title: Extracellular purines promote the differentiation of human bone marrow-derived mesenchymal stem cells to the osteogenic and adipogenic lineages.
abstract: Extracellular nucleotides are potent signaling molecules mediating cell-specific biological functions, mostly within the processes of tissue damage and repair and flogosis. We previously demonstrated that adenosine 5'-triphosphate (ATP) inhibits the proliferation of human bone marrow-derived mesenchymal stem cells (BM-hMSCs), while stimulating, in vitro and in vivo, their migration. Here, we investigated the effects of ATP on BM-hMSC differentiation capacity. Molecular analysis showed that ATP treatment modulated the expression of several genes governing adipogenic and osteoblastic (i.e., WNT-pathway-related genes) differentiation of MSCs. Functional studies demonstrated that ATP, under specific culture conditions, stimulated adipogenesis by significantly increasing the lipid accumulation and the expression levels of the adipogenic master gene PPARγ (peroxisome proliferator-activated receptor-gamma). In addition, ATP stimulated osteogenic differentiation by promoting mineralization and expression of the osteoblast-related gene RUNX2 (runt-related transcription factor 2). Furthermore, we demonstrated that ATP stimulated adipogenesis via its triphosphate form, while osteogenic differentiation was induced by the nucleoside adenosine, resulting from ATP degradation induced by CD39 and CD73 ectonucleotidases expressed on the MSC membrane. The pharmacological profile of P2 purinergic receptors (P2Rs) suggests that adipogenic differentiation is mainly mediated by the engagement of P2Y1 and P2Y4 receptors, while stimulation of the P1R adenosine-specific subtype A2B is involved in adenosine-induced osteogenic differentiation. Thus, we provide new insights into molecular regulation of MSC differentiation.
authors.affiliation: Department of Hematology and Oncological Sciences, L. & A. Seràgnoli, Institute of Hematology, Stem Cell Research Center, Azienda Ospedaliero-Universitaria Policlinico S. Orsola-Malpighi, University of Bologna, Bologna, Italy. marilenaci@hotmail.com
authors.forename: Marilena
authors.initials: M
authors.lastname: Ciciarello
authors.forename: Roberta
authors.initials: R
authors.lastname: Zini
authors.forename: Lara
authors.initials: L
authors.lastname: Rossi
authors.forename: Valentina
authors.initials: V
authors.lastname: Salvestrini
authors.forename: Davide
authors.initials: D
authors.lastname: Ferrari
authors.forename: Rossella
authors.initials: R
authors.lastname: Manfredini
authors.forename: Roberto M
authors.initials: RM
authors.lastname: Lemoli
mesh_terms: D000241:Adenosine / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D050156:Adipogenesis; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis; D047495:PPAR gamma / Q000096:biosynthesis / Q000378:metabolism; D011687:Purines / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058472:Receptors, Purinergic P2Y1 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D047495:PPAR gamma; D011687:Purines; C493709:RUNX2 protein, human; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; C104749:purinoceptor P2Y4; D000255:Adenosine Triphosphate; D000241:Adenosine