Fas-L promotes the stem cell potency of adipose-derived mesenchymal cells

Inna Solodeev,Shai Yarkoni,Dov Zipori,Eyal Gur,Meirav Sela,Benjamin Meilik,Nir Shani,Sharon Manheim,Ilan Volovitz

doi:10.1038/s41419-018-0702-y

Abstract

Fas-L is a TNF family member known to trigger cell death. It has recently become evident that Fas-L can transduce also non-apoptotic signals. Mesenchymal stem cells (MSCs) are multipotent cells that are derived from various adult tissues. Although MSCs from different tissues display common properties they also display tissue-specific characteristics. Previous works have demonstrated massive apoptosis following Fas-L treatment of bone marrow-derived MSCs both in vitro and following their administration in vivo. We therefore set to examine Fas-L-induced responses in adipose-derived stem cells (ASCs). Human ASCs were isolated from lipoaspirates and their reactivity to Fas-L treatment was examined. ASCs responded to Fas-L by simultaneous apoptosis and proliferation, which yielded a net doubling of cell quantities and a phenotypic shift, including reduced expression of CD105 and increased expression of CD73, in association with increased bone differentiation potential. Treatment of freshly isolated ASCs led to an increase in large colony forming unit fibroblasts, likely produced by early stem cell progenitor cells. Fas-L-induced apoptosis and proliferation signaling were found to be independent as caspase inhibition attenuated Fas-L-induced apoptosis without impacting proliferation, whereas inhibition of PI3K and MEK, but not of JNK, attenuated Fas-L-dependent proliferation, but not apoptosis. Thus, Fas-L signaling in ASCs leads to their expansion and phenotypic shift toward a more potent stem cell state. We speculate that these reactions ensure the survival of ASC progenitor cells encountering Fas-L-enriched environments during tissue damage and inflammation and may also enhance ASC survival following their administration in vivo.

Highlights

Fas ligand (Fas-L), a member of the tumor necrosis factor (TNF) family, is a type II transmembrane protein expressed on the surface of immune cells, such as lymphocytes, natural killer (NK) cells, and macrophages
To evaluate the effect of Fas-L treatment on stromal vascular fraction (SVF) cells, we compared the cell yield and apoptosis rate of P0 adiposederived stem cells (ASCs) cultured for 14 days immediately following their isolation from fat in normal growth medium in the presence vs. absence of increasing Fas-L concentrations
At concentrations of 25 ng/ml and above, P0 ASCs demonstrated a dose-dependent increase in apoptosis rates (Fig. 1aII, b)

Summary

Introduction

Fas ligand (Fas-L), a member of the tumor necrosis factor (TNF) family, is a type II transmembrane protein expressed on the surface of immune cells, such as lymphocytes, natural killer (NK) cells, and macrophages. Upon binding to its receptor (CD95 or Fas receptor (FasR)[1], the intracellular ‘death-inducing signaling complex’[2], which includes the aspartate-specific cysteine protease, caspase-83–5, its adaptor/activator, FADD,[6,7] and its modulator, c-FLIP (FLICE (i.e., caspase-8) inhibitory protein) forms[8]. Caspase-8 is activated and undergoes proteolytic processing, allowing it to leave the complex[9], activate caspase-3/7 and induce apoptosis. The relatively ubiquitous expression of CD95 (FasR) in a variety of cells and tissues, corroborates this new line of thought Increasing evidence demonstrate involvement of Fas-L signaling in onset of additional cellular responses, such as inflammation[10,11,12], proliferation[13,14,15,16] regeneration[17], and cancer progression[18].

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