International Journal of Immunology

| Peer-Reviewed |

Increase in Intracellular Calcium Concentration Induced Differentiation of Hematopoietic Stem Cells

Received: Jul. 24, 2019    Accepted: Sep. 10, 2019    Published: Jun. 03, 2020
Views:       Downloads:

Share This Article

Abstract

Calcium (Ca2+) is a key secondary messenger. It is responsible for the generation of intracellular signals which regulates the cellular division, differentiation and cell death. Intracellular calcium concentration ([Ca2+]i) is maintained at a 105-fold lower level than the extracellular calcium concentration. The rise in [Ca2+]i induces differentiation in stem cells and this increased [Ca2+]i also serves as an early indicator of cellular death by apoptosis. In haematological malignancies such as chronic myeloid leukaemia (CML), the cells are arrested in the megakaryocytic stage and are unable to differentiate into platelets. In this study, we treated two cell lines derived from CML patients-K562 and Marimo, with Ca2+ channel blockers (CCBs) - fendiline and BTP2. We examined the effects of CCBs on cellular differentiation and growth in the two cell lines. The [Ca2+]i was found to increase with the increasing concentration of the CCBs. The morphology of the cells was then examined under a light microscope. It was observed that this increasing [Ca2+]i subsequently induced differentiation in both the cell lines. Differentiation is closely linked with proliferation. At even higher concentrations (25 µM), it was observed that these CCBs led to a decline in the number of cells. Cell cycle analysis was then performed to verify if the CCBs had an apoptotic effect on the cell lines. On performing cell cycle analysis, it was concluded that these CCBs at a higher concentration triggered apoptosis in the cells. The results suggest that CCBs causes increase in the intracellular calcium concentration in the cell lines which leads to differentiation of the hematopoietic stem cells. In addition to this, these CCBs are toxic for the cells at high concentrations as they induce apoptosis in the cell lines.

DOI 10.11648/j.iji.20200802.12
Published in International Journal of Immunology ( Volume 8, Issue 2, June 2020 )
Page(s) 18-24
Creative Commons

This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.

Copyright

Copyright © The Author(s), 2024. Published by Science Publishing Group

Keywords

Calcium, Differentiation, Chronic Myeloid Leukaemia

References
[1] Parkash J, & Asotra K. Calcium wave signaling in cancer cells. Life Sciences. 2010; 87 (19-22): 587–595.
[2] Berridge MJ, Bootman MD & Roderick HL. Calcium signalling: Dynamics, homeostasis and re-modelling. Nature Reviews Molecular Cell Biology. 2003; 4: 517-529.
[3] Li GR, Sun H, Deng X, Lau CP. Characterization of ionic currents in human mesenchymal stem cells from bone marrow. Stem Cells. 2005; 23: 371–382.
[4] Schwarz DS & Blower MD. The endoplasmic reticulum: structure, function and response to cellular signaling. Cellular and Molecular Life Sciences. 2016; 73: 79–94.
[5] Jaken S, Yuspa SH. Early signals for keratinocyte differentiation: role of Ca2+-mediated inositol lipid metabolism in normal and neoplastic epidermal cells. Carcinogenesis. 1988; 9 (6): 1033–1038.
[6] Tonelli FM, Santos AK, Gomes DA, et al. Stem cells and calcium signaling. Adv Exp Med Biol. 2012; 740: 891–916.
[7] Tang W, Ziboh VA, Isseroff R, Martinez D. Turnover of inositol phospholipids in cultured murine keratinocytes: possible involvement of inositol triphosphate in cellular differentiation. J. Invest. Dermatol. h1988; 90 (1): 37–43.
[8] Moscat J, Fleming TP, Molloy CJ, Lopez-Barahona M, Aaronson SA. The calcium signal for Balb/MK keratinocyte terminal differentiation induces sustained alterations in phosphoinositide metabolism without detectable protein kinase C activation. J. Biol. Chem. 1989; 264 (19): 11228–11235.
[9] Sattler R., Tymianski M. Molecular mechanisms of calcium-dependent excitotoxicity. J. Mol. Med. 2000; 78: 3–13.
[10] Xu C, Bailly-Maitre B, Reed JC. Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest. 2005; 115 (10): 2656–2664.
[11] Pedriali G, Rimessi A, Sbano L, et al. Regulation of Endoplasmic Reticulum-Mitochondria Ca2+ Transfer and Its Importance for Anti-Cancer Therapies. Front Oncol. 2017; 7: 180.
[12] Hetz C, Chevet E, Oakes SA. Proteostasis control by the unfolded protein response [published correction appears in Nat Cell Biol. 2015 Aug; 17 (8): 1088]. Nat Cell Biol. 2015; 17 (7): 829–838.
[13] Walter P & Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011; 334: 1081-1086.
[14] Shore GC, Papa FR, Oakes SA. Signaling cell death from the endoplasmic reticulum stress response. Curr Opin Cell Biol. 2010; 23 (2): 143–149.
[15] Woods N, Trevino J, Coppola D, Chellappan S, Yang S & Padmanabhan J. Fendiline inhibits proliferation and invasion of pancreatic cancer cells by interfering with ADAM10 activation and β-catenin signaling. Oncotarget. 2015; 6 (34): 35931–35948.
[16] Núñez L, Valero RA, Senovilla L, Sanz-Blasco S, García-Sancho J, Villalobos C. Cell proliferation depends on mitochondrial Ca2+ uptake: inhibition by salicylate. J Physiol. 2005; 571 (Pt 1): 57–73.
[17] Jan CR, Yu CC & Huang JK. Dual effect of the antianginal drug fendiline on bladder female transitional carcinoma cells: Mobilization of intracellular Ca2+ and induction of cell death. Pharmacology. 2001; 62: 218-223.
[18] Lock JT, Parker I, & Smith IF. A comparison of fluorescent Ca2+indicators for imaging local Ca2+ signals in cultured cells. Cell Calcium. 2015; 58 (6): 638–648.
[19] Hotchkiss A, Feridooni T, Zhang F & Pasumarthi KB. The effects of calcium channel blockade on proliferation and differentiationof cardiac progenitor cells. Cell Calcium. 2014; 55 (5): 238-251.
[20] Lee CW, Sokoloski JA, Sartorelli AC, & Handschumacher RE. Induction of the differentiation of HL-60 cells by phorbol 12-myristate 13-acetate activates a Na (+) -dependent uridine-transport system. Involvement of protein kinase C. The Biochemical journal. 1991; 274: 85–90.
[21] Dekker ED, Heemskerk JWM & Gorter G et al. Cyclic AMP raises intracellular Ca2+ in human megakaryocytes independent of protein kinase A. Arteriosclerosis, Thrombosis and Vascular Biology. 2002; 22: 179-186.
[22] Mencalha AL, Corrêa S, Abdelhay E. Role of calcium-dependent protein kinases in chronic myeloid leukemia: combined effects of PKC and BCR-ABL signaling on cellular alterations during leukemia development. Onco Targets Ther. 2014; 7: 1247–1254.
[23] Hitchcock, I. S., Kaushansky, K. Thrombopoietin from beginning to end. British Journal of Haematology. 2014; 165 (2): 259-68.
[24] Duchen MR. Mitochondria and calcium: from cell signalling to cell death. The Journal of Physiology. 2000; 529 (1): 57–68.
[25] Orrenius S, Zhivotovsky B, Nicotera P. Regulation of cell death: the calcium–apoptosis link. Nature Reviews Molecular Cell Biology. 2003; 4: 552–565.
Cite This Article
  • APA Style

    Aditi Singh, Elcim Eroglulari, Athar Aziz. (2020). Increase in Intracellular Calcium Concentration Induced Differentiation of Hematopoietic Stem Cells. International Journal of Immunology, 8(2), 18-24. https://doi.org/10.11648/j.iji.20200802.12

    Copy | Download

    ACS Style

    Aditi Singh; Elcim Eroglulari; Athar Aziz. Increase in Intracellular Calcium Concentration Induced Differentiation of Hematopoietic Stem Cells. Int. J. Immunol. 2020, 8(2), 18-24. doi: 10.11648/j.iji.20200802.12

    Copy | Download

    AMA Style

    Aditi Singh, Elcim Eroglulari, Athar Aziz. Increase in Intracellular Calcium Concentration Induced Differentiation of Hematopoietic Stem Cells. Int J Immunol. 2020;8(2):18-24. doi: 10.11648/j.iji.20200802.12

    Copy | Download

  • @article{10.11648/j.iji.20200802.12,
      author = {Aditi Singh and Elcim Eroglulari and Athar Aziz},
      title = {Increase in Intracellular Calcium Concentration Induced Differentiation of Hematopoietic Stem Cells},
      journal = {International Journal of Immunology},
      volume = {8},
      number = {2},
      pages = {18-24},
      doi = {10.11648/j.iji.20200802.12},
      url = {https://doi.org/10.11648/j.iji.20200802.12},
      eprint = {https://download.sciencepg.com/pdf/10.11648.j.iji.20200802.12},
      abstract = {Calcium (Ca2+) is a key secondary messenger. It is responsible for the generation of intracellular signals which regulates the cellular division, differentiation and cell death. Intracellular calcium concentration ([Ca2+]i) is maintained at a 105-fold lower level than the extracellular calcium concentration. The rise in [Ca2+]i induces differentiation in stem cells and this increased [Ca2+]i also serves as an early indicator of cellular death by apoptosis. In haematological malignancies such as chronic myeloid leukaemia (CML), the cells are arrested in the megakaryocytic stage and are unable to differentiate into platelets. In this study, we treated two cell lines derived from CML patients-K562 and Marimo, with Ca2+ channel blockers (CCBs) - fendiline and BTP2. We examined the effects of CCBs on cellular differentiation and growth in the two cell lines. The [Ca2+]i was found to increase with the increasing concentration of the CCBs. The morphology of the cells was then examined under a light microscope. It was observed that this increasing [Ca2+]i subsequently induced differentiation in both the cell lines. Differentiation is closely linked with proliferation. At even higher concentrations (25 µM), it was observed that these CCBs led to a decline in the number of cells. Cell cycle analysis was then performed to verify if the CCBs had an apoptotic effect on the cell lines. On performing cell cycle analysis, it was concluded that these CCBs at a higher concentration triggered apoptosis in the cells. The results suggest that CCBs causes increase in the intracellular calcium concentration in the cell lines which leads to differentiation of the hematopoietic stem cells. In addition to this, these CCBs are toxic for the cells at high concentrations as they induce apoptosis in the cell lines.},
     year = {2020}
    }
    

    Copy | Download

  • TY  - JOUR
    T1  - Increase in Intracellular Calcium Concentration Induced Differentiation of Hematopoietic Stem Cells
    AU  - Aditi Singh
    AU  - Elcim Eroglulari
    AU  - Athar Aziz
    Y1  - 2020/06/03
    PY  - 2020
    N1  - https://doi.org/10.11648/j.iji.20200802.12
    DO  - 10.11648/j.iji.20200802.12
    T2  - International Journal of Immunology
    JF  - International Journal of Immunology
    JO  - International Journal of Immunology
    SP  - 18
    EP  - 24
    PB  - Science Publishing Group
    SN  - 2329-1753
    UR  - https://doi.org/10.11648/j.iji.20200802.12
    AB  - Calcium (Ca2+) is a key secondary messenger. It is responsible for the generation of intracellular signals which regulates the cellular division, differentiation and cell death. Intracellular calcium concentration ([Ca2+]i) is maintained at a 105-fold lower level than the extracellular calcium concentration. The rise in [Ca2+]i induces differentiation in stem cells and this increased [Ca2+]i also serves as an early indicator of cellular death by apoptosis. In haematological malignancies such as chronic myeloid leukaemia (CML), the cells are arrested in the megakaryocytic stage and are unable to differentiate into platelets. In this study, we treated two cell lines derived from CML patients-K562 and Marimo, with Ca2+ channel blockers (CCBs) - fendiline and BTP2. We examined the effects of CCBs on cellular differentiation and growth in the two cell lines. The [Ca2+]i was found to increase with the increasing concentration of the CCBs. The morphology of the cells was then examined under a light microscope. It was observed that this increasing [Ca2+]i subsequently induced differentiation in both the cell lines. Differentiation is closely linked with proliferation. At even higher concentrations (25 µM), it was observed that these CCBs led to a decline in the number of cells. Cell cycle analysis was then performed to verify if the CCBs had an apoptotic effect on the cell lines. On performing cell cycle analysis, it was concluded that these CCBs at a higher concentration triggered apoptosis in the cells. The results suggest that CCBs causes increase in the intracellular calcium concentration in the cell lines which leads to differentiation of the hematopoietic stem cells. In addition to this, these CCBs are toxic for the cells at high concentrations as they induce apoptosis in the cell lines.
    VL  - 8
    IS  - 2
    ER  - 

    Copy | Download

Author Information
  • Laboratory of Translational Medicine, University of Salford, Manchester, UK

  • Laboratory of Translational Medicine, University of Salford, Manchester, UK

  • Department of Biomedical Sciences, University of Salford, Manchester, UK

  • Section