Bone Marrow Mesenchymal Stem Cells Can Prevent Pancreatic Fibrosis in Mice with Chronic Pancreatitis by Inhibiting the Activation of Pancreatic Stellate Cells

Tong Jin,1,* Haoxuan Cheng,1,* Miaomiao Li,1 Xue Wei,1 Xinye Wang,1 Xinyu Li,1 Guangyong Sun,2 Dong Zhang,2 Jianyu Hao,1 Xinjuan Liu1 1Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Laboratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xinjuan Liu, Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8, South Road of Workers Stadium, Chaoyang District, Beijing, 100020, People’s Republic of China, Email [email protected] Jianyu Hao, Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8, South Road of Workers Stadium, Chaoyang District, Beijing, 100020, People’s Republic of China, Email [email protected]: Chronic pancreatitis (CP) is a progressive fibroinflammatory disorder primarily driven by a complex interplay of environmental and genetic risk factors. Fibrosis, mediated by activated pancreatic stellate cells (PSCs), represents a key pathological feature of CP. Bone marrow mesenchymal stem cells (BMSCs) are known for their anti-fibrotic and anti-inflammatory properties; however, their role in pancreatic fibrosis remains inadequately understood.Aim of the Study: This study aims to investigate the effects of BMSCs on CP and elucidate the underlying mechanisms.Methods: To evaluate the effects of BMSCs on pancreatic tissue alterations in CP, a mouse CP model was established using Ceruletide, followed by tail vein injection of BMSCs. Histological assessments of pancreatic injury were performed using hematoxylin and eosin (H&E) staining and Masson’s trichrome staining. The role of BMSCs in PSC activation and function was investigated through co-culture experiments with PSCs. Furthermore, to elucidate the underlying mechanisms by which BMSCs influence PSCs, transcriptomic analysis of PSCs was performed to identify key molecules and signaling pathways.Results: In vivo, BMSCs mitigated pathological changes and collagen deposition while suppressing PSC activation in CP mice. In vitro, BMSCs inhibited PSC activation and function, as evidenced by reduced collagen secretion, decreased proliferation, and increased apoptosis. RNA sequencing identified the aryl hydrocarbon receptor (AhR) and peroxisome proliferator-activated receptor gamma (PPARγ) as potential key mediators. Notably, AhR antagonism reversed the inhibitory effects of BMSCs on PSCs and attenuated the BMSC-induced upregulation of PPARγ in PSCs.Conclusion: Transplantation of BMSCs suppresses PSCs activation and attenuates the pancreatic fibrosis in CP. This process may be mediated by the activation of AhR and PPARγ in PSC.Keywords: chronic pancreatitis, pancreatic stellate cells, pancreatic fibrosis, α-smooth muscle actin, bone marrow mesenchymal stem cells