Theranostics 2023; 13(3):991-1009. doi:10.7150/thno.82552 This issue Cite

Research Paper

Exosomal STIMATE derived from type II alveolar epithelial cells controls metabolic reprogramming of tissue-resident alveolar macrophages

Zunyong Feng1,2,3,4, Zhou Jing6, Qiang Li6, Liuxi Chu1, YuXin Jiang7, Xuanbo Zhang3, Liang Yan6, Yinhua Liu5, Jing Jiang6, Ping Xu4, Qun Chen5, Ming Wang8, Hui Yang2, Guoren Zhou9✉, Xiaochun Jiang2✉, Xiaoyuan Chen3✉, Hongping Xia1,2,4✉

1. School of Biological Sciences and Medical Engineering & Zhongda Hospital, School of Medicine, Advanced Institute for Life and Health & Interdisciplinary Innovation Institute for Medicine and Engineering, Southeast University, Nanjing, China.
2. The Translational Research Institute for Neurological Disorders & Interdisciplinary Research Center of Neuromedicine and Chemical Biology of Wannan Medical College and Anhui Normal University, Department of Neurosurgery, the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, China.
3. Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Clinical Imaging Research Centre, Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, Singapore. Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore.
4. Department of Pathology, School of Basic Medical Sciences & Sir Run Run Hospital & Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing, China.
5. Department of Pathology & Central Laboratory Intensive & Care Unit, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, China.
6. Department of Anatomy & Biochemistry and Molecular Biology, Wannan Medical College, Wuhu, China.
7. Department of Pathogenic Biology and Immunology, School of Medicine, Jiaxing University, Jiaxing, China.
8. Department of Neurosurgery, The Second Xiangya Hospital, Central South University, Changsha, China.
9. Department of Oncology, Jiangsu Cancer Hospital and The Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Institute of Cancer Research, Nanjing, China.

Citation:
Feng Z, Jing Z, Li Q, Chu L, Jiang Y, Zhang X, Yan L, Liu Y, Jiang J, Xu P, Chen Q, Wang M, Yang H, Zhou G, Jiang X, Chen X, Xia H. Exosomal STIMATE derived from type II alveolar epithelial cells controls metabolic reprogramming of tissue-resident alveolar macrophages. Theranostics 2023; 13(3):991-1009. doi:10.7150/thno.82552. https://www.thno.org/v13p0991.htm
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Abstract

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Background: Complete abolition of alveolar epithelial cells (AECs) is characteristic of end-stage lung disease. Transplantation therapy of type II AECs (AEC-IIs) or AEC-IIs-derived exosomes (ADEs) have been proposed as a means of repairing injury and preventing fibrosis. However, the mechanism by which ADEs balances airway immunity and alleviates damage and fibrosis remains unknown.

Methods: We investigated STIM-activating enhancer-positive ADEs (STIMATE+ ADEs) in the lung of 112 ALI/ARDS and 44 IPF patients, and observed the correlation between STIMATE+ ADEs and subpopulation proportion and metabolic status of tissue-resident alveolar macrophages (TRAMs). We constructed the conditional knockout mice STIMATEsftpc, in which STIMATE was specifically knocked out in mouse AEC-IIs and observed the effects of STIMATE+ ADEs deficiency on disease progression, immune selection and metabolic switching of TRAMs. We constructed a BLM-induced AEC-IIs injury model to observe the salvage treatment of damage/fibrosis progression with STIMATE+ ADEs supplementation.

Results: In clinical analysis, the distinct metabolic phenotypes of AMs in ALI/ARFS and IPF were significantly perturbed by STIMATE+ ADEs. The immune and metabolic status of TRAMs in the lungs of STIMATEsftpc mice was imbalanced, resulting in spontaneous inflammatory injury and respiratory disorders. STIMATE+ ADEs are taken up by tissue-resident alveolar macrophages TRAMs to regulate high Ca2+ responsiveness and long-term Ca2+ signal transduction, which maintains M2-like immunophenotype and metabolism selection. This involves calcineurin (CaN)-PGC-1α pathway mediated mitochondrial biogenesis and mtDNA coding. In a bleomycin-induced mouse fibrosis model, supplementation with inhaled STIMATE+ ADEs lessened early acute injury, prevented advanced fibrosis, alleviated ventilatory impairment and reduced mortality.

Keywords: STIMATE, Exosome, ALI/ARDS, Alveolar macrophages, Type 2 alveolar epithelial.


Citation styles

APA
Feng, Z., Jing, Z., Li, Q., Chu, L., Jiang, Y., Zhang, X., Yan, L., Liu, Y., Jiang, J., Xu, P., Chen, Q., Wang, M., Yang, H., Zhou, G., Jiang, X., Chen, X., Xia, H. (2023). Exosomal STIMATE derived from type II alveolar epithelial cells controls metabolic reprogramming of tissue-resident alveolar macrophages. Theranostics, 13(3), 991-1009. https://doi.org/10.7150/thno.82552.

ACS
Feng, Z.; Jing, Z.; Li, Q.; Chu, L.; Jiang, Y.; Zhang, X.; Yan, L.; Liu, Y.; Jiang, J.; Xu, P.; Chen, Q.; Wang, M.; Yang, H.; Zhou, G.; Jiang, X.; Chen, X.; Xia, H. Exosomal STIMATE derived from type II alveolar epithelial cells controls metabolic reprogramming of tissue-resident alveolar macrophages. Theranostics 2023, 13 (3), 991-1009. DOI: 10.7150/thno.82552.

NLM
Feng Z, Jing Z, Li Q, Chu L, Jiang Y, Zhang X, Yan L, Liu Y, Jiang J, Xu P, Chen Q, Wang M, Yang H, Zhou G, Jiang X, Chen X, Xia H. Exosomal STIMATE derived from type II alveolar epithelial cells controls metabolic reprogramming of tissue-resident alveolar macrophages. Theranostics 2023; 13(3):991-1009. doi:10.7150/thno.82552. https://www.thno.org/v13p0991.htm

CSE
Feng Z, Jing Z, Li Q, Chu L, Jiang Y, Zhang X, Yan L, Liu Y, Jiang J, Xu P, Chen Q, Wang M, Yang H, Zhou G, Jiang X, Chen X, Xia H. 2023. Exosomal STIMATE derived from type II alveolar epithelial cells controls metabolic reprogramming of tissue-resident alveolar macrophages. Theranostics. 13(3):991-1009.

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