Selective cargo sorting in stem cell‐derived small extracellular vesicles: impact on therapeutic efficacy for intervertebral disc degeneration
Abstract Background Growing evidence has suggested the role of stem cell‐derived small extracellular vesicles (sEVs) in intervertebral disc degeneration (IVDD). The cargo sorting of sEVs, particularly miRNAs, may be influenced when the donor cell is subjected to oxidative stress. Here, we discovered...
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| Format: | Article |
| Language: | English |
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Wiley
2023-12-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.1494 |
| _version_ | 1827397687398367232 |
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| author | Zhiwei Liao Bide Tong Xiaoguang Zhang Weifeng Zhang Wencan Ke Huaizhen Liang Ming Lei Wenbin Hua Shuai Li Yu Song Xinghuo Wu Cao Yang |
| author_facet | Zhiwei Liao Bide Tong Xiaoguang Zhang Weifeng Zhang Wencan Ke Huaizhen Liang Ming Lei Wenbin Hua Shuai Li Yu Song Xinghuo Wu Cao Yang |
| author_sort | Zhiwei Liao |
| collection | DOAJ |
| description | Abstract Background Growing evidence has suggested the role of stem cell‐derived small extracellular vesicles (sEVs) in intervertebral disc degeneration (IVDD). The cargo sorting of sEVs, particularly miRNAs, may be influenced when the donor cell is subjected to oxidative stress. Here, we discovered that miRNAs containing specific motifs are selectively sorted into intraluminal vesicles within mesenchymal stem cells (MSCs) in response to oxidative stress. Methods Analysis of miRNA cargoes in sEVs derived from normal MSCs (C‐sEVs) or stressed MSCs (T‐sEVs) was conducted using miRNA sequencing. Differential expressed miRNAs in sEVs and the identification of motifs were evaluated through bioinformatics analysis. Protein binding was assessed using immunofluorescent staining and immunoprecipitation analysis. Additionally, RNA pull down and RNA immunoprecipitation (RIP) immunoprecipitation were employed to determine the binding between miRNAs and proteins. The effects of C‐sEVs and T‐sEVs on IVDD were compared by detecting the expression levels of phenotypic genes in vitro or histological evaluation in vivo. Results The sorting process of miRNAs is mediated by the nucleocytoplasmic transport of heterogeneous nuclear ribonucleoproteins, which in turn facilitates the phosphorylation of SNAP25 and promotes the transport and secretion of sEVs. Additionally, CHMP1B plays a role in membrane repair and protects against cell ferroptosis upon oxidative stress, concurrently affecting the release of sEVs. Notably, stem cell‐derived sEVs associated with ferroptosis impair the therapeutic efficacy for IVDD. However, the application of engineered sEVs containing a specific miRNA inhibitor exhibits the potential to reinstate the therapeutic efficacy for IVDD both in vitro and in vivo. Conclusions Taken together, our findings shed light on the mechanism of miRNAs sorting into sEVs and offer new insights for the optimization of sEV‐based treatments during intervertebral disc regeneration. regeneration. |
| first_indexed | 2024-03-08T19:15:12Z |
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| id | doaj.art-11858d7c60dc4f62ba312da7d6a9e6ba |
| institution | Directory Open Access Journal |
| issn | 2001-1326 |
| language | English |
| last_indexed | 2024-03-08T19:15:12Z |
| publishDate | 2023-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Medicine |
| spelling | doaj.art-11858d7c60dc4f62ba312da7d6a9e6ba2023-12-27T07:30:35ZengWileyClinical and Translational Medicine2001-13262023-12-011312n/an/a10.1002/ctm2.1494Selective cargo sorting in stem cell‐derived small extracellular vesicles: impact on therapeutic efficacy for intervertebral disc degenerationZhiwei Liao0Bide Tong1Xiaoguang Zhang2Weifeng Zhang3Wencan Ke4Huaizhen Liang5Ming Lei6Wenbin Hua7Shuai Li8Yu Song9Xinghuo Wu10Cao Yang11Department of Orthopaedics Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan ChinaDepartment of Orthopaedics Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan ChinaDepartment of Orthopaedics Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan ChinaDepartment of Orthopaedics Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan ChinaDepartment of Orthopaedics Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan ChinaDepartment of Orthopaedics Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan ChinaDepartment of Orthopaedics Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan ChinaDepartment of Orthopaedics Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan ChinaDepartment of Orthopaedics Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan ChinaDepartment of Orthopaedics Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan ChinaDepartment of Orthopaedics Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan ChinaDepartment of Orthopaedics Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan ChinaAbstract Background Growing evidence has suggested the role of stem cell‐derived small extracellular vesicles (sEVs) in intervertebral disc degeneration (IVDD). The cargo sorting of sEVs, particularly miRNAs, may be influenced when the donor cell is subjected to oxidative stress. Here, we discovered that miRNAs containing specific motifs are selectively sorted into intraluminal vesicles within mesenchymal stem cells (MSCs) in response to oxidative stress. Methods Analysis of miRNA cargoes in sEVs derived from normal MSCs (C‐sEVs) or stressed MSCs (T‐sEVs) was conducted using miRNA sequencing. Differential expressed miRNAs in sEVs and the identification of motifs were evaluated through bioinformatics analysis. Protein binding was assessed using immunofluorescent staining and immunoprecipitation analysis. Additionally, RNA pull down and RNA immunoprecipitation (RIP) immunoprecipitation were employed to determine the binding between miRNAs and proteins. The effects of C‐sEVs and T‐sEVs on IVDD were compared by detecting the expression levels of phenotypic genes in vitro or histological evaluation in vivo. Results The sorting process of miRNAs is mediated by the nucleocytoplasmic transport of heterogeneous nuclear ribonucleoproteins, which in turn facilitates the phosphorylation of SNAP25 and promotes the transport and secretion of sEVs. Additionally, CHMP1B plays a role in membrane repair and protects against cell ferroptosis upon oxidative stress, concurrently affecting the release of sEVs. Notably, stem cell‐derived sEVs associated with ferroptosis impair the therapeutic efficacy for IVDD. However, the application of engineered sEVs containing a specific miRNA inhibitor exhibits the potential to reinstate the therapeutic efficacy for IVDD both in vitro and in vivo. Conclusions Taken together, our findings shed light on the mechanism of miRNAs sorting into sEVs and offer new insights for the optimization of sEV‐based treatments during intervertebral disc regeneration. regeneration.https://doi.org/10.1002/ctm2.1494extracellular vesiclesferroptosisintervertebral disc regenerationmiRNA sortingoxidative stress |
| spellingShingle | Zhiwei Liao Bide Tong Xiaoguang Zhang Weifeng Zhang Wencan Ke Huaizhen Liang Ming Lei Wenbin Hua Shuai Li Yu Song Xinghuo Wu Cao Yang Selective cargo sorting in stem cell‐derived small extracellular vesicles: impact on therapeutic efficacy for intervertebral disc degeneration Clinical and Translational Medicine extracellular vesicles ferroptosis intervertebral disc regeneration miRNA sorting oxidative stress |
| title | Selective cargo sorting in stem cell‐derived small extracellular vesicles: impact on therapeutic efficacy for intervertebral disc degeneration |
| title_full | Selective cargo sorting in stem cell‐derived small extracellular vesicles: impact on therapeutic efficacy for intervertebral disc degeneration |
| title_fullStr | Selective cargo sorting in stem cell‐derived small extracellular vesicles: impact on therapeutic efficacy for intervertebral disc degeneration |
| title_full_unstemmed | Selective cargo sorting in stem cell‐derived small extracellular vesicles: impact on therapeutic efficacy for intervertebral disc degeneration |
| title_short | Selective cargo sorting in stem cell‐derived small extracellular vesicles: impact on therapeutic efficacy for intervertebral disc degeneration |
| title_sort | selective cargo sorting in stem cell derived small extracellular vesicles impact on therapeutic efficacy for intervertebral disc degeneration |
| topic | extracellular vesicles ferroptosis intervertebral disc regeneration miRNA sorting oxidative stress |
| url | https://doi.org/10.1002/ctm2.1494 |
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