Extracellular vesicles from human urine-derived stem cells inhibit glucocorticoid-induced osteonecrosis of the femoral head by transporting and releasing pro-angiogenic DMBT1 and anti-apoptotic TIMP1.,Acta Biomaterialia

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Extracellular vesicles from human urine-derived stem cells inhibit glucocorticoid-induced osteonecrosis of the femoral head by transporting and releasing pro-angiogenic DMBT1 and anti-apoptotic TIMP1.
Acta Biomaterialia ( IF 9.4 ) Pub Date : 2020-05-22 , DOI: 10.1016/j.actbio.2020.05.020
Chun-Yuan Chen ₁ , Wei Du ₂ , Shan-Shan Rao ₃ , Yi-Juan Tan ₁ , Xiong-Ke Hu ₁ , Ming-Jie Luo ₄ , Qi-Feng Ou ₅ , Pan-Feng Wu ₅ , Li-Ming Qing ₅ , Zhe-Ming Cao ₅ , Hao Yin ₁ , Tao Yue ₁ , Chao-Hong Zhan ₆ , Jie Huang ₁ , Yan Zhang ₇ , Yi-Wei Liu ₇ , Zhen-Xing Wang ₁ , Zheng-Zhao Liu ₈ , Jia Cao ₁ , Jiang-Hua Liu ₁ , Chun-Gu Hong ₉ , Ze-Hui He ₁ , Jun-Xiao Yang ₁₀ , Si-Yuan Tang ₄ , Ju-Yu Tang ₅ , Hui Xie ₁₁

Affiliation

Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Hand & Microsurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Rehabilitation, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Xiangya Nursing School, Central South University, Changsha, Hunan 410013, China.
Xiangya Nursing School, Central South University, Changsha, Hunan 410013, China.
Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Hand & Microsurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Hunan Key Laboratory of Organ Injury, Aging and Regenerative Medicine, Changsha, Hunan 410008, China; Hunan Key Laboratory of Bone Joint Degeneration and Injury, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Key Laboratory of Biological Nanotechnology of National Health Commission, Changsha, Hunan 410008, China.

Osteonecrosis of the femoral head (ONFH) frequently occurs after glucocorticoid (GC) treatment. Extracellular vesicles (EVs) are important nano-sized paracrine mediators of intercellular crosstalk. This study aimed to determine whether EVs from human urine-derived stem cells (USC-EVs) could protect against GC-induced ONFH and focused on the impacts of USC-EVs on angiogenesis and apoptosis to explore the mechanism by which USC-EVs attenuated GC-induced ONFH. The results in vivo showed that the intravenous administration of USC-EVs at the early stage of GC exposure could rescue angiogenesis impairment, reduce apoptosis of trabecular bone and marrow cells, prevent trabecular bone destruction and improve bone microarchitecture in the femoral heads of rats. In vitro, USC-EVs reversed the GC-induced suppression of endothelial angiogenesis and activation of apoptosis. Deleted in malignant brain tumors 1 (DMBT1) and tissue inhibitor of metalloproteinases 1 (TIMP1) proteins were enriched in USC-EVs and essential for the USC-EVs-induced pro-angiogenic and anti-apoptotic effects in GC-treated cells, respectively. Knockdown of TIMP1 attenuated the protective effects of USC-EVs against GC-induced ONFH. Our study suggests that USC-EVs are a promising nano-sized agent for the prevention of GC-induced ONFH by delivering pro-angiogenic DMBT1 and anti-apoptotic TIMP1.

Statement of Significance

This study demonstrates that the intravenous injection of extracellular vesicles from human urine-derived stem cells (USC-EVs) at the early stage of glucocorticoid (GC) exposure efficiently protects the rats from the GC-induced osteonecrosis of the femoral head (ONFH). Moreover, this study identifies that the promotion of angiogenesis and inhibition of apoptosis by transferring pro-angiogenic DMBT1 and anti-apoptotic TIMP1 proteins contribute importantly to the USC-EVs-induced protective effects against GC-induced ONFH. This study suggests the promising prospect of USC-EVs as a new nano-sized agent for protecting against GC-induced ONFH, and the potential of DMBT1 and TIMP1 as the molecular targets for further augmenting the protective function of USC-EVs.

中文翻译：

来自人尿干细胞的细胞外囊泡通过转运和释放促血管生成 DMBT1 和抗凋亡 TIMP1 来抑制糖皮质激素诱导的股骨头坏死。

股骨头坏死 (ONFH) 经常发生在糖皮质激素 (GC) 治疗后。细胞外囊泡 (EVs) 是细胞间串扰的重要纳米级旁分泌介质。本研究旨在确定来自人尿源性干细胞 (USC-EVs) 的 EVs 是否可以防止 GC 诱导的 ONFH，并重点关注 USC-EVs 对血管生成和细胞凋亡的影响，以探索 USC-EVs 减弱 GC 的机制-诱导的ONFH。体内研究结果表明，在 GC 暴露早期静脉注射 USC-EVs 可以挽救血管生成障碍，减少小梁骨和骨髓细胞的凋亡，防止骨小梁破坏并改善大鼠股骨头的骨微结构。体外, USC-EVs 逆转了 GC 诱导的内皮血管生成抑制和细胞凋亡激活。恶性脑肿瘤中缺失的 1 (DMBT1) 和金属蛋白酶组织抑制剂 1 (TIMP1) 蛋白在 USC-EV 中富集，并且分别对 USC-EV 诱导的 GC 处理细胞中的促血管生成和抗凋亡作用至关重要。敲低 TIMP1 减弱了 USC-EVs 对 GC 诱导的 ONFH 的保护作用。我们的研究表明，USC-EVs 是一种很有前途的纳米级药物，可通过递送促血管生成 DMBT1 和抗凋亡 TIMP1 来预防 GC 诱导的 ONFH。

重要性声明

本研究表明，在糖皮质激素 (GC) 暴露的早期，静脉注射来自人尿源性干细胞 (USC-EVs) 的细胞外囊泡可有效保护大鼠免受 GC 诱导的股骨头坏死 (ONFH)。此外，本研究表明，通过转移促血管生成 DMBT1 和抗凋亡 TIMP1 蛋白促进血管生成和抑制细胞凋亡，这对 USC-EVs 诱导的对 GC 诱导的 ONFH 的保护作用有重要作用。这项研究表明，USC-EVs 作为一种新型纳米级药物可预防 GC 诱导的 ONFH，具有广阔的前景，DMBT1 和 TIMP1 作为分子靶标可进一步增强 USC-EVs 的保护功能。

更新日期：2020-06-24

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