Kodali Maheedhar, Madhu Leelavathi N, Reger Roxanne L, Milutinovic Bojana, Upadhya Raghavendra, Attaluri Sahithi, Shuai Bing, Shankar Goutham, Shetty Ashok K
Institute for Regenerative Medicine, Department of Cell Biology and Genetics, Texas A&M University School of Medicine, College Station, TX, United States.
Front Mol Neurosci. 2023 May 22;16:1185883. doi: 10.3389/fnmol.2023.1185883. eCollection 2023.
An optimal intranasal (IN) dose of human mesenchymal stem cell-derived extracellular vesicles (hMSC-EVs), 90 min post-traumatic brain injury (TBI), has been reported to prevent the evolution of acute neuroinflammation into chronic neuroinflammation resulting in the alleviation of long-term cognitive and mood impairments. Since hippocampal neurogenesis decline and synapse loss contribute to TBI-induced long-term cognitive and mood dysfunction, this study investigated whether hMSC-EV treatment after TBI can prevent hippocampal neurogenesis decline and synapse loss in the chronic phase of TBI. C57BL6 mice undergoing unilateral controlled cortical impact injury (CCI) received a single IN administration of different doses of EVs or the vehicle at 90 min post-TBI. Quantifying neurogenesis in the subgranular zone-granule cell layer (SGZ-GCL) through 5'-bromodeoxyuridine and neuron-specific nuclear antigen double labeling at ~2 months post-TBI revealed decreased neurogenesis in TBI mice receiving vehicle. However, in TBI mice receiving EVs (12.8 and 25.6 × 10 EVs), the extent of neurogenesis was matched to naive control levels. A similar trend of decreased neurogenesis was seen when doublecortin-positive newly generated neurons were quantified in the SGZ-GCL at ~3 months post-TBI. The above doses of EVs treatment after TBI also reduced the loss of pre-and post-synaptic marker proteins in the hippocampus and the somatosensory cortex. Moreover, at 48 h post-treatment, brain-derived neurotrophic factor (BDNF), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), and phosphorylated cyclic AMP response-element binding protein (p-CREB) levels were downregulated in TBI mice receiving the vehicle but were closer to naïve control levels in TBI mice receiving above doses of hMSC-EVs. Notably, improved BDNF concentration observed in TBI mice receiving hMSC-EVs in the acute phase was sustained in the chronic phase of TBI. Thus, a single IN dose of hMSC-EVs at 90 min post-TBI can ease TBI-induced declines in the BDNF-ERK-CREB signaling, hippocampal neurogenesis, and synapses.
据报道，在创伤性脑损伤（TBI）后90分钟给予最佳鼻内（IN）剂量的人间充质干细胞衍生的细胞外囊泡（hMSC-EV），可防止急性神经炎症演变为慢性神经炎症，从而减轻长期认知和情绪障碍。由于海马神经发生减少和突触丢失导致TBI引起的长期认知和情绪功能障碍，本研究调查了TBI后hMSC-EV治疗是否可以预防TBI慢性期海马神经发生减少和突触丢失。遭受单侧控制性皮质撞击伤（CCI）的C57BL6小鼠在TBI后90分钟接受单次鼻内给予不同剂量的细胞外囊泡或赋形剂。在TBI后约2个月通过5'-溴脱氧尿苷和神经元特异性核抗原双重标记定量颗粒下区-颗粒细胞层（SGZ-GCL）中的神经发生，结果显示接受赋形剂的TBI小鼠神经发生减少。然而，在接受细胞外囊泡（12.8和25.6×10个细胞外囊泡）的TBI小鼠中，神经发生程度与未受伤对照水平相当。在TBI后约3个月对SGZ-GCL中双皮质素阳性的新生神经元进行定量时，也观察到了类似的神经发生减少趋势。TBI后上述剂量的细胞外囊泡治疗还减少了海马和体感皮层中突触前和突触后标记蛋白的丢失。此外，在治疗后48小时，接受赋形剂的TBI小鼠中脑源性神经营养因子（BDNF）、磷酸化细胞外信号调节激酶1/2（p-ERK1/2）和磷酸化环磷酸腺苷反应元件结合蛋白（p-CREB）水平下调，但在接受上述剂量hMSC-EV的TBI小鼠中更接近未受伤对照水平。值得注意的是，在急性期接受hMSC-EV的TBI小鼠中观察到的BDNF浓度改善在TBI慢性期得以维持。因此，在TBI后90分钟单次鼻内给予hMSC-EV可以缓解TBI诱导的BDNF-ERK-CREB信号传导、海马神经发生和突触的下降。
