VH298-loaded extracellular vesicles released from gelatin methacryloyl hydrogel facilitate diabetic wound healing by HIF-1α-mediated enhancement of angiogenesis
Abstract
Endothelial malfunction is responsible for impaired angiogenesis in diabetic patients, thereby causing the delayed healing progress of diabetic wounds. Exosomes or extracellular vesicles (EVs) have emerged as potential therapeutic vectors carrying drug cargoes to diseased cells. In the present study, EVs were reported as a new treatment for diabetic wounds by delivering VH298 into endothelial cells. Firstly, EVs derived from epidermal stem cells (ESCs) were loaded with VH298 (VH-EVs), and the characteristics of VH-EVs were identified. VH-EVs showed promotive action on the function of human umbilical vein endothelial cells (HUVECs) in vitro by activating HIF-1α signaling pathway. VH-EVs were also found to have a therapeutic effect on wound healing and angiogenesis in vivo. We further fabricated gelatin methacryloyl (GelMA) hydrogel for sustained release of VH-EVs, which possessed high biocompatibility and proper mechanical properties. In diabetic mice, GelMA hydrogel containing VH-EVs (Gel-VH-EVs) effectively promoted wound healing by locally enhancing blood supply and angiogenesis. The underlying mechanism for enhanced angiogenesis was possibly associated with the activation of HIF-1α/VEGFA signaling pathway. Collectively, our findings suggest a promising EV-based strategy for the VH298 delivery to endothelial cells and provide a new bioactive dressing for diabetic wound treatment. STATEMENT OF SIGNIFICANCE: The angiogenic dysfunction is the main cause of diabetic wound unhealing. Extracellular vesicles (EVs) have been reported to be helpful but their efficacy is limited for angiogenesis in cutaneous regeneration. VH298 holds great promise to improve angiogenesis by stabilizing HIF-1α which is reported at low level in diabetic wounds. Here, we loaded EVs with VH298 (VH-EVs) to exert an on-target enhancement of proangiogenic capacity in diabetic wound. Then, we applied a photo-crosslinkable hydrogel, gelatin methacryloyl (GelMA) containing VH-EVs (Gel-VH-EVs) as a convenient biomaterial and an adaptable scaffold for sustained releasing VH-EVs. The results showed significant therapeutic effect of Gel-VH-EVs on skin defect repair. Our findings suggest a promising EVs-based drug delivery strategy and a new functional wound dressing for patients.
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VH-EV promoted function of HUVECs in vitro through HIF-1α signaling and displayed great therapeutic effects on skin regeneration.
“Similarly, Wang et al. loaded epidermal stem cell (ESC)-derived exosomes with VH298 (VH-EV), and VH-EV was shown to promote the function of HUVECs in vitro through HIF-1α signaling. This special exosome displayed great therapeutic effects on skin regeneration [106].”
From The Therapeutic Potential and Clinical Significance of Exosomes as Carriers of Drug Delivery System (2022) · cites this paper as [106]
Cites
Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes
Alvarez-Erviti, L., Seow, Y., Yin, H., Betts, C., Lakhal, S., & Wood, M. J. A. (2011) · Nature Biotechnology · doi:10.1038/nbt.1807 · Cited by 4,930 · see citing works
Synthesis, properties, and biomedical applications of gelatin methacryloyl (GelMA) hydrogels
Yue, K., Trujillo-de Santiago, G., Alvarez, M. M., Tamayol, A., Annabi, N., & Khademhosseini, A. (2015) · Biomaterials · doi:10.1016/j.biomaterials.2015.08.045 · Cited by 3,146 · see citing works
Lötvall, J. O., Hill, A. F., Hochberg, F. H., Buzás, E. I., Vizio, D. D., Gardiner, C., Gho, Y. S., Kurochkin, I. V., Mathivanan, S., Quesenberry, P. J., et al. (2014) · Journal of Extracellular Vesicles · doi:10.3402/jev.v3.26913 · Cited by 2,710 · see citing works
Cell-laden microengineered gelatin methacrylate hydrogels
Nichol, J. W., Koshy, S. T., Bae, H., Hwang, C. M., Yamanlar, S., & Khademhosseini, A. (2010) · Biomaterials · doi:10.1016/j.biomaterials.2010.03.064 · Cited by 2,377 · see citing works
Extracellular vesicles as a next-generation drug delivery platform
Herrmann, I. K., Wood, M. J. A., & Fuhrmann, G. (2021) · Nature Nanotechnology · doi:10.1038/s41565-021-00931-2 · Cited by 1,951 · see citing works
Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells
Kim, M. S., Haney, M. J., Zhao, Y., Mahajan, V., Le‐Deygen, I. M., Klyachko, N. L., Inskoe, E., Piroyan, A., Sokolsky‐Papkov, M., Okolie, O., et al. (2015) · Nanomedicine Nanotechnology Biology and Medicine · doi:10.1016/j.nano.2015.10.012 · Cited by 1,498 · see citing works
Wound healing and treating wounds
Powers, J. G., Higham, C., Broussard, K. C., & Phillips, T. J. (2016) · Journal of the American Academy of Dermatology · doi:10.1016/j.jaad.2015.08.070 · Cited by 758 · see citing works
Wang, M., Wang, C., Chen, M., Xi, Y., Cheng, W., Mao, C., Xu, T., Zhang, X., Lin, C., Gao, W., et al. (2019) · ACS Nano · doi:10.1021/acsnano.9b03656 · Cited by 552 · see citing works
Stabilization of HIF-1α is critical to improve wound healing in diabetic mice
Botusan, I. R., Sunkari, V. G., Savu, O., Catrina, A. I., Grünler, J., Lindberg, S., Pereira, T., Ylä-Herttuala, S., Poellinger, L., Brismar, K., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0805230105 · Cited by 533 · see citing works
Wound healing and treating wounds
Morton, L. M., & Phillips, T. J. (2016) · Journal of the American Academy of Dermatology · doi:10.1016/j.jaad.2015.08.068 · Cited by 475 · see citing works
Li, X., Xie, X., Lian, W., Shi, R., Han, S., Zhang, H., Lu, L., & Li, M. (2018) · Experimental & Molecular Medicine · doi:10.1038/s12276-018-0058-5 · Cited by 472 · see citing works
Sun, M., Sun, X., Wang, Z., Guo, S., Yu, G., & Yang, H. (2018) · Polymers · doi:10.3390/polym10111290 · Cited by 453 · see citing works
Zhang, J., Liu, X., Li, H., Chen, C., Hu, B., Niu, X., Li, Q., Zhao, B., Xie, Z., & Wang, Y. (2016) · Stem Cell Research & Therapy · doi:10.1186/s13287-016-0391-3 · Cited by 431 · see citing works
Self-citationExosomes: The next generation of endogenous nanomaterials for advanced drug delivery and therapy
Liao, W., Du, Y., Zhang, C., Pan, F., Yao, Y., Zhang, T., & Peng, Q. (2018) · Acta Biomaterialia · doi:10.1016/j.actbio.2018.12.045 · Cited by 416 · see citing works
Self-citationBakker, K., Apelqvist, J., Lipsky, B. A., van Netten, J. J., & on behalf of the International Working Group on the Diabetic Foot (IWGDF) (2015) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.2694 · Cited by 409 · see citing works
Shi, Q., Qian, Z., Liu, D., Sun, J., Wang, X., Liu, H., Xu, J., & Guo, X. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00904 · Cited by 396 · see citing works
Hyperglycemia Regulates Hypoxia-Inducible Factor-1α Protein Stability and Function
Catrina, S., Okamoto, K., Pereira, T., Brismar, K., & Poellinger, L. (2004) · Diabetes · doi:10.2337/diabetes.53.12.3226 · Cited by 385 · see citing works
Xu, X., Liang, Y., Li, X., Ouyang, K., Wang, M., Cao, T., Li, W., Liu, J., Xiong, J., Li, B., et al. (2021) · Biomaterials · doi:10.1016/j.biomaterials.2020.120539 · Cited by 377 · see citing works
The microRNA regulatory landscape of MSC-derived exosomes: a systems view
Ferguson, S. W., Wang, J., Lee, C. J., Liu, M., Neelamegham, S., Canty, J. M., & Nguyen, J. (2018) · Scientific Reports · doi:10.1038/s41598-018-19581-x · Cited by 360 · see citing works
Galkowska, H., Wojewodzka, U., & Olszewski, W. L. (2006) · Wound Repair and Regeneration · doi:10.1111/j.1743-6109.2006.00155.x · Cited by 317 · see citing works
Hu, H., Dong, L., Bu, Z., Shen, Y., Luo, J., Zhang, H., Zhao, S., Lv, F., & Liu, Z. (2020) · Journal of Extracellular Vesicles · doi:10.1080/20013078.2020.1778883 · Cited by 310 · see citing works
Rehman, S. R. U., Augustine, R., Zahid, A. A., et al. (2019) · International Journal of Nanomedicine · doi:10.2147/ijn.s218120 · Cited by 304 · see citing works
Shafei, S., Khanmohammadi, M., Heidari, R., Ghanbari, H., Nooshabadi, V. T., Farzamfar, S., Akbariqomi, M., Sanikhani, N. S., Absalan, M., & Tavoosidana, G. (2019) · Journal of Biomedical Materials Research Part A · doi:10.1002/jbm.a.36835 · Cited by 271 · see citing works
A small molecule HIF-1α stabilizer that accelerates diabetic wound healing
Li, G., Ko, C.-N., Li, D., Yang, C., Wang, W., Yang, G., Primo, C. D., Wong, V. K. W., Xiang, Y., Lin, L., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23448-7 · Cited by 263 · see citing works
Frost, J., Galdeano, C., Soares, P., Gadd, M. S., Grzes, K. M., Ellis, L. C. J., Epemolu, O., Shimamura, S., Bantscheff, M., Grandi, P., et al. (2016) · Nature Communications · doi:10.1038/ncomms13312 · Cited by 242 · see citing works
Managing Diabetic Foot Ulcers: Pharmacotherapy for Wound Healing
Dixon, D. J., & EDMONDS, M. E. (2020) · Drugs · doi:10.1007/s40265-020-01415-8 · Cited by 228 · see citing works
Curcumin-induced angiogenesis hastens wound healing in diabetic rats
Kant, V., Gopal, A., Kumar, D., Pathak, N. N., Ram, M., Jangir, B. L., Tandan, S. K., & Kumar, D. (2014) · Journal of Surgical Research · doi:10.1016/j.jss.2014.10.019 · Cited by 217 · see citing works
Drug loading techniques for exosome-based drug delivery systems.
Xi, X.-M., Xia, S.-J., & Lu, R. (2021) · PubMed · doi:10.1691/ph.2021.0128 · Cited by 200 · see citing works
Extracellular Vesicle-Associated Proteins in Tissue Repair
Roefs, M. T., Sluijter, J. P. G., & Vader, P. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.09.009 · Cited by 199 · see citing works
Mace, K. A., Yu, D. H., Paydar, K. Z., Boudreau, N. J., & Young, D. M. (2007) · Wound Repair and Regeneration · doi:10.1111/j.1524-475x.2007.00278.x · Cited by 178 · see citing works
Free and hydrogel encapsulated exosome-based therapies in regenerative medicine
Akbari, A., Jabbari, N., Sharifi, R., Ahmadi, M., Vahhabi, A., Seyedzadeh, S. J., Nawaz, M., Szafert, S., Mahmoodi, M., Jabbari, E., et al. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.117447 · Cited by 173 · see citing works
Epidermal stem cells in wound healing and their clinical applications
Yang, R., Liu, F., Wang, J., Chen, X., Xie, J., & Xiong, K. (2019) · Stem Cell Research & Therapy · doi:10.1186/s13287-019-1312-z · Cited by 171 · see citing works
Extracellular vesicles as modulators of wound healing
Cabral, J., Ryan, A. E., Griffin, M. D., & Ritter, T. (2018) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.01.018 · Cited by 168 · see citing works
Hu, P., Yang, Q., Wang, Q., Shi, C., Wang, D., Armato, U., Prà, I. D., & Chiarini, A. (2019) · Burns & Trauma · doi:10.1186/s41038-019-0178-8 · Cited by 163 · see citing works
In vivo printing of growth factor-eluting adhesive scaffolds improves wound healing
Nuutila, K., Samandari, M., Endo, Y., Zhang, Y., Quint, J. P., Schmidt, T. A., Tamayol, A., & Sinha, I. (2021) · Bioactive Materials · doi:10.1016/j.bioactmat.2021.06.030 · Cited by 149 · see citing works
Bian, X., Ma, K., Zhang, C., & Fu, X. (2019) · Stem Cell Research & Therapy · doi:10.1186/s13287-019-1276-z · Cited by 143 · see citing works
Self-citationZhao, D., Yu, Z., Li, Y., Wang, Y., Li, Q., & Han, D. (2020) · Journal of Molecular Histology · doi:10.1007/s10735-020-09877-6 · Cited by 139 · see citing works
Self-citationGudbergsson, J. M., Jønsson, K., Simonsen, J. B., & Johnsen, K. B. (2019) · Journal of Controlled Release · doi:10.1016/j.jconrel.2019.06.006 · Cited by 138 · see citing works
Mesenchymal Stem Cell-Derived Extracellular Vesicles in Tissue Regeneration
Zhang, B., Tian, X., Hao, J., Xu, G., & Zhang, W. (2020) · Cell Transplantation · doi:10.1177/0963689720908500 · Cited by 122 · see citing works
Duan, M., Zhang, Y., Zhang, H., Meng, Y., Qian, M. D., & Zhang, G. (2020) · Stem Cell Research & Therapy · doi:10.1186/s13287-020-01971-6 · Cited by 120 · see citing works
Bertozzi, N., Simonacci, F., Grieco, M. P., et al. (2017) · Annals of Medicine and Surgery · doi:10.1016/j.amsu.2017.06.058 · Cited by 113 · see citing works
Wei, Q., Wang, Y., Ma, K., Li, Q., Li, B., Hu, W., Fu, X., & Zhang, C. (2021) · Stem Cell Reviews and Reports · doi:10.1007/s12015-021-10176-0 · Cited by 93 · see citing works
Self-citationApplication of stem cell-derived exosomes in ischemic diseases: opportunity and limitations
Babaei, M., & Rezaie, J. (2021) · Journal of Translational Medicine · doi:10.1186/s12967-021-02863-w · Cited by 89 · see citing works
Chavez-Munoz, C. I., Kilani, R. T., & Ghahary, A. (2009) · Journal of Cellular Physiology · doi:10.1002/jcp.21847 · Cited by 86 · see citing works
Liu, T., Weng, W., Zhang, Y., Sun, X., & Yang, H. (2020) · Molecules · doi:10.3390/molecules25225305 · Cited by 83 · see citing works
Bailey, A. J.-M., Li, H. O., Kirkham, A. M., Tieu, A., Maganti, H. B., Shorr, R., Fergusson, D. A., Lalu, M. M., Elomazzen, H., & Allan, D. (2021) · Stem Cell Reviews and Reports · doi:10.1007/s12015-021-10164-4 · Cited by 67 · see citing works
Self-citationEmbryonic stem cell extracts improve wound healing in diabetic mice
Loretelli, C., Nasr, M. B., Giatsidis, G., et al. (2020) · Acta Diabetologica · doi:10.1007/s00592-020-01500-0 · Cited by 39 · see citing works
Wu, K., He, C. H., Wu, Y., et al. (2021) · International Journal of Nanomedicine · doi:10.2147/ijn.s334194 · Cited by 38 · see citing works
Magnetic PVA/laponite RD hydrogel nanocomposites for adsorption of model protein BSA
Soleymani, M., Akbari, A., & Mahdavinia, G. R. (2018) · Polymer Bulletin · doi:10.1007/s00289-018-2480-1 · Cited by 34 · see citing works
Iacobini, C., Vitale, M., Pugliese, G., & Menini, S. (2021) · Biomedicines · doi:10.3390/biomedicines9091139 · Cited by 34 · see citing works
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The Therapeutic Potential and Clinical Significance of Exosomes as Carriers of Drug Delivery System
Li, T., Li, X., Han, G., Liang, M., Yang, Z., Zhang, C., Huang, S., Tai, S., & Yu, S. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics15010021 · Cited by 110 · see citing works
Self-citationExosomes and Biomaterials: In Search of a New Therapeutic Strategy for Multiple Sclerosis
Ojeda-Hernández, D. D., Hernández-Sapiéns, M. A., Reza-Zaldívar, E. E., Canales-Aguirre, A., Matías-Guiu, J. A., Matías-Guiu, J., Mateos-Díaz, J. C., Gómez-Pinedo, U., & Sancho-Bielsa, F. (2022) · Life · doi:10.3390/life12091417 · Cited by 25 · see citing works
Li, Z., Dong, H., Yang, S., Wang, X., & Li, Z. (2025) · International Journal of Nanomedicine · doi:10.2147/ijn.s504924 · Cited by 12 · see citing works
“33,34 To enhance the mechanical properties and biofunctionality of alginate-based hydrogels, oxidized alginate (OSA) is synthesized via partial oxidation.”
- Authors
- Wang, Y., Cao, Z., Wei, Q., Ma, K., Hu, W., Huang, Q., Su, J., Li, H., Zhang, C., & Fu, X.
- Affiliations
- Chinese PLA General Hospital (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Nankai University (CN)
- Hubei University of Medicine (CN)
- Corresponding author
- Li, Haihong
- Zhang, Cuiping
- Fu, Xiaobing
- Venue
- Acta Biomaterialia
- Publisher
- Elsevier BV
- Published
- 2022-07
- Volume
- 147
- Pages
- 342-355
- ISSN
- 1742-7061 (ISSN-L)
- OpenAlex
- W4280530584
- Cited by
- 225
- References
- 50
- Citations by year
- 2026: 39 · 2025: 54 · 2024: 58 · 2023: 62 · 2022: 12
- FWCI
- 20.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Acta Biomaterialia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Beijing Municipal Natural Science Foundation (7202197)
- National Natural Science Foundation of China (81830064, 82172231, 82172211, 82103507)
- CAMS Innovation Fund for Medical Sciences
- Chinese Academy of Meteorological Sciences (2019-I2M-5\u2013059)
- Topics
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- extracellular vesicles, diabetic wound healing, angiogenesis, HIF-1α, gelatin methacryloyl hydrogel, epidermal stem cells, endothelial cells, VEGF-A signaling, sustained drug release, wound dressings, endothelial dysfunction
- MeSH terms
- Extracellular Vesicles, Animals, Cyclopropanes, Diabetes Mellitus, Experimental, Gelatin, Humans, Methacrylates, Neovascularization, Pathologic, Pyrrolidines, Thiazoles, Wound Healing, Hydrogels, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Human Umbilical Vein Endothelial Cells
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