Damaged brain accelerates bone healing by releasing small extracellular vesicles that target osteoprogenitors

Wei Xia, Jing Xie, Zhiqing Cai, Xuhua Liu, Jing Wen, Zhong-Kai Cui, Run Zhao, Xiaomei Zhou, Jiahui Chen, Xinru Mao, Zhengtao Gu, Zhimin Zou, Zhipeng Zou, Yue Zhang, Ming Zhao, Maegele Mac, Qiancheng Song () and Xiaochun Bai ()
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Wei Xia: Southern Medical University
Jing Xie: Southern Medical University
Zhiqing Cai: Southern Medical University
Xuhua Liu: The Third Affiliated Hospital of Southern Medical University
Jing Wen: Nanfang Hospital, Southern Medical University
Zhong-Kai Cui: Southern Medical University
Run Zhao: Southern Medical University
Xiaomei Zhou: Southern Medical University
Jiahui Chen: The Third Affiliated Hospital of Southern Medical University
Xinru Mao: Nanfang Hospital, Southern Medical University
Zhengtao Gu: Southern Medical University
Zhimin Zou: Southern Medical University
Zhipeng Zou: Southern Medical University
Yue Zhang: Southern Medical University
Ming Zhao: Southern Medical University
Maegele Mac: Private University of Witten-Herdecke, Cologne Merheim Medical Center
Qiancheng Song: Southern Medical University
Xiaochun Bai: Southern Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract Clinical evidence has established that concomitant traumatic brain injury (TBI) accelerates bone healing, but the underlying mechanism is unclear. This study shows that after TBI, injured neurons, mainly those in the hippocampus, release osteogenic microRNA (miRNA)-enriched small extracellular vesicles (sEVs), which targeted osteoprogenitors in bone to stimulate bone formation. We show that miR-328a-3p and miR-150-5p, enriched in the sEVs after TBI, promote osteogenesis by directly targeting the 3′UTR of FOXO4 or CBL, respectively, and hydrogel carrying miR-328a-3p-containing sEVs efficiently repaires bone defects in rats. Importantly, increased fibronectin expression on sEVs surface contributes to targeting of osteoprogenitors in bone by TBI sEVs, thereby implying that modification of the sEVs surface fibronectin could be used in bone-targeted drug delivery. Together, our work unveils a role of central regulation in bone formation and a clear link between injured neurons and osteogenitors, both in animals and clinical settings.

Date: 2021
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DOI: 10.1038/s41467-021-26302-y

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