BICD1 mediates HIF1? nuclear translocation in mesenchymal stem cells during hypoxia adaptation.

ABSTRACT: Hypoxia inducible factor 1? (HIF1?) is a master regulator leading to metabolic adaptation, an essential physiological process to maintain the survival of stem cells under hypoxia. However, it is poorly understood how HIF1? translocates into the nucleus in stem cells under hypoxia. Here, we investigated the role of a motor adaptor protein Bicaudal D homolog 1 (BICD1) in dynein-mediated HIF1? nuclear translocation and the effect of BICD1 regulation on hypoxia adaptation and its therapeutic potential on human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs). In our results, silencing of BICD1 but not BICD2 abolished HIF1? nuclear translocation and its activity. BICD1 overexpression further enhanced hypoxia-induced HIF1? nuclear translocation. Hypoxia stimulated direct bindings of HIF1? to BICD1 and the intermediate chain of dynein (Dynein IC), which was abolished by BICD1 silencing. Akt inhibition reduced the binding of BICD1 to HIF1? and nuclear translocation of HIF1?. Conversely, Akt activation or GSK3? silencing further enhanced the hypoxia-induced HIF1? nuclear translocation. Furthermore, BICD1 silencing abolished hypoxia-induced glycolytic reprogramming and increased mitochondrial ROS accumulation and apoptosis in UCB-MSCs under hypoxia. In the mouse skin wound healing model, the transplanted cell survival and skin wound healing capacities of hypoxia-pretreated UCB-MSCs were reduced by BICD1 silencing and further increased by GSK3? silencing. In conclusion, we demonstrated that BICD1-induced HIF1? nuclear translocation is critical for hypoxia adaptation, which determines the regenerative potential of UCB-MSCs.

SUBMITTER: Lee HJ 

PROVIDER: S-EPMC6748134 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature