biostudies-literatureAhamad NU.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial ResearchU.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research (NIDCR)67https://www.ebi.ac.uk/biostudies/studies/S-EPMC8528841biostudies-literatureUnknown6(1)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 tNPJ Regenerative medicineDifferential activation of Ca²⁺ influx channels modulate stem cell potency, their proliferation/viability and tissue regeneration.PMC8528841R01DE017102R21DE028265Xavier Paul Ezhilan CRDNascimento Da Conceicao VNatarajan MSingh BBAhamad NSun YfalseDifferential 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 t2021-01-01T00:00:00Z2021 Oct2025-04-19T15:09:42.986Z2025-02-19T00:18:36.892ZS-EPMC85288413467105810.1038/s41536-021-00180-w