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Cyclosporin A enhances neural precursor cell survival in mice through a calcineurin-independent pathway

Cyclosporin A (CsA) has direct effects on neural stem and progenitor cells (together termed neural precursor cells; NPCs) in the adult central nervous system. Administration of CsA in vitro or in vivo promotes the survival of NPCs and expands the pools of NPCs in mice. Moreover, CsA administration i...

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Autores principales: Sachewsky, Nadia, Hunt, Jessica, Cooke, Michael J., Azimi, Ashkan, Zarin, Taraneh, Miu, Carween, Shoichet, Molly S., Morshead, Cindi M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Limited 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4107324/
https://www.ncbi.nlm.nih.gov/pubmed/25056698
http://dx.doi.org/10.1242/dmm.014480
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author Sachewsky, Nadia
Hunt, Jessica
Cooke, Michael J.
Azimi, Ashkan
Zarin, Taraneh
Miu, Carween
Shoichet, Molly S.
Morshead, Cindi M.
author_facet Sachewsky, Nadia
Hunt, Jessica
Cooke, Michael J.
Azimi, Ashkan
Zarin, Taraneh
Miu, Carween
Shoichet, Molly S.
Morshead, Cindi M.
author_sort Sachewsky, Nadia
collection PubMed
description Cyclosporin A (CsA) has direct effects on neural stem and progenitor cells (together termed neural precursor cells; NPCs) in the adult central nervous system. Administration of CsA in vitro or in vivo promotes the survival of NPCs and expands the pools of NPCs in mice. Moreover, CsA administration is effective in promoting NPC activation, tissue repair and functional recovery in a mouse model of cortical stroke. The mechanism(s) by which CsA mediates this cell survival effect remains unknown. Herein, we examined both calcineurin-dependent and calcineurin-independent pathways through which CsA might mediate NPC survival. To examine calcineurin-dependent pathways, we utilized FK506 (Tacrolimus), an immunosuppressive molecule that inhibits calcineurin, as well as drugs that inhibit cyclophilin A-mediated activation of calcineurin. To evaluate the calcineurin-independent pathway, we utilized NIM811, a non-immunosuppressive CsA analog that functions independently of calcineurin by blocking mitochondrial permeability transition pore formation. We found that only NIM811 can entirely account for the pro-survival effects of CsA on NPCs. Indeed, blocking signaling pathways downstream of calcineurin activation using nNOS mice did not inhibit CsA-mediated cell survival, which supports the proposal that the effects are calcinuerin-independent. In vivo studies revealed that NIM811 administration mimics the pro-survival effects of CsA on NPCs and promotes functional recovery in a model of cortical stroke, identical to the effects seen with CsA administration. We conclude that CsA mediates its effect on NPC survival through calcineurin-independent inhibition of mitochondrial permeability transition pore formation and suggest that this pathway has potential therapeutic benefits for developing NPC-mediated cell replacement strategies.
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spelling pubmed-41073242014-08-27 Cyclosporin A enhances neural precursor cell survival in mice through a calcineurin-independent pathway Sachewsky, Nadia Hunt, Jessica Cooke, Michael J. Azimi, Ashkan Zarin, Taraneh Miu, Carween Shoichet, Molly S. Morshead, Cindi M. Dis Model Mech Research Article Cyclosporin A (CsA) has direct effects on neural stem and progenitor cells (together termed neural precursor cells; NPCs) in the adult central nervous system. Administration of CsA in vitro or in vivo promotes the survival of NPCs and expands the pools of NPCs in mice. Moreover, CsA administration is effective in promoting NPC activation, tissue repair and functional recovery in a mouse model of cortical stroke. The mechanism(s) by which CsA mediates this cell survival effect remains unknown. Herein, we examined both calcineurin-dependent and calcineurin-independent pathways through which CsA might mediate NPC survival. To examine calcineurin-dependent pathways, we utilized FK506 (Tacrolimus), an immunosuppressive molecule that inhibits calcineurin, as well as drugs that inhibit cyclophilin A-mediated activation of calcineurin. To evaluate the calcineurin-independent pathway, we utilized NIM811, a non-immunosuppressive CsA analog that functions independently of calcineurin by blocking mitochondrial permeability transition pore formation. We found that only NIM811 can entirely account for the pro-survival effects of CsA on NPCs. Indeed, blocking signaling pathways downstream of calcineurin activation using nNOS mice did not inhibit CsA-mediated cell survival, which supports the proposal that the effects are calcinuerin-independent. In vivo studies revealed that NIM811 administration mimics the pro-survival effects of CsA on NPCs and promotes functional recovery in a model of cortical stroke, identical to the effects seen with CsA administration. We conclude that CsA mediates its effect on NPC survival through calcineurin-independent inhibition of mitochondrial permeability transition pore formation and suggest that this pathway has potential therapeutic benefits for developing NPC-mediated cell replacement strategies. The Company of Biologists Limited 2014-08 /pmc/articles/PMC4107324/ /pubmed/25056698 http://dx.doi.org/10.1242/dmm.014480 Text en © 2014. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Sachewsky, Nadia
Hunt, Jessica
Cooke, Michael J.
Azimi, Ashkan
Zarin, Taraneh
Miu, Carween
Shoichet, Molly S.
Morshead, Cindi M.
Cyclosporin A enhances neural precursor cell survival in mice through a calcineurin-independent pathway
title Cyclosporin A enhances neural precursor cell survival in mice through a calcineurin-independent pathway
title_full Cyclosporin A enhances neural precursor cell survival in mice through a calcineurin-independent pathway
title_fullStr Cyclosporin A enhances neural precursor cell survival in mice through a calcineurin-independent pathway
title_full_unstemmed Cyclosporin A enhances neural precursor cell survival in mice through a calcineurin-independent pathway
title_short Cyclosporin A enhances neural precursor cell survival in mice through a calcineurin-independent pathway
title_sort cyclosporin a enhances neural precursor cell survival in mice through a calcineurin-independent pathway
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4107324/
https://www.ncbi.nlm.nih.gov/pubmed/25056698
http://dx.doi.org/10.1242/dmm.014480
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