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Theranostics 2021; 11(5):2170-2181. doi:10.7150/thno.53136 This issue Cite

Research Paper

Clinical analysis and pluripotent stem cells-based model reveal possible impacts of ACE2 and lung progenitor cells on infants vulnerable to COVID-19

Zhao Zhang1,8#, Liyan Guo1#, Xiaoxia Lu12#, Che Zhang14#, Li Huang1,14#, Xianfeng Wang16#, Fuyu Duan1,15#, Huiying Liang2, Peikai Chen10, Liang Zeng3, Jianbo Shao16, Hui Li13, Le Li6, Li Liu9, Cheng Li8, Jinqiu Zhang1, Chui Yan Ma8, Ka Yi Kwan9, Wei Liu5, Yi Xu7, Xiaoqiong Gu4, Hua Jiang6, Hui Du12, Ting Zhang17, Yanheng Wu18, Guangyin Yu19, Junhui Chen19, Ruibang Luo11, Can Liao1, Hung-fat Tse8, Zhiwei Chen9, Huanhuan Joyce Chen15✉, Huimin Xia2✉, Qizhou Lian8,1,*,✉

1. Prenatal Diagnostic Center and Cord Blood Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
2. Guangdong Provincial Children's Medical Research Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
3. Department of Pathology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
4. Department of Clinical Biological Resource Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
5. Department of Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
6. Department of Haematology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
7. Department of Emergency Medicine, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
8. Department of Medicine, the University of Hong Kong, Hong Kong SAR, China
9. AIDS Institute and Department of Microbiology, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China
10. School of Biomedical Sciences, the University of Hong Kong, Hong Kong SAR, China
11. Department of Computer Science, the University of Hong Kong, Hong Kong SAR, China
12. Department of Respiratory Medicine, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
13. Department of Haematology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
14. Department of Paediatrics, Affiliated Taihe Hospital of Hubei University of Medicine, Shiyan, Hubei, China
15. The Pritzker school of Molecular Engineering, the Ben May department of Cancer Research, The University of Chicago, Chicago, USA
16. Department of Pediatric, Third People's Hospital of Shenzhen, Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China
17. Department of Pathology, Fuyang People's Hospital, Anhui, China
18. Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, Australia
19. Department of Pathology, Intervention and Cell Therapy Center, Peking University Shenzhen Hospital, Shenzhen, China
#These authors contributed equally to this study.
* Lead Contact

✉ Corresponding authors: Qizhou Lian, MD, PhD (Email: qzlianhk), Department of Medicine, The University of Hong Kong, Hong Kong. Or Huimin Xia (Email: huiminxiacom), Guangzhou Women and Children's Medical Center). Or Huanhuan Joyce Chen More

Citation:
Zhang Z, Guo L, Lu X, Zhang C, Huang L, Wang X, Duan F, Liang H, Chen P, Zeng L, Shao J, Li H, Li L, Liu L, Li C, Zhang J, Ma CY, Kwan KY, Liu W, Xu Y, Gu X, Jiang H, Du H, Zhang T, Wu Y, Yu G, Chen J, Luo R, Liao C, Tse Hf, Chen Z, Chen HJ, Xia H, Lian Q. Clinical analysis and pluripotent stem cells-based model reveal possible impacts of ACE2 and lung progenitor cells on infants vulnerable to COVID-19. Theranostics 2021; 11(5):2170-2181. doi:10.7150/thno.53136. https://www.thno.org/v11p2170.htm
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Abstract

Graphic abstract

Introduction: An increasing number of children with severe coronavirus disease 2019 (COVID-19) is being reported, yet the spectrum of disease severity and expression patterns of angiotensin-converting enzyme 2 (ACE2) in children at different developmental stages are largely unknow.

Methods: We analysed clinical features in a cohort of 173 children with COVID-19 (0-15 yrs.-old) between January 22, 2020 and March 15, 2020. We systematically examined the expression and distribution of ACE2 in different developmental stages of children by using a combination of children's lung biopsies, pluripotent stem cell-derived lung cells, RNA-sequencing profiles, and ex vivo SARS-CoV-2 pseudoviral infections.

Results: It revealed that infants (< 1yrs.-old), with a weaker potency of immune response, are more vulnerable to develop pneumonia whereas older children (> 1 yrs.-old) are more resistant to lung injury. The expression levels of ACE2 however do not vary by age in children's lung. ACE2 is notably expressed not only in Alveolar Type II (AT II) cells, but also in SOX9 positive lung progenitor cells detected in both pluripotent stem cell derivatives and infants' lungs. The ACE2+SOX9+ cells are readily infected by SARS-CoV-2 pseudovirus and the numbers of the double positive cells are significantly decreased in older children.

Conclusions: Infants (< 1 yrs.-old) with SARS-CoV-2 infection are more vulnerable to lung injuries. ACE2 expression in multiple types of lung cells including SOX9 positive progenitor cells, in cooperation with an unestablished immune system, could be risk factors contributing to vulnerability of infants with COVID-19. There is a need to continue monitoring lung development in young children who have recovered from SARS-CoV-2 infection.

Keywords: COVID-19, SARS-CoV-2 virus, children, lung development, vulnerability, ACE2, lung progenitor cells, single cell RNA sequencing, pluripotent stem cells

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APA
Zhang, Z., Guo, L., Lu, X., Zhang, C., Huang, L., Wang, X., Duan, F., Liang, H., Chen, P., Zeng, L., Shao, J., Li, H., Li, L., Liu, L., Li, C., Zhang, J., Ma, C.Y., Kwan, K.Y., Liu, W., Xu, Y., Gu, X., Jiang, H., Du, H., Zhang, T., Wu, Y., Yu, G., Chen, J., Luo, R., Liao, C., Tse, H.f., Chen, Z., Chen, H.J., Xia, H., Lian, Q. (2021). Clinical analysis and pluripotent stem cells-based model reveal possible impacts of ACE2 and lung progenitor cells on infants vulnerable to COVID-19. Theranostics, 11(5), 2170-2181. https://doi.org/10.7150/thno.53136.

ACS
Zhang, Z.; Guo, L.; Lu, X.; Zhang, C.; Huang, L.; Wang, X.; Duan, F.; Liang, H.; Chen, P.; Zeng, L.; Shao, J.; Li, H.; Li, L.; Liu, L.; Li, C.; Zhang, J.; Ma, C.Y.; Kwan, K.Y.; Liu, W.; Xu, Y.; Gu, X.; Jiang, H.; Du, H.; Zhang, T.; Wu, Y.; Yu, G.; Chen, J.; Luo, R.; Liao, C.; Tse, H.f.; Chen, Z.; Chen, H.J.; Xia, H.; Lian, Q. Clinical analysis and pluripotent stem cells-based model reveal possible impacts of ACE2 and lung progenitor cells on infants vulnerable to COVID-19. Theranostics 2021, 11 (5), 2170-2181. DOI: 10.7150/thno.53136.

NLM
Zhang Z, Guo L, Lu X, Zhang C, Huang L, Wang X, Duan F, Liang H, Chen P, Zeng L, Shao J, Li H, Li L, Liu L, Li C, Zhang J, Ma CY, Kwan KY, Liu W, Xu Y, Gu X, Jiang H, Du H, Zhang T, Wu Y, Yu G, Chen J, Luo R, Liao C, Tse Hf, Chen Z, Chen HJ, Xia H, Lian Q. Clinical analysis and pluripotent stem cells-based model reveal possible impacts of ACE2 and lung progenitor cells on infants vulnerable to COVID-19. Theranostics 2021; 11(5):2170-2181. doi:10.7150/thno.53136. https://www.thno.org/v11p2170.htm

CSE
Zhang Z, Guo L, Lu X, Zhang C, Huang L, Wang X, Duan F, Liang H, Chen P, Zeng L, Shao J, Li H, Li L, Liu L, Li C, Zhang J, Ma CY, Kwan KY, Liu W, Xu Y, Gu X, Jiang H, Du H, Zhang T, Wu Y, Yu G, Chen J, Luo R, Liao C, Tse Hf, Chen Z, Chen HJ, Xia H, Lian Q. 2021. Clinical analysis and pluripotent stem cells-based model reveal possible impacts of ACE2 and lung progenitor cells on infants vulnerable to COVID-19. Theranostics. 11(5):2170-2181.

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