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

Abstract

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.

Autologous mesenchymal stem cells offer a new paradigm for salivary gland regeneration

“… 179 , 181 – 184 Ahamad et al elucidated specific mechanisms, related to Ca 2+ channel influx, which regulate MSC proliferation and differentiation and play a role in increasing AQP5 expression in IR-damaged SG. 182 Saylam et al employed intraperitoneal injections of allogenic AD-MSCs in a rodent model of radioiodine-induced SG damage, indicating that animals treated with MSCs showed improved healing and reduced fibrosis at 6 months following radioiodine therapy. 185 AD-MSCs appeared to protect against the most severe loss of secretory function and facilitated a relatively high degree of structural recovery in damaged SG tissue, as determined by histological analysis at 6 months.…”

Systematic review of the osteogenic effect of rare earth nanomaterials and the underlying mechanisms

“…Cytosolic Ca 2+ homeostasis is essential for multiple physiological functions, such as stem cell viability, cell proliferation and osteogenic differentiation [ 142 ]. RE NMs promote osteogenic differentiation by increasing intracellular Ca 2+ , mainly through the activation of CaRs and VGCCs, which is attributed to their calcium-mimicking and electrical properties (Fig.…”

“…The mechanism involves pertussis toxin (PTx)-sensitive Gi protein signalling [ 143 ], which indicates that these proteins are associated with Gi protein-coupled CaRs [ 144 ]. The activation of G protein-coupled receptors generates inositol triphosphate (IP3), which, upon binding to inositol triphosphate receptors (IP3Rs) in the ER, leads to ER Ca 2+ release and potentiates the SOCE mechanism [ 142 ], thereby further promoting osteogenesis. Furthermore, CeO NPs have been reported to activate osteogenic differentiation by upregulating the ERK1/2 [ 127 ] and DHX15/p38 MAPK [ 114 ] pathways.…”

Store-Operated Ca2+ Entry as a Putative Target of Flecainide for the Treatment of Arrhythmogenic Cardiomyopathy

“…Therefore, we still do not know whether they support SOCE in BM-hMSCs. Nevertheless, genetic silencing of STIM1, Orai1, and/or Orai3 reduced SOCE in mouse BM-derived MSCs (BM-mMSCs) [ 79 , 80 , 81 ] and in human dental pulp-derived MSCs (DP-hMSCs) [ 82 ].…”

“…As described above, SOCE is crucial to maintaining spontaneous Ca 2+ oscillations in hMSCs; an increase or decrease in the rate of Ca 2+ entry can differentially affect their differentiation outcomes. Therefore, it is not surprising that pharmacological manipulation of SOCE has been put forward as an alternative strategy to control hMSC differentiation [ 10 , 80 ].…”