Bone-Targeted Extracellular Vesicles from Mesenchymal Stem Cells for Osteoporosis Therapy

Overview

Journal Int J Nanomedicine

Publisher Dove Medical Press

Specialty Biotechnology

Date 2020 Oct 29

PMID 33116512

Citations 35

Authors

Yayu Wang

Jie Yao

Lizhao Cai

Tong Liu

Xiaogang Wang

Ye Zhang

Zhiying Zhou

Tingwei Li

Minyi Liu

Renfa Lai

Xiangning Liu

Affiliations

Soon will be listed here.

Abstract

Background: Current drugs used for osteoporosis therapy show strong adverse effects. Stem cell-derived extracellular vesicles (EVs) provide another choice for osteoporosis therapy. Mouse mesenchymal stem cells (mMSCs)-derived EVs promote bone regeneration; however, their clinical application is limited due to non-specific tissue targeting. Alendronate specifically targets bone tissue via hydroxyapatite. Therefore, EVs were combined with alendronate to generate Ale-EVs by "click chemistry" to facilitate EVs targeting bone via alendronate/hydroxyapatite binding.

Methods: Ale-EVs were characterized based on size using dynamic light scattering analysis and morphology was visualized by transmission electron microscopy. Hydroxyapatite affinity of Ale-EVs was detected by flow cytometry. Bone targeting of Ale-EVs was tested by ex vivo ﬂuorescent imaging. Cell viability was assessed by using WST-8 reduction assay kit for testing the ability of Ale-EVs to promote mMSCs proliferation. Alkaline phosphatase experiment was used to detect ability of Ale-EVs to promote differentiation of mouse mesenchymal stem cells in vitro. Western blotting and Q-PCR assay were used to detect the early marker of osteogenic differentiation. Antiosteoporotic effects of Ale-EVs were detected in ovariectomy (OVX)-induced osteoporosis rat model. The safety of the Ale-EVs in vivo was measured by H&E staining and serum markers assay.

Results: In vitro, Ale-EVs had high affinity with hydroxyapatite. Also, ex vivo data indicated that Ale-EVs-DiD treatment of mice induced strong ﬂuorescece in bone tissues compared with EVs-DiD group. Furthermore, results suggested that Ale-EVs promoted the growth and differentiation of mouse MSCs. They also protected against osteoporosis in ovariectomy (OVX)-induced osteoporotic rats. Ale-EVs were well tolerated and no side effects were found, indicating that Ale-EVs specifically target bone and can be used as a new therapeutic in osteoporosis treatment.

Conclusion: We used the Ale-N3 to modify mouse mesenchymal stem cells-derived extracellular vesicles by copper-free "click chemistry" to generate a Ale-EVs system. The Ale-EVs had a high affinity for bone and have great potential for clinical applications in osteoporosis therapy with low systemic toxicity.

Citing Articles

SFRP1-Silencing GapmeR-Loaded Lipid-Polymer Hybrid Nanoparticles for Bone Regeneration in Osteoporosis: Effect of Dosing and Targeting Strategy.

Briffault E, Reyes R, Garcia-Garcia P, Rouco H, Diaz-Gomez L, Arnau M Int J Nanomedicine. 2024; 19:12171-12188.

PMID: 39588258 PMC: 11586229. DOI: 10.2147/IJN.S476546.

Bone-targeting engineered milk-derived extracellular vesicles for MRI-assisted therapy of osteoporosis.

Huang Q, Jiang Y, Cao Y, Ding Y, Cai J, Yang T Regen Biomater. 2024; 11:rbae112.

PMID: 39323741 PMC: 11422186. DOI: 10.1093/rb/rbae112.

Harnessing exosomes for targeted therapy: strategy and application.

Ren X, Xu R, Xu C, Su J Biomater Transl. 2024; 5(1):46-58.

PMID: 39220669 PMC: 11362351. DOI: 10.12336/biomatertransl.2024.01.005.

Potential Targeting Mechanisms for Bone-Directed Therapies.

Celik B, Leal A, Tomatsu S Int J Mol Sci. 2024; 25(15).

PMID: 39125906 PMC: 11312506. DOI: 10.3390/ijms25158339.

Rhizoma Drynariae-derived nanovesicles reverse osteoporosis by potentiating osteogenic differentiation of human bone marrow mesenchymal stem cells targeting ER signaling.

Zhao Q, Feng J, Liu F, Liang Q, Xie M, Dong J Acta Pharm Sin B. 2024; 14(5):2210-2227.

PMID: 38799625 PMC: 11119514. DOI: 10.1016/j.apsb.2024.02.005.

References

Thery C, Zitvogel L, Amigorena S . Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002; 2(8):569-79. DOI: 10.1038/nri855. View

Villasante A, Marturano-Kruik A, Ambati S, Liu Z, Godier-Furnemont A, Parsa H . Recapitulating the Size and Cargo of Tumor Exosomes in a Tissue-Engineered Model. Theranostics. 2016; 6(8):1119-30. PMC: 4893640. DOI: 10.7150/thno.13944. View

Diaz-Borjon A, Seyler T, Chen N, Lim S . Bisphosphonate-associated arthritis. J Clin Rheumatol. 2006; 12(3):131-3. DOI: 10.1097/01.rhu.0000221796.06383.4e. View

Kacprzak K, Skiera I, Piasecka M, Paryzek Z . Alkaloids and Isoprenoids Modification by Copper(I)-Catalyzed Huisgen 1,3-Dipolar Cycloaddition (Click Chemistry): Toward New Functions and Molecular Architectures. Chem Rev. 2016; 116(10):5689-743. DOI: 10.1021/acs.chemrev.5b00302. View

Khan M, Cheung A, Khan A . Drug-Related Adverse Events of Osteoporosis Therapy. Endocrinol Metab Clin North Am. 2017; 46(1):181-192. DOI: 10.1016/j.ecl.2016.09.009. View

Zhang J, Guan J, Niu X, Hu G, Guo S, Li Q . Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis. J Transl Med. 2015; 13:49. PMC: 4371881. DOI: 10.1186/s12967-015-0417-0. View

Nie H, Xie X, Zhang D, Zhou Y, Li B, Li F . Use of lung-specific exosomes for miRNA-126 delivery in non-small cell lung cancer. Nanoscale. 2019; 12(2):877-887. DOI: 10.1039/c9nr09011h. View

Hu Y, Xu R, Chen C, Rao S, Xia K, Huang J . Extracellular vesicles from human umbilical cord blood ameliorate bone loss in senile osteoporotic mice. Metabolism. 2019; 95:93-101. DOI: 10.1016/j.metabol.2019.01.009. View

Schwarzenbock C, Nelson P, Huss R, Rieger B . Synthesis of next generation dual-responsive cross-linked nanoparticles and their application to anti-cancer drug delivery. Nanoscale. 2018; 10(34):16062-16068. DOI: 10.1039/c8nr04760j. View

10.

Jia G, Han Y, An Y, Ding Y, He C, Wang X . NRP-1 targeted and cargo-loaded exosomes facilitate simultaneous imaging and therapy of glioma in vitro and in vivo. Biomaterials. 2018; 178:302-316. DOI: 10.1016/j.biomaterials.2018.06.029. View

11.

Reid I, Bolland M, Grey A . Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity?. Bone. 2007; 41(3):318-20. DOI: 10.1016/j.bone.2007.04.196. View

12.

Gonzalez-Moles M, Bagan-Sebastian J . Alendronate-related oral mucosa ulcerations. J Oral Pathol Med. 2000; 29(10):514-8. DOI: 10.1034/j.1600-0714.2000.291006.x. View

13.

Tamura R, Uemoto S, Tabata Y . Augmented liver targeting of exosomes by surface modification with cationized pullulan. Acta Biomater. 2017; 57:274-284. DOI: 10.1016/j.actbio.2017.05.013. View

14.

Lewis J, Schousboe J, Prince R . Romosozumab versus Alendronate and Fracture Risk in Women with Osteoporosis. N Engl J Med. 2018; 378(2):194-5. DOI: 10.1056/NEJMc1714810. View

15.

Chan K, Lee W, Ni M, Loo Y, Hauser C . C-Terminal Residue of Ultrashort Peptides Impacts on Molecular Self-Assembly, Hydrogelation, and Interaction with Small-Molecule Drugs. Sci Rep. 2018; 8(1):17127. PMC: 6244206. DOI: 10.1038/s41598-018-35431-2. View

16.

Haney M, Klyachko N, Zhao Y, Gupta R, Plotnikova E, He Z . Exosomes as drug delivery vehicles for Parkinson's disease therapy. J Control Release. 2015; 207:18-30. PMC: 4430381. DOI: 10.1016/j.jconrel.2015.03.033. View

17.

Hung M, Leonard J . Stabilization of exosome-targeting peptides via engineered glycosylation. J Biol Chem. 2015; 290(13):8166-72. PMC: 4375473. DOI: 10.1074/jbc.M114.621383. View

18.

Ramirez M, Amorim M, Gadelha C, Milic I, Welsh J, Freitas V . Technical challenges of working with extracellular vesicles. Nanoscale. 2017; 10(3):881-906. DOI: 10.1039/c7nr08360b. View

19.

Lee H, Fernandes-Cunha G, Putra I, Koh W, Myung D . Tethering Growth Factors to Collagen Surfaces Using Copper-Free Click Chemistry: Surface Characterization and in Vitro Biological Response. ACS Appl Mater Interfaces. 2017; 9(28):23389-23399. DOI: 10.1021/acsami.7b05262. View

20.

Sato Y, Umezaki K, Sawada S, Mukai S, Sasaki Y, Harada N . Engineering hybrid exosomes by membrane fusion with liposomes. Sci Rep. 2016; 6:21933. PMC: 4766490. DOI: 10.1038/srep21933. View