects on microglia activation, including microglial expression of CD68, cytokine secretion, proliferation, and migration. Pulse studies with radiolabeled sphingosine demonstrated that LPS treatment of resting microglia induced a significant increase of both cellular and extracellular S1P. Moreover, and of relevance, FTY720, a functional antagonist of S1P receptor, inhibited the multiple LPS-induced proinflammatory effects on microglia, and S1P suppressed the anti-inflammatory effect of ADSC-CM. This suggests that LPS-mediated microglial activation is countered by ADSC-CM through the modulation of sphingosine kinase/S1P signalling.

Concise Review: Mesenchymal Stem Cells in Neurodegenerative Diseases

“…Importantly, hBM‐MSCs‐treated patients showed a lesser decrease in cerebral glucose metabolism and grey matter density as well as decreased deterioration of cognition when compared with placebo group. Finally, recent in vitro and in vivo analyses have indicated the roles of other molecular pathways, such as nuclear factor kappa‐light‐chain‐enhancer of activated B cells signaling and sphingosine‐1‐phosphate signaling in hMSCs mediated of modulation of inflammation.…”

Modulators of microglial activation and polarization after intracerebral haemorrhage

“…The S1PR agonist fingolimod was approved by the FDA in 2010 for the treatment of multiple sclerosis (MS). Microglia express all five S1PRs in vitro 155,156 , and fingolimod treatment reduced proinflammatory cytokine levels in lipopolysaccharide-induced M1-like micro-glia 156,157 . In vivo , fingolimod decreased the production of IL-1β and TNF in animal models of status epilepticus 158 and neonatal hyperoxia 159 .…”

Revisiting the Advances in Isolation, Characterization and Secretome of Adipose-Derived Stromal/Stem Cells

“…Ribeiro et al revealed an increased neuronal cell density and its metabolic activity by introducing ASCs secretome supplemented with growth factor bFGF and B27 [198]. A recent study has reported that sphingosine-1-phosphate (S1P) and cytokine of ASCs secretome control the inflammation of central nervous system [199]. According to Constantin et al ASCs secretome containing bFGF, PDGF-AB, and brain-derived growth factor controlled the experimental autoimmune encephalomyelitis (EAE) [200].…”