Intestinal adipocytes transdifferentiate into myofibroblast-like cells and contribute to fibrosis in Crohn's disease

Zhijun Geng; Jing Li; Lugen Zuo; Xiaofeng Zhang; Lian Wang; Yongsheng Xia; Jingjing Yang; Lixia Yin; Xue Song; Yueyue Wang; Damin Chai; Min Deng; Yuanyuan Ge; Rong Wu; Jianguo Hu

doi:10.1093/ecco-jcc/jjae036

Intestinal adipocytes transdifferentiate into myofibroblast-like cells and contribute to fibrosis in Crohn's disease

J Crohns Colitis. 2024 Mar 11:jjae036. doi: 10.1093/ecco-jcc/jjae036. Online ahead of print.

Authors

Zhijun Geng^{1

2

3}, Jing Li^{2

3

4}, Lugen Zuo^{2

3

5}, Xiaofeng Zhang^{1

2

3}, Lian Wang^{2

5}, Yongsheng Xia⁵, Jingjing Yang⁵, Lixia Yin⁴, Xue Song^{1

2

3}, Yueyue Wang^{2

3

4}, Damin Chai^{2

6}, Min Deng^{2

7}, Yuanyuan Ge⁸, Rong Wu⁹, Jianguo Hu^{2

3

4}

Affiliations

¹ Department of Central Laboratory, First Affiliated Hospital of Bengbu Medical University, Bengbu, China.
² Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-related Diseases, Bengbu, China.
³ Inflammatory Bowel Disease Research Center,First Affiliated Hospital of Bengbu Medical University, Bengbu, China.
⁴ Department of Clinical Laboratory, First Affiliated Hospital of Bengbu Medical University, Bengbu, China.
⁵ Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China.
⁶ Department of Pathology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China.
⁷ Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China.
⁸ Department of Colorectal Surgery, The Third Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
⁹ Department of General Surgery, Zhongda Hospital, Southeast University, Nanjing, China.

PMID: 38466138
DOI: 10.1093/ecco-jcc/jjae036

Abstract

Background and aims: Intestinal fibrotic stenosis is a major reason for surgery in Crohn's disease [CD], but the mechanism is unknown. Thus, we asked whether intestinal adipocytes contribute to intestinal fibrosis. Adipocytes were found to transdifferentiate into myofibroblasts and confirmed to be involved in mesenteric fibrosis in our recent study. Here, we investigated the role and possible mechanisms of intestinal adipocytes in intestinal fibrosis in CD.

Methods: The intestinal tissue of patients with CD with or without fibrotic stenosis [CDS or CDN] and normal intestinal tissue from individuals without CD were obtained to assess alterations in submucosal adipocytes in CDS and whether these cells transdifferentiated into myofibroblasts and participated in the fibrotic process. Human primary adipocytes and adipose organoids were used to evaluate whether adipocytes could be induced to transdifferentiate into myofibroblasts and to investigate the fibrotic behaviour of adipocytes. LPS/TLR4/TGF-β signalling was also studied to explore the underlying mechanism.

Results: Submucosal adipocytes were reduced in number or even absent in CDS tissue, and the extent of the reduction correlated negatively with the degree of submucosal fibrosis. Interestingly, submucosal adipocytes in CDS tissue transdifferentiated into myofibroblast-like cells and expressed collagenous components, possibly due to stimulation by submucosally translocated bacteria. LPS-stimulated human primary adipocytes and adipose organoids also exhibited transdifferentiation and profibrotic behaviour. Mechanistically, TLR4-mediated TGF-β signalling was associated with the transdifferentiation and profibrotic behaviour of intestinal adipocytes in CDS tissue.

Conclusions: Intestinal adipocytes transdifferentiate into myofibroblasts and participate in the intestinal fibrosis process in CD, possibly through LPS/TLR4/TGF-β signalling.

Keywords: Crohn's disease; TLR4/TGF-β signalling; intestinal adipocytes; intestinal fibrotic stenosis; myofibroblast-like cells; transdifferentiate.