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

Yayu Wang,1,* Jie Yao,2– 4,* Lizhao Cai,2– 4,* Tong Liu,1 Xiaogang Wang,2,4 Ye Zhang,2– 4 Zhiying Zhou,2– 4 Tingwei Li,2– 4 Minyi Liu,2– 4 Renfa Lai,2– 4 Xiangning Liu2– 4 1Department of Cell Biology & Institute...

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Autores principales:	Wang Y, Yao J, Cai L, Liu T, Wang X, Zhang Y, Zhou Z, Li T, Liu M, Lai R, Liu X
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2020
Materias:	extracellular vesicles (evs) mesenchymal stem cells (mscs) bone-targeting osteoporosis click chemistry Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/614d8fdad7d5495198638ebcfa05601a
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id	oai:doaj.org-article:614d8fdad7d5495198638ebcfa05601a
record_format	dspace
institution	DOAJ
collection	DOAJ
language	EN
topic	extracellular vesicles (evs) mesenchymal stem cells (mscs) bone-targeting osteoporosis click chemistry Medicine (General) R5-920
spellingShingle	extracellular vesicles (evs) mesenchymal stem cells (mscs) bone-targeting osteoporosis click chemistry Medicine (General) R5-920 Wang Y Yao J Cai L Liu T Wang X Zhang Y Zhou Z Li T Liu M Lai R Liu X Bone-Targeted Extracellular Vesicles from Mesenchymal Stem Cells for Osteoporosis Therapy
description	Yayu Wang,1,* Jie Yao,2– 4,* Lizhao Cai,2– 4,* Tong Liu,1 Xiaogang Wang,2,4 Ye Zhang,2– 4 Zhiying Zhou,2– 4 Tingwei Li,2– 4 Minyi Liu,2– 4 Renfa Lai,2– 4 Xiangning Liu2– 4 1Department of Cell Biology & Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, People’s Republic of China; 2Department of Stomatology Medical Center, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, People’s Republic of China; 3School of Stomatology, Jinan University, Guangzhou 510632, People’s Republic of China; 4Clinical Research Platform for Interdiscipline of Stomatology, Jinan University, Guangzhou 510630, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiangning Liu; Renfa LaiThe First Affiliated Hospital of Jinan University, Guangzhou 510632, People’s Republic of ChinaTel +86 20 3868 8109Fax +86 20 3868 8000Email liuxiangning2003@126.com; prof.dr.lai@163.comBackground: 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.Keywords: extracellular vesicles, EVs, mesenchymal stem cells, MSCs, bone-targeting, osteoporosis, click chemistry
format	article
author	Wang Y Yao J Cai L Liu T Wang X Zhang Y Zhou Z Li T Liu M Lai R Liu X
author_facet	Wang Y Yao J Cai L Liu T Wang X Zhang Y Zhou Z Li T Liu M Lai R Liu X
author_sort	Wang Y
title	Bone-Targeted Extracellular Vesicles from Mesenchymal Stem Cells for Osteoporosis Therapy
title_short	Bone-Targeted Extracellular Vesicles from Mesenchymal Stem Cells for Osteoporosis Therapy
title_full	Bone-Targeted Extracellular Vesicles from Mesenchymal Stem Cells for Osteoporosis Therapy
title_fullStr	Bone-Targeted Extracellular Vesicles from Mesenchymal Stem Cells for Osteoporosis Therapy
title_full_unstemmed	Bone-Targeted Extracellular Vesicles from Mesenchymal Stem Cells for Osteoporosis Therapy
title_sort	bone-targeted extracellular vesicles from mesenchymal stem cells for osteoporosis therapy
publisher	Dove Medical Press
publishDate	2020
url	https://doaj.org/article/614d8fdad7d5495198638ebcfa05601a
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spelling	oai:doaj.org-article:614d8fdad7d5495198638ebcfa05601a2021-12-02T11:35:51ZBone-Targeted Extracellular Vesicles from Mesenchymal Stem Cells for Osteoporosis Therapy1178-2013https://doaj.org/article/614d8fdad7d5495198638ebcfa05601a2020-10-01T00:00:00Zhttps://www.dovepress.com/bone-targeted-extracellular-vesicles-from-mesenchymal-stem-cells-for-o-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Yayu Wang,1,* Jie Yao,2– 4,* Lizhao Cai,2– 4,* Tong Liu,1 Xiaogang Wang,2,4 Ye Zhang,2– 4 Zhiying Zhou,2– 4 Tingwei Li,2– 4 Minyi Liu,2– 4 Renfa Lai,2– 4 Xiangning Liu2– 4 1Department of Cell Biology & Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, People’s Republic of China; 2Department of Stomatology Medical Center, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, People’s Republic of China; 3School of Stomatology, Jinan University, Guangzhou 510632, People’s Republic of China; 4Clinical Research Platform for Interdiscipline of Stomatology, Jinan University, Guangzhou 510630, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiangning Liu; Renfa LaiThe First Affiliated Hospital of Jinan University, Guangzhou 510632, People’s Republic of ChinaTel +86 20 3868 8109Fax +86 20 3868 8000Email liuxiangning2003@126.com; prof.dr.lai@163.comBackground: 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.Keywords: extracellular vesicles, EVs, mesenchymal stem cells, MSCs, bone-targeting, osteoporosis, click chemistryWang YYao JCai LLiu TWang XZhang YZhou ZLi TLiu MLai RLiu XDove Medical Pressarticleextracellular vesicles (evs)mesenchymal stem cells (mscs)bone-targetingosteoporosisclick chemistryMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 15, Pp 7967-7977 (2020)

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

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