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Inhibiting Heat Shock Protein 90 Protects Nucleus Pulposus-Derived Stem/Progenitor Cells From Compression-Induced Necroptosis and Apoptosis

Nucleus pulposus-derived stem/progenitor cells (NPSCs) provide novel prospects for the regeneration of degenerated intervertebral disc (IVD). Nevertheless, with aging and degeneration of IVD, the frequency of NPSCs markedly decreases. Excessive cell death could be the main reason for declined freque...

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Autores principales: Hu, Binwu, Zhang, Shuo, Liu, Weijian, Wang, Peng, Chen, Songfeng, Lv, Xiao, Shi, Deyao, Ma, Kaige, Wang, Baichuan, Wu, Yongchao, Shao, Zengwu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427414/
https://www.ncbi.nlm.nih.gov/pubmed/32850811
http://dx.doi.org/10.3389/fcell.2020.00685
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author Hu, Binwu
Zhang, Shuo
Liu, Weijian
Wang, Peng
Chen, Songfeng
Lv, Xiao
Shi, Deyao
Ma, Kaige
Wang, Baichuan
Wu, Yongchao
Shao, Zengwu
author_facet Hu, Binwu
Zhang, Shuo
Liu, Weijian
Wang, Peng
Chen, Songfeng
Lv, Xiao
Shi, Deyao
Ma, Kaige
Wang, Baichuan
Wu, Yongchao
Shao, Zengwu
author_sort Hu, Binwu
collection PubMed
description Nucleus pulposus-derived stem/progenitor cells (NPSCs) provide novel prospects for the regeneration of degenerated intervertebral disc (IVD). Nevertheless, with aging and degeneration of IVD, the frequency of NPSCs markedly decreases. Excessive cell death could be the main reason for declined frequency of NPSCs, however, the exact mechanisms remain elusive. Thus, the present study was undertaken to explore the mechanisms of compression-induced NPSCs death, and the effects of heat shock protein 90 (HSP90) on NPSCs survival. Here, we found that compression could trigger receptor-interacting protein kinase 1 (RIPK1)/receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis of NPSCs. Furthermore, we found that elevated expression of HSP90 was involved in compression-induced NPSCs death, and inhibiting HSP90 could dramatically attenuate compression-induced necroptosis of NPSCs via regulating the expression and activity of RIPK1/RIPK3/MLKL, and alleviating the mitochondrial dysfunction (mitochondrial membrane potential loss and ATP depletion) and oxidative stress [production of mitochondrial reactive oxygen species (ROS), cellular total ROS and malondialdehyde, and downregulation of superoxide dismutase 2]. Besides necroptosis, compression-induced apoptosis of NPSCs was also attenuated by HSP90 inhibition. In addition, we found that enhanced expression of HSP70 contributed to the cytoprotective effects of inhibiting HSP90. More encouragingly, our results demonstrated that inhibiting HSP90 could also mitigate the exhaustion of NPSCs in vivo. In conclusion, RIPK1/RIPK3/MLKL-mediated necroptosis participates in compression-induced NPSCs death. Furthermore, targeting HSP90 to simultaneously inhibit necroptosis and apoptosis of NPSCs might be an efficient strategy for preventing the death of NPSCs, thus rescuing the endogenous repair capacity of NP tissue.
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spelling pubmed-74274142020-08-25 Inhibiting Heat Shock Protein 90 Protects Nucleus Pulposus-Derived Stem/Progenitor Cells From Compression-Induced Necroptosis and Apoptosis Hu, Binwu Zhang, Shuo Liu, Weijian Wang, Peng Chen, Songfeng Lv, Xiao Shi, Deyao Ma, Kaige Wang, Baichuan Wu, Yongchao Shao, Zengwu Front Cell Dev Biol Cell and Developmental Biology Nucleus pulposus-derived stem/progenitor cells (NPSCs) provide novel prospects for the regeneration of degenerated intervertebral disc (IVD). Nevertheless, with aging and degeneration of IVD, the frequency of NPSCs markedly decreases. Excessive cell death could be the main reason for declined frequency of NPSCs, however, the exact mechanisms remain elusive. Thus, the present study was undertaken to explore the mechanisms of compression-induced NPSCs death, and the effects of heat shock protein 90 (HSP90) on NPSCs survival. Here, we found that compression could trigger receptor-interacting protein kinase 1 (RIPK1)/receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis of NPSCs. Furthermore, we found that elevated expression of HSP90 was involved in compression-induced NPSCs death, and inhibiting HSP90 could dramatically attenuate compression-induced necroptosis of NPSCs via regulating the expression and activity of RIPK1/RIPK3/MLKL, and alleviating the mitochondrial dysfunction (mitochondrial membrane potential loss and ATP depletion) and oxidative stress [production of mitochondrial reactive oxygen species (ROS), cellular total ROS and malondialdehyde, and downregulation of superoxide dismutase 2]. Besides necroptosis, compression-induced apoptosis of NPSCs was also attenuated by HSP90 inhibition. In addition, we found that enhanced expression of HSP70 contributed to the cytoprotective effects of inhibiting HSP90. More encouragingly, our results demonstrated that inhibiting HSP90 could also mitigate the exhaustion of NPSCs in vivo. In conclusion, RIPK1/RIPK3/MLKL-mediated necroptosis participates in compression-induced NPSCs death. Furthermore, targeting HSP90 to simultaneously inhibit necroptosis and apoptosis of NPSCs might be an efficient strategy for preventing the death of NPSCs, thus rescuing the endogenous repair capacity of NP tissue. Frontiers Media S.A. 2020-08-07 /pmc/articles/PMC7427414/ /pubmed/32850811 http://dx.doi.org/10.3389/fcell.2020.00685 Text en Copyright © 2020 Hu, Zhang, Liu, Wang, Chen, Lv, Shi, Ma, Wang, Wu and Shao. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Hu, Binwu
Zhang, Shuo
Liu, Weijian
Wang, Peng
Chen, Songfeng
Lv, Xiao
Shi, Deyao
Ma, Kaige
Wang, Baichuan
Wu, Yongchao
Shao, Zengwu
Inhibiting Heat Shock Protein 90 Protects Nucleus Pulposus-Derived Stem/Progenitor Cells From Compression-Induced Necroptosis and Apoptosis
title Inhibiting Heat Shock Protein 90 Protects Nucleus Pulposus-Derived Stem/Progenitor Cells From Compression-Induced Necroptosis and Apoptosis
title_full Inhibiting Heat Shock Protein 90 Protects Nucleus Pulposus-Derived Stem/Progenitor Cells From Compression-Induced Necroptosis and Apoptosis
title_fullStr Inhibiting Heat Shock Protein 90 Protects Nucleus Pulposus-Derived Stem/Progenitor Cells From Compression-Induced Necroptosis and Apoptosis
title_full_unstemmed Inhibiting Heat Shock Protein 90 Protects Nucleus Pulposus-Derived Stem/Progenitor Cells From Compression-Induced Necroptosis and Apoptosis
title_short Inhibiting Heat Shock Protein 90 Protects Nucleus Pulposus-Derived Stem/Progenitor Cells From Compression-Induced Necroptosis and Apoptosis
title_sort inhibiting heat shock protein 90 protects nucleus pulposus-derived stem/progenitor cells from compression-induced necroptosis and apoptosis
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427414/
https://www.ncbi.nlm.nih.gov/pubmed/32850811
http://dx.doi.org/10.3389/fcell.2020.00685
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