Development of a 3D Brain Model to Study Sex-Specific Neuroinflammation After Hemorrhagic Stroke.
Development of a 3D Brain Model to Study Sex-Specific Neuroinflammation After Hemorrhagic Stroke.
复制标题
开发 3D 大脑模型来研究出血性中风后性别特异性神经炎症。
DOI：
10.1007/s12975-024-01243-y
复制
发表时间：
2024
影响因子：
6.9
通讯作者：
Hanafy,KhalidA
中科院分区：
文献类型：
--
作者：
Islam,Rezwanul;Choudhary,HadiHasan;Mehta,Hritik;Zhang,Feng;Jovin,TudorG;Hanafy,KhalidA
蛛网膜下腔出血（SAH）占中风的5%，与男性相比，女性的炎症反应降低;然而，这种机制尚未确定。SAH研究的一个障碍是缺乏人类大脑模型。在小鼠模型中的研究是有帮助的，但人类模型应结合使用，以提高可翻译性。这些观察结果使我们开发了一个3D系统，以研究性别特异性小胶质细胞和神经胶质细胞的功能在一个新的体外人类SAH模型，并将其与我们验证的体内SAH模型进行比较。我们的实验室已经开发了一个3D的，基于膜的体外细胞培养系统与人类星形胶质细胞，小胶质细胞和神经元从两种性别。将3D培养物与来自Neuro-ICU中SAH患者的男性和女性脑脊液一起孵育。此外，小胶质细胞形态，红细胞吞噬，小胶质细胞炎性细胞因子的产生，和神经元凋亡进行了研究，并与我们的小鼠SAH模型进行了比较。人类3D系统展示了与成人大脑相似的三种细胞类型的细胞间相互作用和比例。SAH的体外和体内模型显示，通过形态学和流式细胞术，雄性小胶质细胞比雌性更具炎症性。相反，体外和体内模型都显示，雌性小胶质细胞比雄性更具有吞噬作用，更不容易损伤神经元。雌性小胶质细胞吞噬能力增加的一个可能解释是CD 206和MerTK表达增加。当比较性别时，我们的体外人3D细胞培养SAH模型在小胶质细胞形态、炎症和吞噬作用方面显示出与我们的体内鼠SAH模型相似的结果。SAH的人类3D大脑模型可能是鼠模型的有用辅助，以改善对SAH患者的转化。
Subarachnoid hemorrhage (SAH) accounts for 5% of stroke, with women having a decreased inflammatory response compared to men; however, this mechanism has yet to be identified. One hurdle in SAH research is the lack of human brain models. Studies in murine models are helpful, but human models should be used in conjunction for improved translatability. These observations lead us to develop a 3D system to study the sex-specific microglial and neuroglial function in a novel in vitro human SAH model and compare it to our validated in vivo SAH model. Our lab has developed a 3D, membrane-based in vitro cell culture system with human astrocytes, microglia, and neurons from both sexes. The 3D cultures were incubated with male and female cerebrospinal fluid from SAH patients in the Neuro-ICU. Furthermore, microglial morphology, erythrophagocytosis, microglial inflammatory cytokine production, and neuronal apoptosis were studied and compared with our murine SAH models. The human 3D system demonstrated intercellular interactions and proportions of the three cell types similar to the adult human brain. In vitro and in vivo models of SAH showed concordance in male microglia being more inflammatory than females via morphology and flow cytometry. On the contrary, both in vitro and in vivo models revealed that female microglia were more phagocytic and less prone to damaging neurons than males. One possible explanation for the increased phagocytic ability of female microglia was the increased expression of CD206 and MerTK. Our in vitro, human, 3D cell culture SAH model showed similar results to our in vivo murine SAH model with respect to microglial morphology, inflammation, and phagocytosis when comparing the sexes. A human 3D brain model of SAH may be a useful adjunct to murine models to improve translation to SAH patients.