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Cell death and differentiation
09, 2019;26 (9): 1716-1734.

BICD1 mediates HIF1α nuclear translocation in mesenchymal stem cells during hypoxia adaptation.

Hyun Jik Lee, Young Hyun Jung, Ji Young Oh, Gee Euhn Choi, Chang Woo Chae, Jun Sung Kim, Jae Ryong Lim, Seo Yihl Kim, Sei-Jung Lee, Je Kyung Seong, Ho Jae Han
Author Information
  1. Hyun Jik Lee: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, Seoul National University, Seoul, 08826, Republic of Korea.
  2. Young Hyun Jung: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, Seoul National University, Seoul, 08826, Republic of Korea.
  3. Ji Young Oh: Department of Agricultural Biotechnology, Animal Biotechnology Major, and Research Institute of Agriculture and Life Science, Seoul National University, Seoul, 08826, Republic of Korea.
  4. Gee Euhn Choi: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, Seoul National University, Seoul, 08826, Republic of Korea.
  5. Chang Woo Chae: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, Seoul National University, Seoul, 08826, Republic of Korea.
  6. Jun Sung Kim: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, Seoul National University, Seoul, 08826, Republic of Korea.
  7. Jae Ryong Lim: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, Seoul National University, Seoul, 08826, Republic of Korea.
  8. Seo Yihl Kim: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, Seoul National University, Seoul, 08826, Republic of Korea.
  9. Sei-Jung Lee: Department of Pharmaceutical Engineering, Daegu Haany University, Gyeongsan, 38610, Republic of Korea.
  10. Je Kyung Seong: Laboratory of Developmental Biology and Genomics, Research Institute for Veterinary Science, BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, and Korea Mouse Phetnotyping Center (KMPC), Seoul National University, Seoul, 08826, Republic of Korea.
  11. Ho Jae Han: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, Seoul National University, Seoul, 08826, Republic of Korea. hjhan@snu.ac.kr.
PMID: 30464225 DOI: 10.1038/s41418-018-0241-1

Abstract

Hypoxia inducible factor 1α (HIF1α) 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 HIF1α 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 HIF1α 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 HIF1α nuclear translocation and its activity. BICD1 overexpression further enhanced hypoxia-induced HIF1α nuclear translocation. Hypoxia stimulated direct bindings of HIF1α to BICD1 and the intermediate chain of dynein (Dynein IC), which was abolished by BICD1 silencing. Akt inhibition reduced the binding of BICD1 to HIF1α and nuclear translocation of HIF1α. Conversely, Akt activation or GSK3β silencing further enhanced the hypoxia-induced HIF1α 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 GSK3β silencing. In conclusion, we demonstrated that BICD1-induced HIF1α nuclear translocation is critical for hypoxia adaptation, which determines the regenerative potential of UCB-MSCs.

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MeSH Term

Adaptation, Physiological
Adaptor Proteins, Signal Transducing
Animals
Cell Hypoxia
Cytoskeletal Proteins
Disease Models, Animal
Dyneins
Fetal Blood
Gene Expression Regulation, Developmental
Gene Silencing
Glycogen Synthase Kinase 3 beta
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
Mesenchymal Stem Cells
Mice
Proto-Oncogene Proteins c-akt
Skin
Wound Healing

Chemicals

Adaptor Proteins, Signal Transducing
BICD1 protein, human
Cytoskeletal Proteins
HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
GSK3B protein, human
Glycogen Synthase Kinase 3 beta
Proto-Oncogene Proteins c-akt
Dyneins
Journal Article Research Support, Non-U.S. Gov't

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