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oai:repisalud.isciii.es:20.500.12105/51082024-09-27T09:15:49Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Ciria, Maria author Garcia, Nahuel A. author Ontoria-Oviedo, Imelda author Gonzalez-King, Hernan author Carrero, Ruben author de la Pompa, Jose Luis author Anastasio Montero, Jose author Sepulveda, Pilar author 2017 Mesenchymal stem cells (MSCs) are effective in treating several pathologies. We and others have demonstrated that hypoxia or hypoxia-inducible factor 1 alpha (HIF-1 alpha) stabilization improves several MSC functions, including cell adhesion, migration, and proliferation, thereby increasing their therapeutic potential. To further explore the mechanisms induced by HIF-1 alpha in MSCs, we studied its relationship with Notch signaling and observed that overexpression of HIF-1 alpha in MSCs increased protein levels of the Notch ligands Jagged 1-2 and Delta-like (Dll) 1, Dll3, and Dll4 and potentiated Notch signaling only when this pathway was activated. Crosstalk between HIF and Notch resulted in Notch-dependent migration and spreading of MSCs, which was abolished by gamma-secretase inhibition. However, the HIF-1-induced increase in MSC proliferation was independent of Notch signaling. The ubiquitin family member, small ubiquitin-like modifier (SUMO), has important functions in many cellular processes and increased SUMO1 protein levels have been reported in hypoxia. To investigate the potential involvement of SUMOylation in HIF/Notch crosstalk, we measured general SUMOylation levels and observed increased SUMOylation in HIF-1-expressing MSCs. Moreover, proliferation and migration of MSCs were reduced in the presence of a SUMOylation inhibitor, and this effect was particularly robust in HIF-MSCs. Immunoprecipitation studies demonstrated SUMOylation of the intracellular domain of Notch1 (N1ICD) in HIF-1-expressing MSCs, which contributed to Notch pathway activation and resulted in increased levels of N1ICD nuclear translocation as assessed by subcellular fractionation. SUMOylation of N1ICD was also observed in HEK293T cells with stabilized HIF-1 alpha expression, suggesting that this is a common mechanism in eukaryotic cells. In summary, we describe, for the first time, SUMOylation of N1ICD, which is potentiated by HIF signaling. These phenomena could be relevant for the therapeutic effects of MSCs in hypoxia or under conditions of HIF stabilization. Stem Cells Dev. 2017; 26(13):973-985 10.1089/scd.2016.0331 1557-8534 1547-3287 STEM CELLS AND DEVELOPMENT 28520516 http://hdl.handle.net/20.500.12105/5108 Mesenchymal stem cells Hypoxia-inducible factor Notch SUMOylation Migration Proliferation TRANSCRIPTIONAL ACTIVITY MYOCARDIAL-INFARCTION GAMMA-SECRETASE BREAST-CANCER ACTIVATION SUMOYLATION HIF-1-ALPHA HIF-1 DIFFERENTIATION Oxygen Mesenchymal Stem Cell Migration and Proliferation Are Mediated by Hypoxia-Inducible Factor-1 alpha Upstream of Notch and SUMO Pathways