Hypoxia and stem cells

Later this month, the international stem cell research community will be travelling to Stockholm for the upcoming International Society for Stem Cell Research (ISSCR) meeting covering diverse topics from reprogramming and pluripotency of stem cells through tissue engineering and organ regeneration to therapy with stem cells.

Hypoxia is a crucial parameter determining the fate and development of stem cells, which leads Don Whitley Scientific to exhibit the Hypoxystation controlled environment workstation for low oxygen cell culture (see us on stand no. B15:33). Dr. Burga Kalz Fuller, Product Manager at our American distributor, HypOxygen, has summarized five recent papers delineating the role of hypoxia in stem cell research:

1.  “Hypoxia promotes stem cell-like phenotype in multiple myeloma cells”, Muz et al., Blood Cancer Journal, 2014

Diverse effects of hypoxia on multiple myeloma MM, where a stem cell-like population causes relapse, are examined. Adaptation to hypoxic conditions causes de-differentiation, decreased proliferation, increased tumor initiation ability, and complete drug resistance in the MM stem cells. These results suggest a strategy of targeting the hypoxic stem cell-like population in order to prevent relapse in MM patients.

2.  “CCL2 enhances pluripotency of human induced pluripotent stem cells by activating hypoxia related genes”, Hasegawa et al., 2014 Scientific Reports 4, Article number:5228

Establishing high quality iPSC’s is critical to the continuing development of stem cell-based therapies, and Hasegawa et al. provide some insight into the mechanisms whereby the hypoxic microenvironment influences stem cell function and differentiation. The role of the chemokine (c-C motif) ligand CCL2 in up-regulating hypoxia-related genes and thus enhancing pluripotency is discussed.

3.  “Hypoxia-Inducible Factors Have Distinct and Stage-Specific Roles during Reprogramming of Human Cells to Pluripotency” Mathieu et al., Cell Stem Cell 14, 592–605, 2014

Hypoxia-inducible factors HIF’s mediate a shift from oxidative to glycolytic metabolism which is required early in the re-programming process of human cells, but which is inhibitory in later stages. iPSC generation but not hESC renewal is repressed in a late stage-specific manner through stabilization of HIF-2α and inhibition of apoptotic caspase 3. Mathieu et al. compare cancer with a slow reprogramming process and speculate that the role of hypoxia in achieving pluripotency may have implications for cancer research.

4.  “Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER” van den Beucken et al., NATURE COMMUNICATIONS 5:5203,  2014

Hypoxia promotes stemness in normal tissues and in cancer, and van den Beucken at al. provide data from breast cancer showing that one parameter effecting this phenotype transition may involve epigenetic suppression of DICER transcription. The DICER promoter is silenced at low oxygen tension, significantly reducing miRNA processing. DICER inhibition stimulates the epithelial-mesenchymal transition EMT and promotes the acquisition of a stem cell phenotype, all of which drive metastasis in cancer.

5.  “Hypoxic Preconditioning of Mesenchymal Stromal Cells Induces Metabolic changes, Enhances Survival and Promotes Cell Retention in vivo” Beegle et al., Stem Cells. 2015 Jun;33(6):1818-28

Mesenchymal stem cells show great promise as therapeutics in regenerative medicine, either as direct transplants or through paracrine effects. Originating as they do in hypoxic regions of the body, such as bone marrow or adipose tissue, MSC’s subjected to standard high oxygen cell culture at 20.8% tend to show unsatisfactory retention and survival rates after transplantation. Beegle et al. at the University of Davis Institute for Regenerative Cures show that pre-conditioning at 1% oxygen reduces cell death and increases cell numbers of transplanted MSC’s in mice. They describe a slower glucose metabolism and other mediators of enhanced survival in pre-conditioned cells as compared to normoxic controls.