线粒体失调导致体外 3D 三重培养人脑组织模型挫伤后继发性神经退行性进展。

Mitochondria dysregulation contributes to secondary neurodegeneration progression post-contusion injury in human 3D in vitro triculture brain tissue model.

机构信息

Department of Biomedical Engineering, Tufts University, Medford, MA, USA.

Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA.

出版信息

Cell Death Dis. 2023 Aug 3;14(8):496. doi: 10.1038/s41419-023-05980-0.

Traumatic Brain injury-induced disturbances in mitochondrial fission-and-fusion dynamics have been linked to the onset and propagation of neuroinflammation and neurodegeneration. However, cell-type-specific contributions and crosstalk between neurons, microglia, and astrocytes in mitochondria-driven neurodegeneration after brain injury remain undefined. We developed a human three-dimensional in vitro triculture tissue model of a contusion injury composed of neurons, microglia, and astrocytes and examined the contributions of mitochondrial dysregulation to neuroinflammation and progression of injury-induced neurodegeneration. Pharmacological studies presented here suggest that fragmented mitochondria released by microglia are a key contributor to secondary neuronal damage progression after contusion injury, a pathway that requires astrocyte-microglia crosstalk. Controlling mitochondrial dysfunction thus offers an exciting option for developing therapies for TBI patients.

创伤性脑损伤引起的线粒体分裂-融合动力学紊乱与神经炎症和神经退行性变的发生和发展有关。然而，创伤后脑损伤后神经元、小胶质细胞和星形胶质细胞中线粒体驱动的神经退行性变中细胞类型特异性的贡献和串扰仍然不清楚。我们开发了一种由神经元、小胶质细胞和星形胶质细胞组成的体外创伤性挫伤三维共培养组织模型，并研究了线粒体功能障碍对神经炎症和损伤诱导的神经退行性变进展的影响。本文提出的药理学研究表明，小胶质细胞释放的碎片化线粒体是挫伤后继发性神经元损伤进展的关键因素，这一途径需要星形胶质细胞-小胶质细胞串扰。因此，控制线粒体功能障碍为创伤性脑损伤患者的治疗提供了一个令人兴奋的选择。