Cargando…

SU16f inhibits fibrotic scar formation and facilitates axon regeneration and locomotor function recovery after spinal cord injury by blocking the PDGFRβ pathway

BACKGROUND: Excessively deposited fibrotic scar after spinal cord injury (SCI) inhibits axon regeneration. It has been reported that platelet-derived growth factor receptor beta (PDGFRβ), as a marker of fibrotic scar-forming fibroblasts, can only be activated by platelet-derived growth factor (PDGF)...

Descripción completa

Detalles Bibliográficos
Autores principales: Li, Ziyu, Yu, Shuisheng, Liu, Yanchang, Hu, Xuyang, Li, Yiteng, Xiao, Zhaoming, Chen, Yihao, Tian, Dasheng, Xu, Xinzhong, Cheng, Li, Zheng, Meige, Jing, Juehua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9013464/
https://www.ncbi.nlm.nih.gov/pubmed/35429978
http://dx.doi.org/10.1186/s12974-022-02449-3
_version_ 1784688000706281472
author Li, Ziyu
Yu, Shuisheng
Liu, Yanchang
Hu, Xuyang
Li, Yiteng
Xiao, Zhaoming
Chen, Yihao
Tian, Dasheng
Xu, Xinzhong
Cheng, Li
Zheng, Meige
Jing, Juehua
author_facet Li, Ziyu
Yu, Shuisheng
Liu, Yanchang
Hu, Xuyang
Li, Yiteng
Xiao, Zhaoming
Chen, Yihao
Tian, Dasheng
Xu, Xinzhong
Cheng, Li
Zheng, Meige
Jing, Juehua
author_sort Li, Ziyu
collection PubMed
description BACKGROUND: Excessively deposited fibrotic scar after spinal cord injury (SCI) inhibits axon regeneration. It has been reported that platelet-derived growth factor receptor beta (PDGFRβ), as a marker of fibrotic scar-forming fibroblasts, can only be activated by platelet-derived growth factor (PDGF) B or PDGFD. However, whether the activation of the PDGFRβ pathway can mediate fibrotic scar formation after SCI remains unclear. METHODS: A spinal cord compression injury mouse model was used. In situ injection of exogenous PDGFB or PDGFD in the spinal cord was used to specifically activate the PDGFRβ pathway in the uninjured spinal cord, while intrathecal injection of SU16f was used to specifically block the PDGFRβ pathway in the uninjured or injured spinal cord. Immunofluorescence staining was performed to explore the distributions and cell sources of PDGFB and PDGFD, and to evaluate astrocytic scar, fibrotic scar, inflammatory cells and axon regeneration after SCI. Basso Mouse Scale (BMS) and footprint analysis were performed to evaluate locomotor function recovery after SCI. RESULTS: We found that the expression of PDGFD and PDGFB increased successively after SCI, and PDGFB was mainly secreted by astrocytes, while PDGFD was mainly secreted by macrophages/microglia and fibroblasts. In addition, in situ injection of exogenous PDGFB or PDGFD can lead to fibrosis in the uninjured spinal cord, while this profibrotic effect could be specifically blocked by the PDGFRβ inhibitor SU16f. We then treated the mice after SCI with SU16f and found the reduction of fibrotic scar, the interruption of scar boundary and the inhibition of lesion and inflammation, which promoted axon regeneration and locomotor function recovery after SCI. CONCLUSIONS: Our study demonstrates that activation of PDGFRβ pathway can directly induce fibrotic scar formation, and specific blocking of this pathway would contribute to the treatment of SCI.
format Online
Article
Text
id pubmed-9013464
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-90134642022-04-18 SU16f inhibits fibrotic scar formation and facilitates axon regeneration and locomotor function recovery after spinal cord injury by blocking the PDGFRβ pathway Li, Ziyu Yu, Shuisheng Liu, Yanchang Hu, Xuyang Li, Yiteng Xiao, Zhaoming Chen, Yihao Tian, Dasheng Xu, Xinzhong Cheng, Li Zheng, Meige Jing, Juehua J Neuroinflammation Research BACKGROUND: Excessively deposited fibrotic scar after spinal cord injury (SCI) inhibits axon regeneration. It has been reported that platelet-derived growth factor receptor beta (PDGFRβ), as a marker of fibrotic scar-forming fibroblasts, can only be activated by platelet-derived growth factor (PDGF) B or PDGFD. However, whether the activation of the PDGFRβ pathway can mediate fibrotic scar formation after SCI remains unclear. METHODS: A spinal cord compression injury mouse model was used. In situ injection of exogenous PDGFB or PDGFD in the spinal cord was used to specifically activate the PDGFRβ pathway in the uninjured spinal cord, while intrathecal injection of SU16f was used to specifically block the PDGFRβ pathway in the uninjured or injured spinal cord. Immunofluorescence staining was performed to explore the distributions and cell sources of PDGFB and PDGFD, and to evaluate astrocytic scar, fibrotic scar, inflammatory cells and axon regeneration after SCI. Basso Mouse Scale (BMS) and footprint analysis were performed to evaluate locomotor function recovery after SCI. RESULTS: We found that the expression of PDGFD and PDGFB increased successively after SCI, and PDGFB was mainly secreted by astrocytes, while PDGFD was mainly secreted by macrophages/microglia and fibroblasts. In addition, in situ injection of exogenous PDGFB or PDGFD can lead to fibrosis in the uninjured spinal cord, while this profibrotic effect could be specifically blocked by the PDGFRβ inhibitor SU16f. We then treated the mice after SCI with SU16f and found the reduction of fibrotic scar, the interruption of scar boundary and the inhibition of lesion and inflammation, which promoted axon regeneration and locomotor function recovery after SCI. CONCLUSIONS: Our study demonstrates that activation of PDGFRβ pathway can directly induce fibrotic scar formation, and specific blocking of this pathway would contribute to the treatment of SCI. BioMed Central 2022-04-16 /pmc/articles/PMC9013464/ /pubmed/35429978 http://dx.doi.org/10.1186/s12974-022-02449-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Li, Ziyu
Yu, Shuisheng
Liu, Yanchang
Hu, Xuyang
Li, Yiteng
Xiao, Zhaoming
Chen, Yihao
Tian, Dasheng
Xu, Xinzhong
Cheng, Li
Zheng, Meige
Jing, Juehua
SU16f inhibits fibrotic scar formation and facilitates axon regeneration and locomotor function recovery after spinal cord injury by blocking the PDGFRβ pathway
title SU16f inhibits fibrotic scar formation and facilitates axon regeneration and locomotor function recovery after spinal cord injury by blocking the PDGFRβ pathway
title_full SU16f inhibits fibrotic scar formation and facilitates axon regeneration and locomotor function recovery after spinal cord injury by blocking the PDGFRβ pathway
title_fullStr SU16f inhibits fibrotic scar formation and facilitates axon regeneration and locomotor function recovery after spinal cord injury by blocking the PDGFRβ pathway
title_full_unstemmed SU16f inhibits fibrotic scar formation and facilitates axon regeneration and locomotor function recovery after spinal cord injury by blocking the PDGFRβ pathway
title_short SU16f inhibits fibrotic scar formation and facilitates axon regeneration and locomotor function recovery after spinal cord injury by blocking the PDGFRβ pathway
title_sort su16f inhibits fibrotic scar formation and facilitates axon regeneration and locomotor function recovery after spinal cord injury by blocking the pdgfrβ pathway
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9013464/
https://www.ncbi.nlm.nih.gov/pubmed/35429978
http://dx.doi.org/10.1186/s12974-022-02449-3
work_keys_str_mv AT liziyu su16finhibitsfibroticscarformationandfacilitatesaxonregenerationandlocomotorfunctionrecoveryafterspinalcordinjurybyblockingthepdgfrbpathway
AT yushuisheng su16finhibitsfibroticscarformationandfacilitatesaxonregenerationandlocomotorfunctionrecoveryafterspinalcordinjurybyblockingthepdgfrbpathway
AT liuyanchang su16finhibitsfibroticscarformationandfacilitatesaxonregenerationandlocomotorfunctionrecoveryafterspinalcordinjurybyblockingthepdgfrbpathway
AT huxuyang su16finhibitsfibroticscarformationandfacilitatesaxonregenerationandlocomotorfunctionrecoveryafterspinalcordinjurybyblockingthepdgfrbpathway
AT liyiteng su16finhibitsfibroticscarformationandfacilitatesaxonregenerationandlocomotorfunctionrecoveryafterspinalcordinjurybyblockingthepdgfrbpathway
AT xiaozhaoming su16finhibitsfibroticscarformationandfacilitatesaxonregenerationandlocomotorfunctionrecoveryafterspinalcordinjurybyblockingthepdgfrbpathway
AT chenyihao su16finhibitsfibroticscarformationandfacilitatesaxonregenerationandlocomotorfunctionrecoveryafterspinalcordinjurybyblockingthepdgfrbpathway
AT tiandasheng su16finhibitsfibroticscarformationandfacilitatesaxonregenerationandlocomotorfunctionrecoveryafterspinalcordinjurybyblockingthepdgfrbpathway
AT xuxinzhong su16finhibitsfibroticscarformationandfacilitatesaxonregenerationandlocomotorfunctionrecoveryafterspinalcordinjurybyblockingthepdgfrbpathway
AT chengli su16finhibitsfibroticscarformationandfacilitatesaxonregenerationandlocomotorfunctionrecoveryafterspinalcordinjurybyblockingthepdgfrbpathway
AT zhengmeige su16finhibitsfibroticscarformationandfacilitatesaxonregenerationandlocomotorfunctionrecoveryafterspinalcordinjurybyblockingthepdgfrbpathway
AT jingjuehua su16finhibitsfibroticscarformationandfacilitatesaxonregenerationandlocomotorfunctionrecoveryafterspinalcordinjurybyblockingthepdgfrbpathway