When exposed to ambient air compared to physioxia, hematopoietic stem cells (HSCs) exhibit decreased recovery and self-renewal with a concurrent increase in differentiation. Although the mechanism(s) behind the differential was not well understood, they may help stem cell transplantation.
HSC self-renewal genes were found to be upregulated, whereas genes implicated in inflammatory pathways and HSC differentiation were found to be downregulated in physioxia, according to single-cell RNA sequencing of HSCs. The epigenetic regulator Tet2 was likewise downregulated in HSCs in physioxia. Tet2 is an iron- and oxygen-dependent, α-ketoglutarate-dependent dioxygenase that turns 5-methylcytosine into 5-hydroxymethylcytosine to encourage active transcription. Researchers examined whether Tet2 deletion impacts the quantity and functionality of HSCs and hematopoietic progenitor cells (HPCs) under physioxia and ambient air.
Tet2/ HSCs and HPCs were completely unresponsive to variations in oxygen tension, in contrast to wild-type HSCs (WT HSCs). Tet2-/- HSCs and HPCs, in contrast to WT HSCs, showed comparable numbers and functionality in either physioxia or ambient air. When WT HSCs were exposed to hypoxia, Tet2-/- HSCs were exposed to hypoxia, and Tet2-/- HSCs were exposed to air, Tet2-/- HSCs did not respond to changes in oxygen tension.
The alterations in self-renewal and quiescence genes were related to the lack of responsiveness. They provided a unique molecular strategy for controlling HSCs in physioxia that uses Tet2.