TY - JOUR
T1 - Hypoxia-inducible factor 1Α may regulate the commitment of mesenchymal stromal cells toward angio-osteogenesis by mirna-675-5P
AU - Costa, Viviana
AU - Raimondi, Lavinia
AU - Conigliaro, Alice
AU - Salamanna, Francesca
AU - Carina, Valeria
AU - De Luca, Angela
AU - Bellavia, Daniele
AU - Alessandro, Riccardo
AU - Fini, Milena
AU - Giavaresi, Gianluca
PY - 2017/12/1
Y1 - 2017/12/1
N2 - Background aims During bone formation, angiogenesis and osteogenesis are regulated by hypoxia, which is able to induce blood vessel formation, as well as recruit and differentiate human mesenchymal stromal cells (hMSCs). The molecular mechanisms involved in HIF-1α response and hMSC differentiation during bone formation are still unclear. This study aimed to investigate the synergistic role of hypoxia and hypoxia-mimetic microRNA miR-675-5p in angiogenesis response and osteo-chondroblast commitment of hMSCs. Methods By using a suitable in vitro cell model of hMSCs (maintained in hypoxia or normoxia), the role of HIF-1α and miR-675-5p in angiogenesis and osteogenesis coupling was investigated, using fluorescence-activated cell sorting (FACS), gene expression and protein analysis. Results Hypoxia induced miR-675-5p expression and a hypoxia-angiogenic response, as demonstrated by increase in vascular endothelial growth factor messenger RNA and protein release. MiR-675-5p overexpression in normoxia promoted the down-regulation of MSC markers and the up-regulation of osteoblast and chondroblast markers, as demonstrated by FACS and protein analysis. Moreover, miR-675-5p depletion in a low-oxygen condition partially abolished the hypoxic response, including angiogenesis, and in particular restored the MSC phenotype, demonstrated by cytofluorimetric analysis. In addition, current preliminary data suggest that the expression of miR-675-5p during hypoxia plays an additive role in sustaining Wnt/β-catenin pathways and the related commitment of hMSCs during bone ossification. Discussion MiR-675-5p may trigger complex molecular mechanisms that promote hMSC osteoblastic differentiation through a dual strategy: increasing HIF-1α response and activating Wnt/β-catenin signaling.
AB - Background aims During bone formation, angiogenesis and osteogenesis are regulated by hypoxia, which is able to induce blood vessel formation, as well as recruit and differentiate human mesenchymal stromal cells (hMSCs). The molecular mechanisms involved in HIF-1α response and hMSC differentiation during bone formation are still unclear. This study aimed to investigate the synergistic role of hypoxia and hypoxia-mimetic microRNA miR-675-5p in angiogenesis response and osteo-chondroblast commitment of hMSCs. Methods By using a suitable in vitro cell model of hMSCs (maintained in hypoxia or normoxia), the role of HIF-1α and miR-675-5p in angiogenesis and osteogenesis coupling was investigated, using fluorescence-activated cell sorting (FACS), gene expression and protein analysis. Results Hypoxia induced miR-675-5p expression and a hypoxia-angiogenic response, as demonstrated by increase in vascular endothelial growth factor messenger RNA and protein release. MiR-675-5p overexpression in normoxia promoted the down-regulation of MSC markers and the up-regulation of osteoblast and chondroblast markers, as demonstrated by FACS and protein analysis. Moreover, miR-675-5p depletion in a low-oxygen condition partially abolished the hypoxic response, including angiogenesis, and in particular restored the MSC phenotype, demonstrated by cytofluorimetric analysis. In addition, current preliminary data suggest that the expression of miR-675-5p during hypoxia plays an additive role in sustaining Wnt/β-catenin pathways and the related commitment of hMSCs during bone ossification. Discussion MiR-675-5p may trigger complex molecular mechanisms that promote hMSC osteoblastic differentiation through a dual strategy: increasing HIF-1α response and activating Wnt/β-catenin signaling.
KW - hypoxia
KW - mesenchymal stromal cells
KW - miR-675-5p
KW - osteoblast commitment
KW - regenerative medicine
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U2 - 10.1016/j.jcyt.2017.09.007
DO - 10.1016/j.jcyt.2017.09.007
M3 - Article
AN - SCOPUS:85032175040
VL - 19
SP - 1412
EP - 1425
JO - Cytotherapy
JF - Cytotherapy
SN - 1465-3249
IS - 12
ER -