Volume 31, No 8, Aug 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 8, August 2021: 886-903

ORIGINAL ARTICLES

Sequential progenitor states mark the generation of pancreatic endocrine lineages in mice and humans

Xin-Xin Yu^1,2,3,4 , Wei-Lin Qiu¹ , Liu Yang^1,2,4 , Yan-Chun Wang⁵ , Mao-Yang He^3,6 , Dan Wang^1,2,4 , Yu Zhang^1,2,4 , Lin-Chen Li^2,3,4 , Jing Zhang⁵ , Yi Wang⁵ , Cheng-Ran Xu^1,2,3,*

¹Department of Human Anatomy, Histology, and Embryology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
²Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
³Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking University, Beijing 100871, China
⁴Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
⁵Haidian Maternal & Child Health Hospital, Beijing 100080, China
⁶PKU-Tsinghua-NIBS Graduate Program, Peking University, Beijing 100871, China
These authors contributed equally: Xin-Xin Yu, Wei-Lin Qiu, Liu Yang, Yan-Chun Wang Correspondence: Cheng-Ran Xu(cxu@pku.edu.cn)

The pancreatic islet contains multiple hormone+ endocrine lineages (α, β, δ, PP and ε cells), but the developmental processes that underlie endocrinogenesis are poorly understood. Here, we generated novel mouse lines and combined them with various genetic tools to enrich all types of hormone+ cells for well-based deep single-cell RNA sequencing (scRNA-seq), and gene coexpression networks were extracted from the generated data for the optimization of high-throughput droplet-based scRNA-seq analyses. These analyses defined an entire endocrinogenesis pathway in which different states of endocrine progenitor (EP) cells sequentially differentiate into specific endocrine lineages in mice. Subpopulations of the EP cells at the final stage (EP4early and EP4late) show different potentials for distinct endocrine lineages. ε cells and an intermediate cell population were identified as distinct progenitors that independently generate both α and PP cells. Single-cell analyses were also performed to delineate the human pancreatic endocrinogenesis process. Although the developmental trajectory of pancreatic lineages is generally conserved between humans and mice, clear interspecies differences, including differences in the proportions of cell types and the regulatory networks associated with the differentiation of specific lineages, have been detected. Our findings support a model in which sequential transient progenitor cell states determine the differentiation of multiple cell lineages and provide a blueprint for directing the generation of pancreatic islets in vitro.

https://doi.org/10.1038/s41422-021-00486-w

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