美国哈佛大学Vijay G. Sankaran等研究人员合作解码细胞状态和人类造血谱系。2024年1月22日，《自然》杂志在线发表了这一最新研究成果。
研究人员介绍了一种改进的单细胞谱系追踪系统，该系统基于对自然发生的线粒体DNA（mtDNA）突变的深度检测，并同时读出转录状态和染色质可及性。研究人员利用该系统确定了造血干细胞（HSC）的克隆结构，并绘制了克隆的生理状态和输出图谱。研究人员发现了HSC克隆的功能异质性，这种异质性在数月内保持稳定，并表现为HSC总输出量的差异以及产生不同成熟细胞类型的偏向。
研究人员还发现，随着年龄的增长，HSC克隆的多样性会急剧下降，从而形成具有多个不同克隆扩增的寡克隆结构。因此，这项研究首次以单细胞分辨率提供了克隆分辨和细胞状态感知的人类造血图谱，揭示了人类HSC克隆未被认识到的功能多样性，并为人类健康和疾病中一系列组织的克隆动态精细研究铺平了道路。
据悉，人类血液系统是通过数量有限的长寿命HSC的分化和大量扩增来维持的。这一过程受到干扰是导致多种疾病的原因，但人们对人类造血的克隆贡献以及这一过程如何随着年龄的增长而发生变化仍不甚了解。虽然最近在模型系统中进行的条形码研究得出了一些见解，但同时检测人类天然条形码中的细胞状态和系统发育一直是个挑战。
附：英文原文
Title: Deciphering cell states and genealogies of human hematopoiesis
Author: Weng, Chen, Yu, Fulong, Yang, Dian, Poeschla, Michael, Liggett, L. Alexander, Jones, Matthew G., Qiu, Xiaojie, Wahlster, Lara, Caulier, Alexis, Hussmann, Jeffrey A., Schnell, Alexandra, Yost, Kathryn E., Koblan, Luke, Martin-Rufino, Jorge D., Min, Joseph, Hammond, Alessandro, Ssozi, Daniel, Bueno, Raphael, Mallidi, Hari, Kreso, Antonia, Escabi, Javier, Rideout, William M., Jacks, Tyler, Hormoz, Sahand, van Galen, Peter, Weissman, Jonathan S., Sankaran, Vijay G.
Issue&Volume: 2024-01-22
Abstract: The human blood system is maintained through the differentiation and massive amplification of a limited number of long-lived hematopoietic stem cells (HSCs)1. Perturbations to this process underlie diverse diseases, but the clonal contributions to human hematopoiesis and how this changes with age remain incompletely understood. While recent insights have emerged from barcoding studies in model systems4,5,16,17, simultaneous detection of cell states and phylogenies from natural barcodes in humans has been challenging. Here, we introduce an improved single-cell lineage tracing system based on deep detection of naturally-occurring mitochondrial DNA (mtDNA) mutations with simultaneous readout of transcriptional states and chromatin accessibility. We use this system to define the clonal architecture of HSCs and map the physiological state and output of clones. We uncover functional heterogeneity in HSC clones, which is stable over months and manifests as differences in total HSC output as well as biases toward the production of different mature cell types. We also find that the diversity of HSC clones decreases dramatically with age leading to an oligoclonal structure with multiple distinct clonal expansions. Our study thus provides the first clonally-resolved and cell-state aware atlas of human hematopoiesis at single-cell resolution revealing an unappreciated functional diversity of human HSC clones and more broadly paves the way for refined studies of clonal dynamics across a range of tissues in human health and disease.
DOI: 10.1038/s41586-024-07066-z
Source: https://www.nature.com/articles/s41586-024-07066-z
来源：科学网 小柯机器人