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Construction of a human cell landscape at single-cell level 期刊论文
NATURE, 2020, 581 (7808) : 303-+
作者:  Han, Yan;  Reyes, Alexis A.;  Malik, Sara;  He, Yuan
收藏  |  浏览/下载:11/0  |  提交时间:2020/07/03

Single-cell analysis is a valuable tool for dissecting cellular heterogeneity in complex systems(1). However, a comprehensive single-cell atlas has not been achieved for humans. Here we use single-cell mRNA sequencing to determine the cell-type composition of all major human organs and construct a scheme for the human cell landscape (HCL). We have uncovered a single-cell hierarchy for many tissues that have not been well characterized. We established a '  single-cell HCL analysis'  pipeline that helps to define human cell identity. Finally, we performed a single-cell comparative analysis of landscapes from human and mouse to identify conserved genetic networks. We found that stem and progenitor cells exhibit strong transcriptomic stochasticity, whereas differentiated cells are more distinct. Our results provide a useful resource for the study of human biology.


Single-cell RNA sequencing is used to generate a dataset covering all major human organs in both adult and fetal stages, enabling comparison with similar datasets for mouse tissues.


  
LRP1 is a master regulator of tau uptake and spread 期刊论文
NATURE, 2020, 580 (7803) : 381-+
作者:  Han, Yan;  Reyes, Alexis A.;  Malik, Sara;  He, Yuan
收藏  |  浏览/下载:7/0  |  提交时间:2020/07/03

The spread of protein aggregates during disease progression is a common theme underlying many neurodegenerative diseases. The microtubule-associated protein tau has a central role in the pathogenesis of several forms of dementia known as tauopathies-including Alzheimer'  s disease, frontotemporal dementia and chronic traumatic encephalopathy(1). Progression of these diseases is characterized by the sequential spread and deposition of protein aggregates in a predictable pattern that correlates with clinical severity(2). This observation and complementary experimental studies(3,4) have suggested that tau can spread in a prion-like manner, by passing to naive cells in which it templates misfolding and aggregation. However, although the propagation of tau has been extensively studied, the underlying cellular mechanisms remain poorly understood. Here we show that the low-density lipoprotein receptor-related protein 1 (LRP1) controls the endocytosis of tau and its subsequent spread. Knockdown of LRP1 significantly reduced tau uptake in H4 neuroglioma cells and in induced pluripotent stem cell-derived neurons. The interaction between tau and LRP1 is mediated by lysine residues in the microtubule-binding repeat region of tau. Furthermore, downregulation of LRP1 in an in vivo mouse model of tau spread was found to effectively reduce the propagation of tau between neurons. Our results identify LRP1 as a key regulator of tau spread in the brain, and therefore a potential target for the treatment of diseases that involve tau spread and aggregation.