Single-cell RNA sequencing and analysis of high endothelial venule in chronic obstructive pulmonary disease for immune cell recruitment_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

PENG Ling ^1,2 ^# , ZHANG Hua ³ ^# , TONG Xia ^1,2 ,  ZHANG Xin ^2,4 ,  ZHANG Lanlan ¹

1. Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. West China (Airport) Hospital of Sichuan University (The First People’s Hospital of Shuangliu District, Chengdu), Chengdu, Sichuan 610200, P. R. China;
3. West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
4. Division of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

ZHANG Xin, Email: llzhang@scu.edu.cn; ZHANG Lanlan, Email: xinzhang201618@gmail.com

Keywords：

Computational biology; bioinformatics; high endothelial venule; chronic obstructive pulmonary disease; single cell sequencing technology; immune regulation

DOI：

10.7507/1671-6205.202201039

Video：

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Objective To explore the role of high endothelial venule (HEV) in chronic obstructive pulmonary disease (COPD) at the single cell level. Methods A total of 219257 cells from the lung tissues of 18 COPD patients and 28 healthy controls in the GEO public database (GSE136831) were used to analyze the relationship between HEV with T lymphocytes, B lymphocytes, and dendritic cells. Results Endothelial cells were extracted using single cell analysis technique, and sorting out venous endothelium, CCL14, IGFBP7, POSTN were used as marker genes for HEV endothelial cells. The ratio of HEV endothelial cells was also identified as up-regulated expression in COPD. The function of the differential genes of HEV endothelial cells was analyzed, suggesting the presence of immune regulation. By trajectory analysis, it was suggested that the differential genes of HEV endothelial cells were enriched for extracellular matrix deposition in late development. Finally, by receptor-ligand pairing, it was suggested that HEV endothelial cells was recruited through a series of ligands with T lymphocytes, B lymphocytes, and dendritic cells. Conclusions HEV endothelial cells are elevated in COPD and have an immunomodulatory role by secreting a series of ligands after recruiting T lymphocytes, B lymphocytes as well as dendritic cells for immune action. HEV may be a potential target for the study of COPD therapy.

Citation： PENG Ling, ZHANG Hua, TONG Xia, ZHANG Xin, ZHANG Lanlan. Single-cell RNA sequencing and analysis of high endothelial venule in chronic obstructive pulmonary disease for immune cell recruitment. Chinese Journal of Respiratory and Critical Care Medicine, 2022, 21(3): 170-177. doi: 10.7507/1671-6205.202201039 Copy

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33.	Park HS, Kim YM, Kim S, et al. High endothelial venule is a surrogate biomarker for T-cell inflamed tumor microenvironment and prognosis in gastric cancer. J Immunother Cancer, 2021, 9(10): e003353.
34.	Alter P, Baker Jr, Dauletbaev N, et al. Update in chronic obstructive pulmonary disease 2019. Am J Respir Crit Care Med, 2020, 202(3): 348-355.
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1. Holzmann B, Weissman IL. Integrin molecules involved in lymphocyte homing to Peyer's patches. Immunol Rev, 1989, 108: 45-61.
2. Milutinovic S, Abe J, Godkin A, et al. The dual role of high endothelial venules in cancer progression versus immunity. Trends Cancer, 2021, 7(3): 214-225.
3. Vella G, Guelfi S, Bergers G. High endothelial venules: a vascular perspective on tertiary lymphoid structures in cancer. Front Immunol, 2021, 12: 736670.
4. Dieu-Nosjean MC, Goc J, Giraldo NA, et al. Tertiary lymphoid structures in cancer and beyond. Trends Immunol, 2014, 35(11): 571-80.
5. Allen E, Jabouille A, Rivera LB, et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci Transl Med, 2017, 9(385): eaak9679.
6. Blanchard L, Girard JP. High endothelial venules (HEVs) in immunity, inflammation and cancer. Angiogenesis, 2021, 24(4): 719-753.
7. Barnes PJ. Cellular and molecular mechanisms of asthma and COPD. Clin Sci (Lond), 2017, 131(13): 1541-1558.
8. Barnes PJ. Inflammatory endotypes in COPD. Allergy, 2019, 74(7): 1249-1256.
9. Brightling C, Greening N. Airway inflammation in COPD: progress to precision medicine. Eur Respir J, 2019, 54(2): 1900651.
10. Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med, 2004, 350(26): 2645-2653.
11. Adams TS, Schupp JC, Poli S, et al. Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis. Sci Adv, 2020, 6(28): eaba1983.
12. Butler A, Hoffman P, Smibert P, et al. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol, 2018, 36(5): 411-420.
13. Aljanahi AA, Danielsen M, Dunbar CE. An introduction to the analysis of single-cell RNA-sequencing data. Mol Ther Methods Clin Dev, 2018, 10: 189-196.
14. Mercer TR, Neph S, Dinger ME, et al. The human mitochondrial transcriptome. Cell, 2011, 146(4): 645-658.
15. Vallejos CA, Risso D, Scialdone A, et al. Normalizing single-cell RNA sequencing data: challenges and opportunities. Nat Methods, 2017, 14(6): 565-571.
16. Korsunsky I, Millard N, Fan J, et al. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat Methods, 2019, 16(12): 1289-1296.
17. Kiselev VY, Andrews TS, Hemberg M. Challenges in unsupervised clustering of single-cell RNA-seq data. Nat Rev Genet, 2019, 20(5): 273-282.
18. Foroutan M, Bhuva DD, Lyu R, et al. Single sample scoring of molecular phenotypes. BMC Bioinformatics, 2018, 19(1): 404.
19. Goshua G, Pine AB, Meizlish ML, et al. Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. Lancet Haematol, 2020, 7(8): e575-e582.
20. Schupp JC, Adams TS, Cosme C Jr, et al. Integrated single-cell atlas of endothelial cells of the human lung. Circulation, 2021, 144(4): 286-302.
21. Travaglini KJ, Nabhan AN, Penland L, et al. A molecular cell atlas of the human lung from single-cell RNA sequencing. Nature, 2020, 587(7835): 619-625.
22. Pan Y, Wang WD, Yago T. Transcriptional regulation of podoplanin expression by Prox1 in lymphatic endothelial cells. Microvasc Res, 2014, 94: 96-102.
23. Goveia J, Rohlenova K, Taverna F, et al. An integrated gene expression landscape profiling approach to identify lung tumor endothelial cell heterogeneity and angiogenic candidates. Cancer Cell, 2020, 37(1): 21-36.e13.
24. Aibar S, González-Blas CB, Moerman T, et al. SCENIC: single-cell regulatory network inference and clustering. Nat Methods, 2017, 14(11): 1083-1086.
25. Cao J, Spielmann M, Qiu X, et al. The single-cell transcriptional landscape of mammalian organogenesis. Nature, 2019, 566(7745): 496-502.
26. Qiu X, Mao Q, Tang Y, et al. Reversed graph embedding resolves complex single-cell trajectories. Nat Methods, 2017, 14(10): 979-982.
27. Browaeys R, Saelens W, Saeys Y. NicheNet: modeling intercellular communication by linking ligands to target genes. Nat Methods, 2020, 17(2): 159-162.
28. von Andrian UH. Intravital microscopy of the peripheral lymph node microcirculation in mice. Microcirculation, 1996, 3(3): 287-300.
29. Elewa YHA, Ichii O, Takada K, et al. Histopathological correlations between mediastinal fat-associated lymphoid clusters and the development of lung inflammation and fibrosis following bleomycin administration in mice. Front Immunol, 2018, 9: 271.
30. Frija-Masson J, Martin C, Regard L, et al. Bacteria-driven peribronchial lymphoid neogenesis in bronchiectasis and cystic fibrosis. Eur Respir J, 2017, 49(4): 1601873.
31. Van Dinther-Janssen AC, Van Maarsseveen TC, Eckert H, et al. Identical expression of ELAM-1, VCAM-1, and ICAM-1 in sarcoidosis and usual interstitial pneumonitis. J Pathol, 1993, 170(2): 157-164.
32. Colbeck EJ, Jones E, Hindley JP, et al. Treg depletion licenses T cell-driven HEV neogenesis and promotes tumor destruction. Cancer Immunol Res, 2017, 5(11): 1005-1015.
33. Park HS, Kim YM, Kim S, et al. High endothelial venule is a surrogate biomarker for T-cell inflamed tumor microenvironment and prognosis in gastric cancer. J Immunother Cancer, 2021, 9(10): e003353.
34. Alter P, Baker Jr, Dauletbaev N, et al. Update in chronic obstructive pulmonary disease 2019. Am J Respir Crit Care Med, 2020, 202(3): 348-355.
35. Caramori G, Casolari P, Barczyk A, et al. COPD immunopathology. Semin Immunopathol, 2016, 38(4): 497-515.
36. Gretz JE, Anderson AO, Shaw S. Cords, channels, corridors and conduits: critical architectural elements facilitating cell interactions in the lymph node cortex. Immunol Rev, 1997, 156: 11-24.
37. Kumar V, Scandella E, Danuser R, et al. Global lymphoid tissue remodeling during a viral infection is orchestrated by a B cell-lymphotoxin-dependent pathway. Blood, 2010, 115(23): 4725-4733.
38. Veerman K, Tardiveau C, Martins F, et al. Single-cell analysis reveals heterogeneity of high endothelial venules and different regulation of genes controlling lymphocyte entry to lymph nodes. Cell Rep, 2019, 26(11): 3116-3131.e5.

Chinese Journal of Respiratory and Critical Care Medicine

Single-cell RNA sequencing and analysis of high endothelial venule in chronic obstructive pulmonary disease for immune cell recruitment

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