Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
Bioinformatics and Research Computing, Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
Proc Natl Acad Sci U S A. 2019 Dec 10;116(50):25293-25303. doi: 10.1073/pnas.1913541116. Epub 2019 Nov 26.
Microglia are essential for maintenance of normal brain function, with dysregulation contributing to numerous neurological diseases. Protocols have been developed to derive microglia-like cells from human induced pluripotent stem cells (hiPSCs). However, primary microglia display major differences in morphology and gene expression when grown in culture, including down-regulation of signature microglial genes. Thus, in vitro differentiated microglia may not accurately represent resting primary microglia. To address this issue, we transplanted microglial precursors derived in vitro from hiPSCs into neonatal mouse brains and found that the cells acquired characteristic microglial morphology and gene expression signatures that closely resembled primary human microglia. Single-cell RNA-sequencing analysis of transplanted microglia showed similar cellular heterogeneity as primary human cells. Thus, hiPSCs-derived microglia transplanted into the neonatal mouse brain assume a phenotype and gene expression signature resembling that of resting microglia residing in the human brain, making chimeras a superior tool to study microglia in human disease.
小胶质细胞对于维持正常的大脑功能至关重要，其功能失调会导致许多神经疾病。已经开发出了从人诱导多能干细胞（hiPSC）中获得类小胶质细胞的方案。然而，原代小胶质细胞在培养中表现出明显的形态和基因表达差异，包括标志性小胶质细胞基因的下调。因此，体外分化的小胶质细胞可能无法准确代表静息的原代小胶质细胞。为了解决这个问题，我们将体外从小胶质细胞诱导分化而来的 hiPSC 前体细胞移植到新生小鼠大脑中，发现这些细胞获得了与原代人小胶质细胞非常相似的特征性小胶质细胞形态和基因表达特征。移植的小胶质细胞的单细胞 RNA 测序分析显示出与原代人细胞相似的细胞异质性。因此，移植到新生小鼠大脑中的 hiPSC 衍生的小胶质细胞表现出类似于驻留在人脑内的静息小胶质细胞的表型和基因表达特征，使嵌合体成为研究人类疾病中小胶质细胞的优越工具。
