The potential role of hypoxia inducible factor 1 alpha in multipotent germ cells and neural stem/progenitor cells

Abstract

Hypoxia inducible factor 1 alpha (HIF1α) is a key transcription factor which transcriptionally activates an array of genes involved in adaptive responses to physiological hypoxia. HIF1α has been implicated in many disease conditions as well as normal development of many organs including the heart, the brain and the bones. In recent years, a number of studies have revealed that HIF1α also maintains undifferentiated state of many types of stem cells such as embryonic stem cells, hematopoietic stem cells and mesenchymal stem cells. In this study, we sought to investigate whether HIF1α is localized in intestinal stem cells, hair follicle stem cells and germline cells, in which HIF1α expression has not yet been reported. Although we did not detect any HIF1α signal in intestinal and hair follicle stem cell compartments, we observed a clear expression of HIF1α in both male and female germ cells. Furthermore, our results showed the presence of HIF1α throughout the fetal and neonatal development of both male and female germ cells, raising a possibility that HIF1α may play a role as a transactivator of glycolytic genes in highly proliferative cells such as primordial germ cells and spermatogonial cell as those cell types heavily depend on glycolysis for energy production. Lastly, we investigated whether HIF1α regulates telomerase activity in the cultured neural stem/progenitor cell (NSPCs) population, as our previous study revealed that HIF1α transactivates mTert and subsequently regulates telomerase activity in mouse embryonic stem cells. Our shRNA-mediated Hif1α knockdown assay resulted in the decreased levels of telomerase activity, strongly suggesting that HIF1α transactivates mTert in NSPCs. Regulation of telomerase activity may be important to ensure the long term survival of NSPCs and continuous neurogenesis throughout the life of an organism. Together, the results of this study illustrate the involvement of HIF1α in normal development and maintenance of types of stem/progenitor cells in which the localization and function of HIF1α was never extensively discussed, pointing out that further investigation may lead to better understanding of the roles of HIF1α in multipotent cells.