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

Autor: Gianluca Fulgenzi, Giulia Borghetti, Laura Graciotti, Maria Rita Rippo, F. Tomassoni Ardori, Lucia Babini, Antonella Poloni, Francesca Fazioli, Saverio Cinti, Antonio Domenico Procopio, Francesco Prattichizzo, Fabiola Olivieri
Rok vydání: 2013
Předmět:
Cancer Research
Fas Ligand Protein
proliferation
Survivin
medicine.medical_treatment
Immunology
Peroxisome proliferator-activated receptor
Bone Marrow Cells
Mice
Transgenic
Biology
Fatty Acid-Binding Proteins
Fas ligand
adipogenesis
peroxisome proliferator-activated receptor gamma
Inhibitor of Apoptosis Proteins
Mice
Cellular and Molecular Neuroscience
medicine
Animals
Humans
Progenitor cell
Cells
Cultured
Cell Proliferation
Mitogen-Activated Protein Kinase 1
chemistry.chemical_classification
Mitogen-Activated Protein Kinase 3
Tibia
Mesenchymal stem cell
Mesenchymal Stem Cells
Cell Biology
Antibodies
Neutralizing
Molecular biology
Recombinant Proteins
Cell biology
Mice
Inbred C57BL
PPAR gamma
Cytokine
medicine.anatomical_structure
chemistry
Adipogenesis
Apoptosis
Caspases
bone marrow-derived mesenchymal stem cells
Original Article
Bone marrow
Zdroj: Cell Death & Disease
Scopus-Elsevier
ISSN: 2041-4889
DOI: 10.1038/cddis.2013.115
Popis: 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 (PPARγ) 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 PPARγ 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.
Databáze: OpenAIRE
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