Hypocapnia Stimuli-Responsive Engineered Exosomes Delivering MiR-218 Facilitate Sciatic Nerve Regeneration

Overview

Journal Front Bioeng Biotechnol

Date 2022 Feb 25

PMID 35211463

Authors

Yingshuai Wang

Tao Yu

Feihu Hu

Affiliations

Soon will be listed here.

Abstract

Therapeutic strategies of microRNAs (miRNAs) and exosomes have been systematically explored as an enhancing application by paracrine and modulating cellular activity after internalization of recipient cells , and progressively developed to meet the requirements of peripheral nerve regeneration . However, how to obtain exosomes with superior properties and effectively deliver miRNAs becomes a key challenge. Hypocapnia environment might play unexpected outcomes in strengthening exosome function when culturing adipose-derived stem cells (ASCs). Previously, we discovered the intensive regulation of miR-218 on the differentiation of ASCs. In the present study, we analyzed the functional differences of secreted exosomes in response to hypocapnia stimulation, and explored the application in combination with miR-218 to facilitate sciatic nerve regeneration. Our results indicated that the delivery system of engineered exosomes derived from ASCs remarkably loads upregulated miR-218 and promotes cellular activity in the recipient cells (PC12 cells), and hypocapnia stimuli-responsive exosomes exhibit strengthening properties. Furthermore, in a sciatic nerve injury model, exosomes delivering miR-218 combined with engineered scaffold facilitated the regeneration of injured sciatic nerves. In the hypocapnia-stimulated exosome group, more encouraging promotion was revealed on the regeneration of motor and nerve fibers. Hypoc-miR-218-ASC exosomes are suggested as a promising cell-free strategy for peripheral nerve repair.

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References

Melnik S, Gabler J, Dreher S, Hecht N, Hofmann N, Grossner T . MiR-218 affects hypertrophic differentiation of human mesenchymal stromal cells during chondrogenesis via targeting RUNX2, MEF2C, and COL10A1. Stem Cell Res Ther. 2020; 11(1):532. PMC: 7727242. DOI: 10.1186/s13287-020-02026-6. View

Xin H, Wang F, Li Y, Lu Q, Cheung W, Zhang Y . Secondary Release of Exosomes From Astrocytes Contributes to the Increase in Neural Plasticity and Improvement of Functional Recovery After Stroke in Rats Treated With Exosomes Harvested From MicroRNA 133b-Overexpressing Multipotent Mesenchymal.... Cell Transplant. 2016; 26(2):243-257. PMC: 5303172. DOI: 10.3727/096368916X693031. View

Liang G, Zhu Y, Sun B, Hu F, Tian T, Li S . PLGA-based gene delivering nanoparticle enhance suppression effect of miRNA in HePG2 cells. Nanoscale Res Lett. 2011; 6:447. PMC: 3211866. DOI: 10.1186/1556-276X-6-447. View

Hu S, Li Z, Lutz H, Huang K, Su T, Cores J . Dermal exosomes containing miR-218-5p promote hair regeneration by regulating β-catenin signaling. Sci Adv. 2020; 6(30):eaba1685. PMC: 7439409. DOI: 10.1126/sciadv.aba1685. View

Bucan V, Vaslaitis D, Peck C, Strauss S, Vogt P, Radtke C . Effect of Exosomes from Rat Adipose-Derived Mesenchymal Stem Cells on Neurite Outgrowth and Sciatic Nerve Regeneration After Crush Injury. Mol Neurobiol. 2018; 56(3):1812-1824. PMC: 6394792. DOI: 10.1007/s12035-018-1172-z. View

Hu F, Zhang X, Liu H, Xu P, Doulathunnisa , Teng G . Neuronally differentiated adipose-derived stem cells and aligned PHBV nanofiber nerve scaffolds promote sciatic nerve regeneration. Biochem Biophys Res Commun. 2017; 489(2):171-178. DOI: 10.1016/j.bbrc.2017.05.119. View

Xin H, Katakowski M, Wang F, Qian J, Liu X, Ali M . MicroRNA cluster miR-17-92 Cluster in Exosomes Enhance Neuroplasticity and Functional Recovery After Stroke in Rats. Stroke. 2017; 48(3):747-753. PMC: 5330787. DOI: 10.1161/STROKEAHA.116.015204. View

Westerink R, Ewing A . The PC12 cell as model for neurosecretion. Acta Physiol (Oxf). 2007; 192(2):273-85. PMC: 2663028. DOI: 10.1111/j.1748-1716.2007.01805.x. View

Yu B, Zhou S, Yi S, Gu X . The regulatory roles of non-coding RNAs in nerve injury and regeneration. Prog Neurobiol. 2015; 134:122-39. DOI: 10.1016/j.pneurobio.2015.09.006. View

10.

Thiebes K, Nam H, Cambronne X, Shen R, Glasgow S, Cho H . miR-218 is essential to establish motor neuron fate as a downstream effector of Isl1-Lhx3. Nat Commun. 2015; 6:7718. PMC: 4518464. DOI: 10.1038/ncomms8718. View

11.

Park D, Seo Y . Engineering of Extracellular Vesicles Based on Payload Changes for Tissue Regeneration. Tissue Eng Regen Med. 2021; 18(4):485-497. PMC: 8325730. DOI: 10.1007/s13770-021-00349-w. View

12.

ZuK P, Zhu M, Ashjian P, De Ugarte D, Huang J, Mizuno H . Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002; 13(12):4279-95. PMC: 138633. DOI: 10.1091/mbc.e02-02-0105. View

13.

Zhu K, Ding H, Wang W, Liao Z, Fu Z, Hong Y . Tumor-suppressive miR-218-5p inhibits cancer cell proliferation and migration via EGFR in non-small cell lung cancer. Oncotarget. 2016; 7(19):28075-85. PMC: 5053710. DOI: 10.18632/oncotarget.8576. View

14.

Caponnetto F, Manini I, Skrap M, Palmai-Pallag T, Di Loreto C, Beltrami A . Size-dependent cellular uptake of exosomes. Nanomedicine. 2016; 13(3):1011-1020. DOI: 10.1016/j.nano.2016.12.009. View

15.

Sun J, Dou G, Yang Z, Liang L, Duan J, Ruan B . Notch activation promotes endothelial quiescence by repressing MYC expression via miR-218. Mol Ther Nucleic Acids. 2021; 25:554-566. PMC: 8463319. DOI: 10.1016/j.omtn.2021.07.023. View

16.

Van Deun J, Mestdagh P, Sormunen R, Cocquyt V, Vermaelen K, Vandesompele J . The impact of disparate isolation methods for extracellular vesicles on downstream RNA profiling. J Extracell Vesicles. 2014; 3. PMC: 4169610. DOI: 10.3402/jev.v3.24858. View

17.

Yousefi F, Arab F, Nikkhah K, Amiri H, Mahmoudi M . Novel approaches using mesenchymal stem cells for curing peripheral nerve injuries. Life Sci. 2019; 221:99-108. DOI: 10.1016/j.lfs.2019.01.052. View

18.

Yang Y, Ye Y, Kong C, Su X, Zhang X, Bai W . MiR-124 Enriched Exosomes Promoted the M2 Polarization of Microglia and Enhanced Hippocampus Neurogenesis After Traumatic Brain Injury by Inhibiting TLR4 Pathway. Neurochem Res. 2019; 44(4):811-828. DOI: 10.1007/s11064-018-02714-z. View

19.

Shafiei M, Ansari M, Razak S, Aslam Khan M . A Comprehensive Review on the Applications of Exosomes and Liposomes in Regenerative Medicine and Tissue Engineering. Polymers (Basel). 2021; 13(15). PMC: 8347192. DOI: 10.3390/polym13152529. View

20.

Hu F, Sun B, Xu P, Zhu Y, Meng X, Teng G . MiR-218 Induces Neuronal Differentiation of ASCs in a Temporally Sequential Manner with Fibroblast Growth Factor by Regulation of the Wnt Signaling Pathway. Sci Rep. 2017; 7:39427. PMC: 5206743. DOI: 10.1038/srep39427. View