美国波士顿大学再生医学中心Darrell N. Kotton和美国卡内基梅隆大学Ziv Bar-Joseph合作揭示重建的单细胞命运轨迹定义了人类PSC来源的远端肺祖细胞分化过程中的血统可塑性窗口。这一研究成果2020年1月30日在线发表在国际学术期刊《细胞—干细胞》上。

他们在体外工程化人多能干细胞（PSC）的肺泡上皮2型细胞（AEC2），并使用具有慢病毒条形码的时间序列单细胞RNA测序，与主要胎儿和成人AEC2基准相比，分析它们的分化动力学。当原始肺祖细胞在体外分化时，他们观察到分叉的细胞命运轨迹，其中一些子代达到其AEC2命运目标，而其他子代则转向其他非肺内胚层命运。他们建立了一种连续状态隐马尔可夫模型，以识别信号的时间和类型，例如过度旺盛的Wnt反应，这些信号会诱导某些早期的多能NKX2-1 +祖细胞失去肺命运。最后，他们发现这种初始发育可塑性是可调节的，并且会随着时间而消退，最终导致PSC来源的AEC2表现出稳定的表型和几乎无限的自我更新能力。

据悉，AEC2s是兼职祖细胞，负责终生维持肺泡，但很难从患者中分离出来。

附：英文原文

Title: Reconstructed Single-Cell Fate Trajectories Define Lineage Plasticity Windows during Differentiation of Human PSC-Derived Distal Lung Progenitors

Author: Killian Hurley, Jun Ding, Carlos Villacorta-Martin, Michael J. Herriges, Anjali Jacob, Marall Vedaie, Konstantinos D. Alysandratos, Yuliang L. Sun, Chieh Lin, Rhiannon B. Werder, Jessie Huang, Andrew A. Wilson, Aditya Mithal, Gustavo Mostoslavsky, Irene Oglesby, Ignacio S. Caballero, Susan H. Guttentag, Farida Ahangari, Naftali Kaminski, Alejo Rodriguez-Fraticelli, Fernando Camargo, Ziv Bar-Joseph, Darrell N. Kotton

Issue&Volume: January 30, 2020

Abstract: Alveolar epithelial type 2 cells (AEC2s) are the facultative progenitors responsiblefor maintaining lung alveoli throughout life but are difficult to isolate from patients.Here, we engineer AEC2s from human pluripotent stem cells (PSCs) in vitro and use time-series single-cell RNA sequencing with lentiviral barcoding to profilethe kinetics of their differentiation in comparison to primary fetal and adult AEC2benchmarks. We observe bifurcating cell-fate trajectories as primordial lung progenitorsdifferentiate in vitro, with some progeny reaching their AEC2 fate target, while others diverge to alternativenon-lung endodermal fates. We develop a Continuous State Hidden Markov model to identifythe timing and type of signals, such as overexuberant Wnt responses, that induce someearly multipotent NKX2-1+ progenitors to lose lung fate. Finally, we find that this initial developmental plasticityis regulatable and subsides over time, ultimately resulting in PSC-derived AEC2s thatexhibit a stable phenotype and nearly limitless self-renewal capacity.

DOI: 10.1016/j.stem.2019.12.009

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30527-2