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Damaged Brain Accelerates Bone Healing by Releasing Exosomes that Target Osteoprogenitors

ABSTRACT: Clinical evidence has established that concomitant traumatic brain injury accelerates bone healing, but the underlying mechanism is unclear. This study showed that after TBI, injured neurons, mainly those in the hippocampus, released osteogenic microRNA (miRNA)-enriched exosomes, which targeted osteoprogenitors in bone to stimulate bone formation. Importantly, increased fibronectin expression on exosomal surface contributed to targeting of osteoprogenitors in bone by TBI exosomes, thereby implying that modification of the exosome surface fibronectin could be used in bone-targeted drug delivery. Together, our findings have established a novel role of central regulation in bone formation and a clear link between injured neurons and osteogenitors, both in animals and clinical settings.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Blood Plasma

SUBMITTER: Wei Xia

LAB HEAD: Xiao-Chun Bai

PROVIDER: PXD022126 | Pride | 2021-07-13

REPOSITORIES: Pride

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Project description:Background Transforming growth factor β1 (TGF-β1) has a neuroprotective function in traumatic brain injury (TBI) through its anti-inflammatory and immunomodulatory properties. In our previous study, we found that TGF-β1 played a critical role in inhibiting apoptosis and increasing neuronal activity in murine cortical neurons following trauma. However, the precise mechanisms underlying the neuroprotective actions of TGF-β1 on the cortex require further investigation. Methods Thus, in this study, we were aimed to investigate the regulatory function of TGF-β1 on neuronal autophagy and apoptosis using an in vitro primary cortical neuron trauma-injury model. Results To establish the landscape of differentially expressed genes (DEGs) with or without TGF-β1 (10ng/ml) treatment for 24 hours, we performed RNA-sequencing. We observed significant enrichment of DEGs related to autophagy, apoptosis, and the lysosome pathway in trauma-injured cortical neurons. Additionally, transmission electron microscopy (TEM) confirmed the presence of autophagosomes as well as autophagolysosomes. Western blot analysis revealed upregulation of autophagy-related protein light chain 3 (LC3)-Ⅱ/LC3-Ⅰ, sequestosome 1 (SQSTM1)/p62, along with apoptosis-related protein Cleaved-caspase3 in trauma-injured primary cortical neurons. Furthermore, mechanically injured neurons showed an upregulation of lysosomal marker protein lysosomal marker protein (LAMP1) and lysosomal enzyme mature cathepsin D (mCTSD), but a decrease in the activity of CTSD enzyme. These results indicated that apoptosis was up-regulated in mechanically injured neurons at 24 hours, accompanied by lysosomal dysfunction and impaired autophagic flux. Notably, TGF-β1 significantly reversed these changes. Conclusions Therefore, our findings suggested that TGF-β1 exerted neuroprotective effects on mechanically injured neurons by reducing lysosomal dysfunction, decreasing the accumulation of autophagosomes and autophagolysosomes, and enhancing autophagic flux.

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Damaged Brain Accelerates Bone Healing by Releasing Exosomes that Target Osteoprogenitors

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