Abstract

THE ROLE OF HYPOXIA AND HIF-1? ON MESENCHYMAL STEM CELLS; POTENTIAL THERAPEUTIC ADVANTAGES & HAZARDS

Syed Faizan Ali Rizvi*, Bushra Wasim, Irfan Khan, Shumaila Usman, Kevin Joseph Jerome Borges, Shumaila Khalid

ABSTRACT

Stem cells can proliferate, differentiate and renew themselves. Mesenchymal stem cells (MSCs) are proving to be the most promising source for supply of stem cells in regenerative medicines. To produce therapeutic efficacy, large number of stem cells (1-10x6 cell/kg) are required. However, in vitro expansion of MSCs, especially of those derived from bone marrow, have a finite number of divisions after which they go into replicative senescence. This limits their use not just in clinical applications but in basic research as well. To overcome this limitation, several parameters have been used, among them one important and widely studied parameter is hypoxia. The role of hypoxic culture on MSC expansion and proliferation is still debatable. Studies have reported that MSCs treated with hypoxia have higher proliferation as compared to normoxic cultures. On the other hand, several studies reported no change or decreased proliferation of MSCs treated with hypoxia. Hypoxia has deleterious effects and is extensively involved in maintenance of cancer stem cells. Hypoxia mediates several cellular processes through hypoxia inducible factor-1α (HIF-1α). HIF1-TWIST (transcription factor) increases MSC proliferation by downregulating E2A and p21 pathway. However, HIF-TWIST affiliation has been confirmed in different cancers and is involved in tumor metastasis. In comparison with normoxic MSCs, expression of tumor suppressor genes and DNA-repair enzymes were found raised in hypoxia treated MSCs. The expression of tumor suppressor gene and DNA repair enzymes raised concerns over hypoxic treatment of MSCs. Hypoxia may or may not increase in-vitro proliferation, but care needs to be taken for hypoxia preconditioning. MSCs cultured under hypoxia must be investigated systematically before they are planned for clinical applications.

Keywords: Mesenchymal Stem Cells, Bone Marrow, Umbilical Cord, Hypoxia treatment, HIF-1?.