Progressive Pulmonary Fibrosis Is Caused by Elevated Mechanical Tension on Alveolar Stem Cells
Authors: Ennan Bin
Huaping Dai
Yuanyuan Yu
Jin Zhang
Zheng Wang
Nan Tang
Chun Yang
Hongbin Zhang
Xi Zhao
Huijuan Wu
Yucheng Hu
Xueyi Yang
Jiao Li
Siling Fu
Tao Cai
Jie Yuan
Mengting Shi
Jingyu Chen
Huanwei Huang
Dong Wei
Journal: Cell (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: TGF-β signaling; regeneration associated intermediate cell state.
Affiliations: School of Life Sciences, Tsinghua University, Beijing 100084, China; National Institute of Biological Sciences, Beijing 102206, China., National Institute of Biological Sciences, Beijing 102206, China., Zhou Pei-yuan Center for Applied Mathematics, Tsinghua University, Beijing 100084, China., National Institute of Biological Sciences, Beijing 102206, China; Graduate School of Peking Union Medical College, Beijing 100730, China., Institute of Biomechanics and Medical Engineering, School of Aerospace Engineering, Tsinghua University, Beijing 100084, China., Wuxi Lung Transplantation Center, Wuxi People's Hospital Affiliated with Nanjing Medical University, Wuxi 214023, China., Department of Thoracic Surgery, Peking University International Hospital, Beijing 102206, China., Department of Thoracic Surgery, China-Japan Friendship Hospital, Beijing 100029, China., Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China., Wuxi Lung Transplantation Center, Wuxi People's Hospital Affiliated with Nanjing Medical University, Wuxi 214023, China. Electronic address: ., National Institute of Biological Sciences, Beijing 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 100084, China. Electronic address: .

Abstract:  Fibrosis can develop in most organs and causes organ failure. The most common type of lung fibrosis is known as idiopathic pulmonary fibrosis, in which fibrosis starts at the lung periphery and then progresses toward the lung center, eventually causing respiratory failure. Little is known about the mechanisms underlying the pathogenesis and periphery-to-center progression of the disease. Here we discovered that loss of Cdc42 function in alveolar stem cells (AT2 cells) causes periphery-to-center progressive lung fibrosis. We further show that Cdc42-null AT2 cells in both post-pneumonectomy and untreated aged mice cannot regenerate new alveoli, resulting in sustained exposure of AT2 cells to elevated mechanical tension. We demonstrate that elevated mechanical tension activates a TGF-β signaling loop in AT2 cells, which drives the periphery-to-center progression of lung fibrosis. Our study establishes a direct mechanistic link between impaired alveolar regeneration, mechanical tension, and progressive lung fibrosis. 

Retracted: No

PubPeer comments:
 Images in Figure 5F appear unexpectedly similar for different treatments. *** ![file] , 
 Thanks for your comments. In the original western data, we analyzed the expression of alpha-SMA and GAPDH in three different groups of mice, including 3-month old, 6-month old, and 12-month old mice (please see attached original scan). We did not investigate the scRNAseq analysis of 6-month old mice. Therefore we removed the result of 6-month old mice from the result.[file] ![file] , 
 #2 I think this response was intended for another thread: https: pubpeer.com publications 78B2E999CDD552AF6634A711685F9B , 
 Thank you very much for pointing out this mistake. The picture of Stretched+GSK3008348 treated sample was mistakenly picked. I am attaching the original pictures of three negative groups here. The original conclusion is not changed. We encourage other researchers to repeat our experiments. We will contact cell editors for correcting this mistake.![file] ![file] ![file] , 
 #4 Can you show the original data of +GSK group, since you mentioned you mis-used the pic for this one? , 
 The pictures above are original results from three experimental groups. The 3rd picture is the original data of +GSK group. And we have sent original results of all experimental groups to the editor for the correction purpose. , 
 February 4, 2021 (Cell 180, 107u2013121.e1u2013e17; January 9, 2020) In our paper we showed that the periphery-to-center progression of lung fibrosis is driven by a TGF-u03b2 signaling loop that is activated by mechanical tension in alveolar stem cells. It has come to our attention that in Figure 5F of our paper the image selected to represent cells from the stretched+GSK3008348 condition came from a non-stretched control image that was inadvertently mislabeled. This error has now been corrected using an image acquired from the raw data, which was properly labeled. The quantification shown in Figure 5G reflects the raw data and was not affected by this error. The new version of the figure is consistent with our reported conclusions. We sincerely apologize for any confusion that this error may have caused. ![file] Corrected Figure 5 *** ,