Exosomes derived from IFNγ-stimulated mesenchymal stem cells protect photoreceptors in RCS rats by restoring immune homeostasis through tsRNAs
Abstract Background Retinitis pigmentosa is a neurodegenerative disease with major pathologies of photoreceptor apoptosis and immune imbalance. Mesenchymal stem cells (MSCs) have been approved for clinical application for treating various immune-related or neurodegenerative diseases. The objective o...
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| Format: | Article |
| Language: | English |
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BMC
2024-11-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-024-01920-3 |
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| author | Luodan A Linghui Qu Juncai He Lingling Ge Hui Gao Xiaona Huang Tianjing You Hong Gong Qingle Liang Siyu Chen Jing Xie Haiwei Xu |
| author_facet | Luodan A Linghui Qu Juncai He Lingling Ge Hui Gao Xiaona Huang Tianjing You Hong Gong Qingle Liang Siyu Chen Jing Xie Haiwei Xu |
| author_sort | Luodan A |
| collection | DOAJ |
| description | Abstract Background Retinitis pigmentosa is a neurodegenerative disease with major pathologies of photoreceptor apoptosis and immune imbalance. Mesenchymal stem cells (MSCs) have been approved for clinical application for treating various immune-related or neurodegenerative diseases. The objective of this research was to investigate the mechanisms underlying the safeguarding effects of MSC-derived exosomes in a retinal degenerative disease model. Methods Interferon gamma-stimulated exosomes (IFNγ-Exos) secreted from MSCs were isolated, purified, and injected into the vitreous body of RCS rats on postnatal day (P) 21. Morphological and functional changes in the retina were examined at P28, P35, P42, and P49 in Royal College of Surgeons (RCS) rats. The mechanism was explored using high-throughput sequencing technology and confirmed in vitro. Results Treatment with IFNγ-Exo produced better protective effects on photoreceptors and improved visual function in RCS rats. IFNγ-Exo significantly suppressed the activated microglia and inhibited the inflammatory responses in the retina of RCS rats, which was also confirmed in the lipopolysaccharide-activated microglia cell line BV2. Furthermore, through tRNA-derived small RNA (tsRNA) sequencing, we found that IFNγ-Exos from MSCs contained higher levels of Other-1_17-tRNA-Phe-GAA-1-M3, Other-6_23-tRNA-Lys-TTT-3, and TRF-57:75-GLN-CGG-2-m2 than native exosomes, which mainly regulated inflammatory and immune-related pathways, including the mTOR signaling pathway and EGFR tyrosine kinase inhibitor resistance. Conclusions IFNγ stimulation enhanced the neuroprotective effects of MSC-derived exosomes on photoreceptors of the degenerative retina, which may be mediated by immune regulatory tsRNAs acting on microglia. In conclusion, IFNγ-Exo is a promising nanotherapeutic agent for the treatment of retinitis pigmentosa. Graphical Abstract |
| format | Article |
| id | doaj-art-971bfd24bb0d421ab85282eac9a260e4 |
| institution | Kabale University |
| issn | 1478-811X |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj-art-971bfd24bb0d421ab85282eac9a260e42024-11-17T12:38:45ZengBMCCell Communication and Signaling1478-811X2024-11-0122112510.1186/s12964-024-01920-3Exosomes derived from IFNγ-stimulated mesenchymal stem cells protect photoreceptors in RCS rats by restoring immune homeostasis through tsRNAsLuodan A0Linghui Qu1Juncai He2Lingling Ge3Hui Gao4Xiaona Huang5Tianjing You6Hong Gong7Qingle Liang8Siyu Chen9Jing Xie10Haiwei Xu11Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical UniversityKey Lab of Visual Damage and Regeneration & Restoration of ChongqingSouthwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical UniversitySouthwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical UniversitySouthwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical UniversitySouthwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical UniversitySouthwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical UniversityKey Lab of Visual Damage and Regeneration & Restoration of ChongqingDepartment of Clinical Laboratory Medicine, First Affiliated Hospital, Third Military Medical University (Army Medical University)Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical UniversitySouthwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical UniversitySouthwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical UniversityAbstract Background Retinitis pigmentosa is a neurodegenerative disease with major pathologies of photoreceptor apoptosis and immune imbalance. Mesenchymal stem cells (MSCs) have been approved for clinical application for treating various immune-related or neurodegenerative diseases. The objective of this research was to investigate the mechanisms underlying the safeguarding effects of MSC-derived exosomes in a retinal degenerative disease model. Methods Interferon gamma-stimulated exosomes (IFNγ-Exos) secreted from MSCs were isolated, purified, and injected into the vitreous body of RCS rats on postnatal day (P) 21. Morphological and functional changes in the retina were examined at P28, P35, P42, and P49 in Royal College of Surgeons (RCS) rats. The mechanism was explored using high-throughput sequencing technology and confirmed in vitro. Results Treatment with IFNγ-Exo produced better protective effects on photoreceptors and improved visual function in RCS rats. IFNγ-Exo significantly suppressed the activated microglia and inhibited the inflammatory responses in the retina of RCS rats, which was also confirmed in the lipopolysaccharide-activated microglia cell line BV2. Furthermore, through tRNA-derived small RNA (tsRNA) sequencing, we found that IFNγ-Exos from MSCs contained higher levels of Other-1_17-tRNA-Phe-GAA-1-M3, Other-6_23-tRNA-Lys-TTT-3, and TRF-57:75-GLN-CGG-2-m2 than native exosomes, which mainly regulated inflammatory and immune-related pathways, including the mTOR signaling pathway and EGFR tyrosine kinase inhibitor resistance. Conclusions IFNγ stimulation enhanced the neuroprotective effects of MSC-derived exosomes on photoreceptors of the degenerative retina, which may be mediated by immune regulatory tsRNAs acting on microglia. In conclusion, IFNγ-Exo is a promising nanotherapeutic agent for the treatment of retinitis pigmentosa. Graphical Abstracthttps://doi.org/10.1186/s12964-024-01920-3ExosomesRetinitis pigmentosaMesenchymal stem cellsInflammatory regulationImmunomodulation |
| spellingShingle | Luodan A Linghui Qu Juncai He Lingling Ge Hui Gao Xiaona Huang Tianjing You Hong Gong Qingle Liang Siyu Chen Jing Xie Haiwei Xu Exosomes derived from IFNγ-stimulated mesenchymal stem cells protect photoreceptors in RCS rats by restoring immune homeostasis through tsRNAs Cell Communication and Signaling Exosomes Retinitis pigmentosa Mesenchymal stem cells Inflammatory regulation Immunomodulation |
| title | Exosomes derived from IFNγ-stimulated mesenchymal stem cells protect photoreceptors in RCS rats by restoring immune homeostasis through tsRNAs |
| title_full | Exosomes derived from IFNγ-stimulated mesenchymal stem cells protect photoreceptors in RCS rats by restoring immune homeostasis through tsRNAs |
| title_fullStr | Exosomes derived from IFNγ-stimulated mesenchymal stem cells protect photoreceptors in RCS rats by restoring immune homeostasis through tsRNAs |
| title_full_unstemmed | Exosomes derived from IFNγ-stimulated mesenchymal stem cells protect photoreceptors in RCS rats by restoring immune homeostasis through tsRNAs |
| title_short | Exosomes derived from IFNγ-stimulated mesenchymal stem cells protect photoreceptors in RCS rats by restoring immune homeostasis through tsRNAs |
| title_sort | exosomes derived from ifnγ stimulated mesenchymal stem cells protect photoreceptors in rcs rats by restoring immune homeostasis through tsrnas |
| topic | Exosomes Retinitis pigmentosa Mesenchymal stem cells Inflammatory regulation Immunomodulation |
| url | https://doi.org/10.1186/s12964-024-01920-3 |
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