Calcium channels and their role in regenerative medicine

Figure 1 Stem cell properties and their types. A: Stem cells have two unique fundamental properties, self-renewal, and differentiation potential; B: Showing the development of different stem cells such as embryonic stem cells, hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), and multipotent adult progenitor stem cells (MAPCs); C: Showing the generation of induced pluripotent stem cells (iPSCs) from mouse fibroblast cells using four factors (octamer-binding transcription factor 3/4, SRY-box transcription factor 2, c-Myc, Kruppel-like factor 4). SSEAs: Stage-specific embryonic antigens.

Figure 2 Calcium toolkit and calcium signaling. A: Calcium (Ca²⁺) signaling toolkit components include cell-surface receptors (G protein-coupled receptors (GPCRs) and protein tyrosine kinase receptors), Ca²⁺ channels (voltage-gated channels and two-pore channels, voltage-gated K⁺ channel, Ca²⁺-activated K⁺ channel, ATP-sensitive K⁺ channels, TRPC1-7 ORAI1-3, IP3R, RyR2), Ca²⁺ pumps and exchangers (Na⁺/Ca²⁺ exchangers (NCX), Na⁺/Ca²⁺-K⁺ exchangers, plasma membrane Ca²⁺ ATPase (PMCA) and sarco-endoplasmic reticulum (ER) Ca²⁺ ATPase), Ca²⁺ buffers (parvalbumin, calbindin, and calretinin [cytoplasmic buffers] and Ca²⁺ buffers of the ER lumen, calsequestrin, calreticulin, glucose-regulated protein [GRP] 78 and GRP94), Ca²⁺ sensors (EF-hand [CaM, TnC, calpains, NCS-1, hippocalcin, neurocalcin, recoverin, MICU1, etc.] or C2 Ca²⁺-binding domains [annexin 1-13, otoferin, protein kinase C, RASAL, etc.], ER Ca²⁺ sensors STIM1 and STIM2), and Ca²⁺-sensitive cellular process. In a typical Ca²⁺-sensitive cellular process, the hormone binds to a specific receptor. This binding causes GDP-GTP exchange on the G protein. G protein (GTP-bound) activates phospholipase C (PLC). Activated PLC breaks phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol trisphosphate (IP₃) and diacylglycerol. IP₃ moves to a specific receptor on the ER, binds with the receptor, and triggers the release of sequestered Ca²⁺. Released Ca²⁺ and diacylglycerol activate protein kinase C enzyme. Activated protein kinase C phosphorylates cellular proteins and activates downstream proteins (Raf1 and other proteins). Activated Raf1 binds and activates MEK1/2 and MEK1/2, which phosphorylate extracellular signal-regulated kinase (ERK) 1/2. ERK1/2 enters the nucleus and on/off the genes against the hormone response. The released Ca²⁺ decreases ER calcium level. Low Ca²⁺ of ER sense by ER Ca²⁺ sensor (STIM) and activate it. An activated Ca²⁺ sensor binds the Ca²⁺ channel protein (ORAI) on the plasma membrane, opens the Ca²⁺ channel, and allows the Ca²⁺ entry into the cytoplasm from extracellular space. This process is called store-operated Ca²⁺ entry; B: Activated transcription factors and other proteins bind to DNA and increase the gene expression for self-renewal, proliferation, and differentiation processes in the stem cells. CaR: Ca²⁺ receptor; CREB: cAMP response element-binding protein; IP₃R: Inositol trisphosphate receptor; NFAT: Nuclear factor of activated T-cells; VDAC: Voltage-dependent anion channel; VGCC: Voltage-gated Ca²⁺ channel.

Figure 3 Calcium-dependent stem cell proliferation. Stem cells cultured in 1, 2, and 5 mmol/L calcium. Our results (not published) reveal that higher calcium-treated stem cells show a high proliferation rate. MSCs: Mesenchymal stem cells.

Figure 4 Treatment of coronavirus disease 2019 patient. We hypothesize that calcium-treated mesenchymal stem cells (MSCs) are a better option to counter the coronavirus’s inflammatory storm response, treat the coronavirus disease 2019 (COVID-19) patient, and other deadly diseases.