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Single-cell RNA sequencing reveals the developmental program underlying proximal–distal patterning of the human lung at the embryonic stage

Shangtao Cao^{1,2,3,4,†,*} , Huijian Feng^3,5,6,† , Hongyan Yi^2,7,† , Mengjie Pan^1,† , Lihui Lin^5,8,† , Yao Santo Zhang^3,† , Ziyu Feng^1,4,† , Weifang Liang³ , Baomei Cai¹ , Qi Li^2,9 , Zhi Xiong^3,5,8 , Qingmei Shen¹ , Minjing Ke^3,5,6 , Xing Zhao^2,9 , Huilin Chen^3,5,6 , Qina He^2,9 , Mingwei Min¹ , Quanyou Cai^3,5,6 , He Liu^3,4 , Jie Wang^5,8 , Duanqing Pei^7,10,* , Jiekai Chen^3,5,6,8,10,* , Yanlin Ma^2,9,*

¹Guangzhou Laboratory, Guangzhou, Guangdong, China
²Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, Hainan Provincial Clinical Research Center for Thalassemia, Reproductive Medical Center, International Technology Cooperation Base “China-Myanmar Joint Research Center for Prevention and Treatment of Regional Major Disease” By the Ministry of Science and Technology of China, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, Hainan, China
³Center for Cell Lineage and Atlas (CCLA), Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, Guangdong, China
⁴The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
⁵CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong, China
⁶University of the Chinese Academy of Sciences, Beijing, China
⁷Laboratory of Cell Fate Control, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
⁸Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong, China
⁹Key Laboratory of the Ministry of Education for Reproductive Health Diseases Research and Translation, Hainan Medical University, Haikou, Hainan, China
¹⁰Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong, China
^†These authors contributed equally: Shangtao Cao, Huijian Feng, Hongyan Yi, Mengjie Pan, Lihui Lin, Yao Santo Zhang, Ziyu Feng
* Correspondence: Shangtao Cao(cao_shangtao@gzlab.ac.cn)Duanqing Pei(peiduanqing@westlake.edu.cn)Jiekai Chen(chen_jiekai@gibh.ac.cn)Yanlin Ma(mayanlinma@hotmail.com)

The lung is the primary respiratory organ in human, in which the proximal airway and the distal alveoli are responsible for air conduction and gas exchange, respectively. However, the regulation of proximal–distal patterning at the embryonic stage of human lung development is largely unknown. Here we investigated the early lung development of human embryos at weeks 4–8 post fertilization (Carnegie stages 12–21) using single-cell RNA sequencing, and obtained a transcriptomic atlas of 169,686 cells. We observed discernible gene expression patterns of proximal and distal epithelia at week 4, upon the initiation of lung organogenesis. Moreover, we identified novel transcriptional regulators of the patterning of proximal (e.g., THRB and EGR3) and distal (e.g., ETV1 and SOX6) epithelia. Further dissection revealed various stromal cell populations, including an early-embryonic BDNF+ population, providing a proximal–distal patterning niche with spatial specificity. In addition, we elucidated the cell fate bifurcation and maturation of airway and vascular smooth muscle progenitor cells at the early stage of lung development. Together, our study expands the scope of human lung developmental biology at early embryonic stages. The discovery of intrinsic transcriptional regulators and novel niche providers deepens the understanding of epithelial proximal–distal patterning in human lung development, opening up new avenues for regenerative medicine.

https://doi.org/10.1038/s41422-023-00802-6

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