Functional and molecular mechanism of intracellular pH regulation in human inducible pluripotent stem cells

Figure 7 Kinetic model of the pHi regulatory mechanism in human induced pluripotent stem cells. A: A kinetic model illustrating the pH_i regulatory mechanism in HPS0077 cell, including acid extrusion, acid loading and passive buffering power. For the first time, we demonstrated that the active membrane pH_i regulators NHE1, NHE3, V-ATPase, NBCe1, NBCe2, NBCn1, AE and CHE functionally coexisted in hiPSCs, and in addition, unknown Na⁺-independent acid extruder(s) and Cl^--independent acid loader(s) were also observed. The length of the triangle indicates the pH_i range of pH_i regulator activation, and the height indicates the magnitude of the pH_i regulatory activity. For example, the NHE, NBC, AE and CHE were activated at pH_i ≤ 7.5, between 6.9 and 7.68, ≥ 7.4 and between 7.6 and 8.1, respectively. The non-NHE acid extruders [V-ATPase, unknown Na⁺-independent acid extruder(s)] and unknown Cl^--independent acid loader(s) were activated during extreme intracellular acidification, i.e., pH_i < 7.1, and alkalization, i.e., pH_i > 7.9, respectively. Moreover, the intracellular passive buffering capacity (β) increased as the pH_i shifted to the alkalization direction; B: In the process of the loss of pluripotency, the activity of the acid extrusion mechanism gradually decreased, including the participation of at least the NHE, the NBC and V-ATPase, and resulted in the resting pH_i shifting from 7.68 to 7.48. hiPSCs: Human induced pluripotent stem cells; NHE: The Na⁺/H⁺ exchanger; NBC: The Na⁺/HCO₃^- cotransporter; V-ATPase: Vacuolar-ATPase; AE: Anion exchanger; CHE: Cl^--OH^- exchanger.