Intracellular pH Regulation in iPSCs-derived Astrocytes from Subjects with Chronic Mountain Sickness.

Chronic Mountain Sickness (CMS) occurs in high-altitude residents with major neurological symptoms such as migraine headaches, dizziness and cognitive deficits. Recent work demonstrated that highlanders have increased intracellular pH (pH i ) in their brain cells, perhaps for the sake of adaptation to hypoxemia and help to facilitate glycolysis, DNA synthesis, and cell cycle progression. Since there are well adapted (non-CMS) and maladapted (CMS) high-altitude dwellers, it is not clear whether pH i is differently regulated in these two high-altitude populations. In this work, we obtained induced pluripotent stem cell (iPSC)-derived astrocytes from both CMS and non-CMS highlanders who live in the Peruvian Andes (>14,000 ft) and studied pH i regulation in these astrocytes using pH-sensitive dye BCECF. Our results show that the steady-state pH i (ss pH i ) is lower in CMS astrocytes compared with non-CMS astrocytes. In addition, the acid extrusion following an acid loading is faster and the pH i dependence of H + flux rate becomes steeper in CMS astrocytes. Furthermore, the Na + dependency of ss pH i is stronger in CMS astrocytes and the Na + /H + exchanger (NHE) inhibitors blunted the acid extrusion in both CMS and non-CMS astrocytes. We conclude that (a) NHE contributes to the ss pH i stabilization and mediates active acid extrusion during the cytosolic acidosis in highlanders; (b) acid extrusion becomes less pH i sensitive in non-CMS (versus CMS) astrocytes which may prevent NHE from over-activated in the hypoxia-induced intracellular acidosis and render the non-CMS astrocytes more resistant to hypoxemia challenges. [ABSTRACT FROM AUTHOR]