Bone-marrow-derived mesenchymal stromal cells (BM-MSCs)–based therapy represents a promising option in the field of regenerative medicine. Their therapeutic potential is mainly dependent on paracrine secretion, proliferation and ECM remodeling abilities whose modulation involves Matrix Metalloproteinase (MMP)-2 functionality. Thus, the identification of paracrine/autocrine factors regulating MMP-2 expression/activity may be of great biological relevance for potentiating BM-MSC theraputic efficacy. Our research group has demonstrated that BM-MSCs release the bioactive lipid sphingosine-1-phosphate (S1P). Here we demonstrated : i) the requirement of S1P production by BM-MSC for their ability to synthesize functional gelatinases; ii) an impairment of gelatinolytic activity and MMP-2 expression/release when the S1P receptor subtype 1 (S1PR1) is blocked. Notably, in these experimental conditions BM-MSCs did not exhibit the formation of plasmamembrane-associated F-actin structures (lamellipodia, filopodia, microspikes) and in turn showed a reduction of the proliferation rate. Moreover, S1P1-mediated signaling is required for HIF-1α expression and MMP-2 expression/activity, reduction of vinculin expression and stress fiber formation and proliferation in hypoxia, an experimental condition mimicking the injured/regenerating tissue microenvironment. In conclusion, our findings, demonstrating for the first time the trophic role exerted by the autocrine S1P/S1PR1 signaling in the maintaining BM-MSC ability to modulate MMP-2 function necessary for ECM remodeling, cytoskeleton assembly and cell proliferation may provide perspectives for considering S1P/S1PR1 as a pharmacological target to preserve BM-MSCs properties and improve their efficacy in tissue repair.

Modulation of MMP-2 function in bone marrow mesenchymal stromal cells requires sphingosine 1-phopsphate receptor 1 mediated signaling: implications for cytoskeletal assembly and proliferation / Zecchi-Orlandini, Sandra; Meacci, Elisabetta; Tani, Alessia; Chellini, Flaminia; Nosi, Daniele; Pierucci, Federica; Frati, Alessia; Matteini, Francesca; Vestri, Ambra; Sassoli, Chiara. - In: ITALIAN JOURNAL OF ANATOMY AND EMBRYOLOGY. - ISSN 2038-5129. - STAMPA. - 122:(2017), pp. 222-222.

Modulation of MMP-2 function in bone marrow mesenchymal stromal cells requires sphingosine 1-phopsphate receptor 1 mediated signaling: implications for cytoskeletal assembly and proliferation

ZECCHI, SANDRA;MEACCI, ELISABETTA;TANI, ALESSIA;CHELLINI, FLAMINIA;NOSI, DANIELE;PIERUCCI, FEDERICA;FRATI, ALESSIA;MATTEINI, FRANCESCA;VESTRI, AMBRA;SASSOLI, CHIARA
2017

Abstract

Bone-marrow-derived mesenchymal stromal cells (BM-MSCs)–based therapy represents a promising option in the field of regenerative medicine. Their therapeutic potential is mainly dependent on paracrine secretion, proliferation and ECM remodeling abilities whose modulation involves Matrix Metalloproteinase (MMP)-2 functionality. Thus, the identification of paracrine/autocrine factors regulating MMP-2 expression/activity may be of great biological relevance for potentiating BM-MSC theraputic efficacy. Our research group has demonstrated that BM-MSCs release the bioactive lipid sphingosine-1-phosphate (S1P). Here we demonstrated : i) the requirement of S1P production by BM-MSC for their ability to synthesize functional gelatinases; ii) an impairment of gelatinolytic activity and MMP-2 expression/release when the S1P receptor subtype 1 (S1PR1) is blocked. Notably, in these experimental conditions BM-MSCs did not exhibit the formation of plasmamembrane-associated F-actin structures (lamellipodia, filopodia, microspikes) and in turn showed a reduction of the proliferation rate. Moreover, S1P1-mediated signaling is required for HIF-1α expression and MMP-2 expression/activity, reduction of vinculin expression and stress fiber formation and proliferation in hypoxia, an experimental condition mimicking the injured/regenerating tissue microenvironment. In conclusion, our findings, demonstrating for the first time the trophic role exerted by the autocrine S1P/S1PR1 signaling in the maintaining BM-MSC ability to modulate MMP-2 function necessary for ECM remodeling, cytoskeleton assembly and cell proliferation may provide perspectives for considering S1P/S1PR1 as a pharmacological target to preserve BM-MSCs properties and improve their efficacy in tissue repair.
2017
Zecchi-Orlandini, Sandra; Meacci, Elisabetta; Tani, Alessia; Chellini, Flaminia; Nosi, Daniele; Pierucci, Federica; Frati, Alessia; Matteini, Francesc...espandi
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1095390
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