Differential activation of Ca²⁺ influx channels modulate stem cell potency, their proliferation/viability and tissue regeneration

Stem cells have indefinite self-renewable capability; however, factors that modulate their pluripotency/function are not fully identified. Here we show that store-dependent Ca²⁺ entry is essential for modulating the function of bone marrow-derived mesenchymal stem cells (MSCs). Increasing external Ca²⁺ modulated cell cycle progression that was critical for MSCs survival. Additionally, Ca²⁺ was critical for stem proliferation, its differentiation, and maintaining stem cell potential. Ca²⁺ channel characterization, including gene silencing, showed two distinct Ca²⁺ entry channels (through Orai1/TRPC1 or via Orai3) that differentially regulate the proliferation and viability of MSCs. Importantly, NFκB translocation, but not JNK/ERK into the nucleus, was observed upon store depletion, which was blocked by the addition of Ca²⁺ channel inhibitors. Radiation lead to a decrease in saliva secretion, decrease in acinar cell number, and enlarged ducts were observed, which were restored by the transplantation of stem cells that were propagated in higher Ca²⁺. Finally radiation showed a decrese in TRPC1 expression along with a decrese in AQP5, which was again restored upon MSC tranplantation. Together these results suggest that Ca²⁺ entry is essential for stem cell function that could be critical for regenerative medicine.