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BICD1 mediates HIF1α nuclear translocation in mesenchymal stem cells during hypoxia adaptation : BICD1 mediates HIF1 alpha nuclear translocation in mesenchymal stem cells during hypoxia adaptation
Cited 23 time in
Web of Science
Cited 24 time in Scopus
- Authors
- Issue Date
- 2019-09
- Publisher
- Nature Publishing Group
- Citation
- Cell Death and Differentiation, Vol.26 No.9, pp.1716-1734
- Abstract
- Hypoxia inducible factor 1 alpha (HIF1 alpha) 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 alpha 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 alpha 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 alpha nuclear translocation and its activity. BICD1 overexpression further enhanced hypoxia-induced HIF1 alpha nuclear translocation. Hypoxia stimulated direct bindings of HIF1 alpha 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 alpha and nuclear translocation of HIF1 alpha. Conversely, Akt activation or GSK3 beta silencing further enhanced the hypoxia-induced HIF1 alpha 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 beta silencing. In conclusion, we demonstrated that BICD1-induced HIF1 alpha nuclear translocation is critical for hypoxia adaptation, which determines the regenerative potential of UCB-MSCs.
- ISSN
- 1350-9047
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