Low FasL levels promote proliferation of human bone marrow-derived mesenchymal stem cells, higher levels inhibit their differentiation into adipocytes

M. R. Rippo, L. Babini, F. Prattichizzo, L. Graciotti, G. Fulgenz, F. Tomassoni Ardori, F. Olivieri, G. Borghetti, S. Cinti, A. Poloni, F. Fazioli, A. D. Procopio

Research output: Contribution to journalArticle

Abstract

Mesenchymal stem cells (MSCs) are multipotent progenitor cells that can differentiate into several cell types. Bone marrow (BM)-MSCs mainly differentiate into osteoblasts or adipocytes. MSC interactions with their microenvironment directly affect their self-renewal/differentiation program. Here, we show for the first time that Fas ligand (FasL), a well-explored proapoptotic cytokine, can promote proliferation of BM-derived MSCs in vitro and inhibits their differentiation into adipocytes. BM-MSCs treated with a low FasL dose (0.5 ng/ml) proliferated more rapidly than untreated cells without undergoing spontaneous differentiation or apoptosis, whereas higher doses (25 ng/ml) induced significant though not massive BM-MSC death, with surviving cells maintaining a stem cell phenotype. At the molecular level, 0.5 ng/ml FasL induced ERK1/2 phosphorylation and survivin upregulation, whereas 25 ng/ml FasL induced caspase activation. Importantly, 25 ng/ml FasL reversibly prevented BM-MSC differentiation into adipocytes by modulating peroxisome proliferator-activated receptor gamma (PPARc) and FABP4/aP2 expression induced by adipogenic medium. All such effects were inhibited by anti-Fas neutralizing antibody. The in vitro data regarding adipogenesis were confirmed using Fas lpr mutant mice, where higher PPARc and FABP4/aP2 mRNA and protein levels were documented in whole tibia. These data show for the first time that the FasL/Fas system can have a role in BM-MSC biology via regulation of both proliferation and adipogenesis, and may have clinical relevance because circulating Fas/FasL levels decline with age and several age-related conditions, including osteoporosis, are characterized by adipocyte accumulation in BM.

Original languageEnglish
Article numbere594
JournalCell Death and Disease
Volume4
Issue number6
Publication statusPublished - Jun 2013

Keywords

  • adipogenesis
  • bone marrow-derived mesenchymal stem cells
  • Fas ligand
  • peroxisome proliferator-activated receptor gamma
  • proliferation

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

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  • Cite this

    Rippo, M. R., Babini, L., Prattichizzo, F., Graciotti, L., Fulgenz, G., Tomassoni Ardori, F., Olivieri, F., Borghetti, G., Cinti, S., Poloni, A., Fazioli, F., & Procopio, A. D. (2013). Low FasL levels promote proliferation of human bone marrow-derived mesenchymal stem cells, higher levels inhibit their differentiation into adipocytes. Cell Death and Disease, 4(6), [e594].