Extracellular Vesicle-Conjugated Functional Matrix Hydrogels Prevent Senescence by Exosomal miR-3594-5p-Targeted HIPK2/p53 Pathway for Disc Regeneration
© 2023 The Authors. Small published by Wiley-VCH GmbH..
Nucleus pulposus stem cells (NPSCs) senescence plays a critical role in the progression of intervertebral disc degeneration (IDD). Stem cell-derived extracellular vesicles (EV) alleviate cellular senescence. Whereas, the underlying mechanism remains unclear. Low stability largely limited the administration of EV in vivo. RGD, an arginine-glycine-aspartic acid tripeptide, strongly binds integrins expressed on the EV membranes, allowing RGD to anchor EV and prolong their bioavailability. An RGD-complexed nucleus pulposus matrix hydrogel (RGD-DNP) is developed to enhance the therapeutic effects of small EV (sEV). RGD-DNP prolonged sEV retention in vitro and ex vivo. sEV-RGD-DNP promoted NPSCs migration, decreased the number of SA-β-gal-positive cells, alleviated cell cycle arrest, and reduced p16, p21, and p53 activation. Small RNA-seq showed that miR-3594-5p is enriched in sEV, and targets the homeodomain-interacting protein kinase 2 (HIPK2)/p53 pathway. The HIPK2 knockdown rescues the impaired therapeutic effects of sEV with downregulated miR-3594-5p. RGD-DNP conjugate with lower amounts of sEV achieved similar disc regeneration with free sEV of higher concentrations in DNP. In conclusion, sEV-RGD-DNP increases sEV bioavailability and relieves NPSCs senescence by targeting the HIPK2/p53 pathway, thereby alleviating IDD. This work achieves better regenerative effects with fewer sEV and consolidates the theoretical basis for sEV application for IDD treatment.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:19 |
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| Enthalten in: |
Small (Weinheim an der Bergstrasse, Germany) - 19(2023), 37 vom: 05. Sept., Seite e2206888 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Peng, Yizhong [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.09.2023 Date Revised 29.09.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/smll.202206888 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM356686264 |
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| 100 | 1 | |a Peng, Yizhong |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Extracellular Vesicle-Conjugated Functional Matrix Hydrogels Prevent Senescence by Exosomal miR-3594-5p-Targeted HIPK2/p53 Pathway for Disc Regeneration |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Completed 14.09.2023 | ||
| 500 | |a Date Revised 29.09.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 The Authors. Small published by Wiley-VCH GmbH. | ||
| 520 | |a Nucleus pulposus stem cells (NPSCs) senescence plays a critical role in the progression of intervertebral disc degeneration (IDD). Stem cell-derived extracellular vesicles (EV) alleviate cellular senescence. Whereas, the underlying mechanism remains unclear. Low stability largely limited the administration of EV in vivo. RGD, an arginine-glycine-aspartic acid tripeptide, strongly binds integrins expressed on the EV membranes, allowing RGD to anchor EV and prolong their bioavailability. An RGD-complexed nucleus pulposus matrix hydrogel (RGD-DNP) is developed to enhance the therapeutic effects of small EV (sEV). RGD-DNP prolonged sEV retention in vitro and ex vivo. sEV-RGD-DNP promoted NPSCs migration, decreased the number of SA-β-gal-positive cells, alleviated cell cycle arrest, and reduced p16, p21, and p53 activation. Small RNA-seq showed that miR-3594-5p is enriched in sEV, and targets the homeodomain-interacting protein kinase 2 (HIPK2)/p53 pathway. The HIPK2 knockdown rescues the impaired therapeutic effects of sEV with downregulated miR-3594-5p. RGD-DNP conjugate with lower amounts of sEV achieved similar disc regeneration with free sEV of higher concentrations in DNP. In conclusion, sEV-RGD-DNP increases sEV bioavailability and relieves NPSCs senescence by targeting the HIPK2/p53 pathway, thereby alleviating IDD. This work achieves better regenerative effects with fewer sEV and consolidates the theoretical basis for sEV application for IDD treatment | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a RGD | |
| 650 | 4 | |a extracellular vesicles | |
| 650 | 4 | |a intervertebral discs | |
| 650 | 4 | |a senescences | |
| 650 | 4 | |a stem cells | |
| 650 | 7 | |a Tumor Suppressor Protein p53 |2 NLM | |
| 650 | 7 | |a MicroRNAs |2 NLM | |
| 650 | 7 | |a Oligopeptides |2 NLM | |
| 650 | 7 | |a HIPK2 protein, human |2 NLM | |
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| 650 | 7 | |a Carrier Proteins |2 NLM | |
| 650 | 7 | |a Protein Serine-Threonine Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 700 | 1 | |a Chen, Xuanzuo |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Sheng |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Shu, Hongyang |e verfasserin |4 aut | |
| 700 | 1 | |a Tian, Shuo |e verfasserin |4 aut | |
| 700 | 1 | |a Xiao, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Kanglu |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, BaiChuan |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Qing, Xiangcheng |e verfasserin |4 aut | |
| 700 | 1 | |a Shao, Zengwu |e verfasserin |4 aut | |
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