School of Biological Sciences, University of Nebraska-Lincoln, NE, United States.
Nebraska Center for Virology, University of Nebraska-Lincoln, NE, United States.
Front Immunol. 2021 May 21;12:672415. doi: 10.3389/fimmu.2021.672415. eCollection 2021.
Humanized bone marrow-liver-thymic (hu-BLT) mice develop a functional immune system in periphery, nevertheless, have a limited reconstitution of human myeloid cells, especially microglia, in CNS. Further, whether bone marrow derived hematopoietic stem and progenitor cells (HSPCs) can enter the brain and differentiate into microglia in adults remains controversial. To close these gaps, in this study we unambiguously demonstrated that human microglia in CNS were extensively reconstituted in adult NOG mice with human interleukin-34 transgene (hIL34 Tg) from circulating CD34+ HSPCs, nonetheless not in hu-BLT NOG mice, providing strong evidence that human CD34+ HSPCs can enter adult brain and differentiate into microglia in CNS in the presence of hIL34. Further, the human microglia in the CNS of hu-BLT-hIL34 NOG mice robustly supported HIV-1 infection reenforcing the notion that microglia are the most important target cells of HIV-1 in CNS and demonstrating its great potential as an model for studying HIV-1 pathogenesis and evaluating curative therapeutics in both periphery and CNS compartments.
人源化骨髓-肝-胸腺（hu-BLT）小鼠在外周会发展出功能性免疫系统，但在中枢神经系统（CNS）中，其对人类髓系细胞（尤其是小胶质细胞）的重建能力有限。此外，骨髓来源的造血干细胞和祖细胞（HSPCs）是否能进入大脑并在成人期分化为小胶质细胞仍存在争议。为了弥补这些空白，在这项研究中，我们明确证实，来自循环 CD34+HSPCs 的人白细胞介素 34 转基因（hIL34 Tg）可使成年 NOG 小鼠的中枢神经系统中的人小胶质细胞广泛重建，但 hu-BLT-NOG 小鼠中则不会，这有力地证明了人类 CD34+HSPCs 可在 hIL34 存在的情况下进入成人大脑并在 CNS 中分化为小胶质细胞。此外，hu-BLT-hIL34-NOG 小鼠中枢神经系统中的人小胶质细胞可强有力地支持 HIV-1 感染，这进一步证实了小胶质细胞是 HIV-1 在 CNS 中的最重要靶细胞，并展示了其作为研究 HIV-1 发病机制和评估外周和中枢神经系统中治疗方法的理想模型的巨大潜力。
