title: Purinergic stimulation of human mesenchymal stem cells potentiates their chemotactic response to CXCL12 and increases the homing capacity and production of proinflammatory cytokines.
abstract: OBJECTIVE
  Extracellular adenosine triphosphate (ATP) is a well-recognized mediator of cell-to-cell communication. Here we show ATP effects on bone marrow (BM)-derived human mesenchymal stem cell (hMSCs) functions.
  
  
  METHODS
  ATP-induced modification of hMSCs gene expression profile was assessed by Affymetrix technology. Clonogenic and migration assays in vitro, as well as xenotransplant experiments in vivo, were performed to evaluate the effects of ATP on hMSCs proliferation and BM homing. Enzyme-linked immunosorbent assays were used to assess hMSCs cytokines production, whereas T-cell cultures demonstrated the immunoregulatory activity of ATP-treated hMSCs.
  
  
  RESULTS
  hMSCs were resistant to the cytotoxic effects of ATP, as demonstrated by the lack of morphological and mitochondrial changes or release of intracellular markers of cell death. Gene expression profiling revealed that ATP-stimulated hMSCs underwent a downregulation of genes involved in cell proliferation, whereas those involved in cell migration were strongly upregulated. The inhibitory activity of ATP on hMSCs proliferation was confirmed by assessing clonogenic stromal progenitors. ATP potentiated the chemotactic response of hMSCs to the chemokine CXCL12, and increased their spontaneous migration. In vivo, the homing capacity of hMSCs to the BM of immunodeficient mice was significantly increased by pretreatment with ATP. Moreover, ATP increased the production of the proinflammatory cytokines interleukin-2, interferon-γ, and interleukin-12p70, while decreasing the anti-inflammatory cytokine interleukin-10, and this finding was associated with the reduced ability of MSCs to inhibit T-cell proliferation.
  
  
  CONCLUSIONS
  Our data show that purinergic signaling modulates hMSCs functions and highlights a role for extracellular nucleotides in hMSCs biology.
authors.affiliation: Department of Experimental and Diagnostic Medicine, Section of General Pathology, University of Ferrara, via Borsari 46, Ferrara, Italy. dfr@unife.it
authors.forename: Davide
authors.initials: D
authors.lastname: Ferrari
authors.forename: Sara
authors.initials: S
authors.lastname: Gulinelli
authors.forename: Valentina
authors.initials: V
authors.lastname: Salvestrini
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lucchetti
authors.forename: Roberta
authors.initials: R
authors.lastname: Zini
authors.forename: Rossella
authors.initials: R
authors.lastname: Manfredini
authors.forename: Luisa
authors.initials: L
authors.lastname: Caione
authors.forename: Wanda
authors.initials: W
authors.lastname: Piacibello
authors.forename: Marilena
authors.initials: M
authors.lastname: Ciciarello
authors.forename: Lara
authors.initials: L
authors.lastname: Rossi
authors.forename: Marco
authors.initials: M
authors.lastname: Idzko
authors.forename: Sergio
authors.initials: S
authors.lastname: Ferrari
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Virgilio
authors.forename: Roberto M
authors.initials: RM
authors.lastname: Lemoli
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000378:metabolism* / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014183:Transplantation, Heterologous
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D007378:Interleukins; D000255:Adenosine Triphosphate