Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan.
GLIA Center, University of Yamanashi, Yamanashi, Japan.
Glia. 2021 Oct;69(10):2332-2348. doi: 10.1002/glia.23985. Epub 2021 Jul 26.
Microglia are the resident immune cells of the brain, and play essential roles in neuronal development, homeostatic function, and neurodegenerative disease. Human microglia are relatively different from mouse microglia. However, most research on human microglia is performed in vitro, which does not accurately represent microglia characteristics under in vivo conditions. To elucidate the in vivo characteristics of human microglia, methods have been developed to generate and transplant induced pluripotent or embryonic stem cell-derived human microglia into neonatal or adult mouse brains. However, its widespread use remains limited by the technical difficulties of generating human microglia, as well as the need to use immune-deficient mice and conduct invasive surgeries. To address these issues, we developed a simplified method to generate induced pluripotent stem cell-derived human microglia and transplant them into the brain via a transnasal route in immunocompetent mice, in combination with a colony stimulating factor 1 receptor antagonist. We found that human microglia were able to migrate through the cribriform plate to different regions of the brain, proliferate, and become the dominant microglia in a region-specific manner by occupying the vacant niche when exogenous human cytokine is administered, for at least 60 days.
小胶质细胞是大脑的常驻免疫细胞，在神经元发育、内稳态功能和神经退行性疾病中发挥着重要作用。人类小胶质细胞与小鼠小胶质细胞有很大的不同。然而，大多数关于人类小胶质细胞的研究都是在体外进行的，这并不能准确地代表体内条件下小胶质细胞的特征。为了阐明人类小胶质细胞的体内特征，已经开发了一些方法来生成诱导多能干细胞或胚胎干细胞衍生的人类小胶质细胞，并将其移植到新生或成年小鼠的大脑中。然而，由于生成人类小胶质细胞的技术难度以及需要使用免疫缺陷小鼠和进行侵入性手术，其广泛应用仍然受到限制。为了解决这些问题，我们开发了一种简化的方法来生成诱导多能干细胞衍生的人类小胶质细胞，并通过免疫活性小鼠的经鼻途径将其移植到大脑中，同时使用集落刺激因子 1 受体拮抗剂。我们发现，当给予外源性人类细胞因子时，人类小胶质细胞能够通过筛板迁移到大脑的不同区域，以特定的方式增殖，并通过占据空位成为优势小胶质细胞，这种情况至少持续 60 天。
