Reproduction Abstracts

Human embryonic stem cells (hESCs) derived from the inner cell mass of the blastocyst, propagate by self-renewal and can give rise to all cells of the body. Thus, they are a useful model to investigate a range of degenerative disorders such as type 1 insulin-dependent diabetes, multiple sclerosis and Parkinson’s disease. However, hESCs are notoriously difficult to maintain in culture as colonies have a propensity to spontaneously differentiate making it difficult to uniformly direct all cells down a specific lineage pathway. Thus, to expedite the use of these cells in regenerative medicine, fundamental research is required to understand the mechanisms that regulate hESC maintenance. In vivo, the blastocyst is thought to reside in a low oxygen atmosphere and thus, the routine use of atmospheric oxygen to culture hESCs may be detrimental to pluripotency. Research in my lab has found that reducing the oxygen tension to a more physiological level supports the maintenance of a highly proliferative, pluripotent population of cells; a response mediated by a family of hypoxia inducible factors. Moreover, highly pluripotent hESCs cultured at a low oxygen tension display an altered metabolism compared to early differentiating cells, or those maintained under atmospheric oxygen; a reduction in expression of pluripotency markers is associated with a more oxidative metabolism. Our data suggest that a low environmental oxygen tension is an important regulator of energy metabolism and intrinsic to hESC self-renewal.

Funded by MRC UK, Gerald Kerkut Trust UK and University of Southampton.