Calcium channels and their role in regenerative medicine

Table 1 Stem cells and their phenotypic markers and transcription factors

Embryonic stem cells (expression of SM/TF)
Human	Positive SM	SSEA-3, SSEA-4, TRA-1-60, TRA-1-81, alkaline phosphatase (ALP), CD9, Thy1, HLA-I CD133, and CD326[92-94]
	Negative SM	SSEA-1[92-94]
	TF	Oct 3/4, Sox2, Nanog, activin/nodal, FGF, Esrrb, and Tfcp2l1, Klf4, Klf2, Tbx3, and Gbx2[92,94,95]
Mouse	Positive SM	SSEA-1 and alkaline phosphatase[92,94]
	Negative SM	SSEA-3, SSEA-4, TRA-1-60, and TRA-1-81[92,94]
	TF	Oct-3/4, Sox2, Nanog, LIF, BMP, genesis, germ cell nuclear factor, GDF-3, FGF-4, UTF1, Fbx15, and Sall4[92,94,96]
Hematopoietic stem cells (expression of SM/TF)
Human	Positive SM	CD34, CD90, CD49R, and CD133[7,97,98]
	Negative SM	Lin, CD38, and CD45RA[7,97,98]
	TF	AHR, BMI1, GFI1, HES1, HLF, Runx-1, Scl/tal-1, Lmo-2, MII, Tel, and GATA-2[97,99]
Mouse	Positive SM	Sca-1, c-kit, CD49b, CD150, (endoglin), and Slamf1[7,97,100]
	Negative SM	Lin, FLT3, CD34, CD41, Flk2, and CD48[7,97,100]
	TF	Runx-1, Scl/tal-1, Lmo-2, MII, Tel, Bmi-1, Gfi-1, and GATA-2[99,101]
Multipotent stem cells (expression of SM/TF)
Human	Positive SM	CD146, CD44, CD13, CD73, CD90, CD105, and MHC class I[18,102]
	Negative SM	CD34, CD45, c-kit, KDR, CD56, CD271, CD140a, CD140b, and ALP[18,102]
	TF	Oct-4 Rex-1, Nanog, and BmI-1[102,103]
Mouse	Positive SM	c-Kit, CD9, CD13, CD31, SSEA-1, and Sca-1[17,104]
	Negative SM	CD3, CD19, CD34, CD44, CD45, c-Kit Thy1, Flk-1MHC-I, MHC class II, Gr-1, and Mac-1[17,104]
	TF	Oct-4, Rex-1, and Nanog[16,102]
Mesenchymal stem cells (expression of SM/TF)
Human	Positive SM	CD10, CD13, CD29, CD44, CD49e (a5-integrin), CD54 (intercellular adhesion molecule [ICAM]-1), CD58, CD71, CD73, CD90, CD105, CD140a, CD140b, CD146, CD166 (activated leukocyte cell adhesion molecule), CD271, Sca-1, ALP MHC class I, vimentin, cytokeratin (CK) 8, CK-18, and nestin[18,27-29]
	Negative SM	CD4, CD8, CD11a, CD11b, CD14, CD15, CD16, CD19, CD25, CD31, CD33, CD34, CD45, CD49b, CD49d, CD49f, CD50, CD56, CD62E, CD62L, CD62P, CD79a, CD80, CD86, CD106 (vascular cell adhesion molecule [VCAM]-1), CD117, CD271, c-kit, KDR, HLA-DR, cadherin V, and glycophorin A[18,27-29]
	TF	Oct-4, Rex-1, and Sox-2[105]
Mouse	Positive SM	CD29, CD44, CD73, CD90, CD105, and Sca-1, Thy1.2, and CD135[10,23,24,26,28]
	Negative SM	CD11b, CD14, CD31, CD34, CD45, and CD86, CD135, c-Kit, and VCAM-1[10,23,24,26,28]
	TF	HOX, stage-specific embryonic antigen 1 (SSEA-1), Nanog, Oct-4, Rex-1, and GATA-4[25]

SM: Surface marker; TF: Transcription factor.

Table 2 Calcium signaling toolkit

Component of toolkit	Name of calcium signaling toolkit components
Cell-surface receptors	G protein-coupled receptors and protein tyrosine kinase receptors such as muscarinic, bradykinin B2, cholecystokinin, α, β-adrenergic, P2X and P2Y, angiotensin II, Ca2+-sensing receptor, chemokine, metabotrophic glutamate, serotonin, oxytocin, epidermal growth factor receptor, and platelet-derived growth factor[46,106,107]
Calcium channels	Voltage-gated channels (Cav1.1 to 1.4 [L-type], Cav2.1 to 2.3 [N-, P/Q- and R-type] and Cav3.1 to 3.3 [T-type]) and two-pore channels (TPCs)[46], voltage-gated K+ channel, Ca2+-activated K+ channel, ATP-sensitive K+ channels, TRPC1-7 ORAI1-3, IP3R, and RyR2[108-110]
Calcium pumps and exchangers	Na+/Ca2+ exchangers, Na+/Ca2+-K+ exchangers, plasma membrane Ca2+-ATPase (PMCA) and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pumps[46,111]
Calcium buffers (Ca2+-binding proteins)	Cytoplasmic buffers (PV [parvalbumin], CB [calbindin D-28k], and calretinin)[112] and buffers in lumen of the endoplasmic reticulum (ER) (calsequestrin, calreticulin, glucose-regulated protein [GRP] 78 and GRP94), ERp72, and mitochondrial calcium uniporter (MCU), Golgi buffers (Cab45, CALNUC P54/NEFA[46,113], troponin C, myosin, calmodulin, and sarcolemma (cellular buffers in myocytes)[114]
Calcium sensors	EF-hand (CaM, TnC, calpains, miro1-2, S100A1-14, S100B, S100C, S100P, NCS-1, hippocalcin, neurocalcin, recoverin, VILIP1-3, GCAP1-3, MICU1 etc.) or C2 Ca2+-binding domains (annexin 1-13, otoferin, protein kinase C, RASAL etc.)[46], ER Ca2+ sensors STIM1 and STIM2[115]

Table 3 Stem cell transplantation therapy in disease

SCT	SCT therapy in preclinical condition
BMCs	Myelofibrosis[116]
HSCs	Fanconi anemia[117], chronic granulomatous disease[118], and Friedreich's ataxia[119]
MAPCs	Myocardial infarction[120], and neonatal hypoxic-ischemic injury[121]
MSCs	Musculoskeletal disease[122], spinal cord injury[123], liver fibrosis[124], idiopathic pneumonia syndrome[125], Alzheimer’s disease[126], and Parkinson's disease[127]
	SCT therapy in clinical condition
BMCs	Post-myocardial infarction[128], and sickle cell diseases[129]
HSCs	Sickle cell disease[130], human cytomegalovirus infection[131], childhood acute t-lymphoblastic leukemia[132], ankylosing spondylitis autoimmune disease[133], Crohn's disease[134], SARS-CoV-2[135], refractory lupus nephritis[136], Pemphigus disease[137], Richter syndrome[138]
MAPCs	Parkinson’s disease[139]
MSCs	Graft vs host disease[140], diabetes mellitus type 2[86], spinal cord injury[141], SARS-CoV-2[142], multiple sclerosis[143], systemic lupus erythematous[144]

BMCs: Bone marrow cells; HSCs: Hematopoietic stem cells; MAPCs: Multipotent adult progenitor stem cells; MSCs: Mesenchymal stem cells; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; SCT: Stem cell transplantation.