Hic-5 is required for activation of pancreatic stellate cells and development of pancreatic fibrosis in chronic pancreatitis

Lin Gao,Masahito Noguchi,Xiao-Feng Lei,Shogo Haraguchi,Akira Miyazaki,Takuro Miyazaki,Joo-Ri Kim-Kaneyama,Tomokatsu Omoto,Aya Miyauchi

doi:10.1038/s41598-020-76095-1

Abstract

Accumulated evidence suggests that activated pancreatic stellate cells (PSCs) serve as the main source of the extracellular matrix proteins accumulated under the pathological conditions leading to pancreatic fibrosis in chronic pancreatitis (CP). However, little is known about the mechanisms of PSC activation. PSCs have morphologic and functional similarities to hepatic stellate cells, which are activated by hydrogen peroxide-inducible clone-5 (Hic-5), a TGF-β1-induced protein. In this study, we investigated whether Hic-5 activates PSCs, which promote pancreatic fibrosis development in CP. Hic-5-knockout and wild type mice were subjected to caerulein injection to induce CP. Hic-5 expression was strongly upregulated in activated PSCs from human CP tissue and from mouse pancreatic fibrosis in caerulein-induced CP. Hic-5 deficiency significantly attenuated mouse pancreatic fibrosis and PSC activation in the experimental murine CP model. Mechanistically, Hic-5 knock down significantly inhibited the TGF-β/Smad2 signaling pathway, resulting in reduced collagen production and α-smooth muscle actin expression in the activated PSCs. Taken together, we propose Hic-5 as a potential marker of activated PSCs and a novel therapeutic target in CP treatment.

Highlights

Accumulated evidence suggests that activated pancreatic stellate cells (PSCs) serve as the main source of the extracellular matrix proteins accumulated under the pathological conditions leading to pancreatic fibrosis in chronic pancreatitis (CP)
We performed an immunofluorescence staining of hydrogen peroxide-inducible clone-5 (Hic-5) and α-smooth muscle actin (α-SMA), which is a marker of activated PSCs
Both Hic-5 and α-SMA were not detected in quiescent PSCs (2 h and day 1 of culture), they were significantly upregulated in activated PSCs, suggesting that Hic-5 is a potential marker of activated PSCs

Summary

Introduction

Accumulated evidence suggests that activated pancreatic stellate cells (PSCs) serve as the main source of the extracellular matrix proteins accumulated under the pathological conditions leading to pancreatic fibrosis in chronic pancreatitis (CP). PSCs have morphologic and functional similarities to hepatic stellate cells, which are activated by hydrogen peroxide-inducible clone-5 (Hic-5), a TGF-β1-induced protein. There is accumulating evidence suggesting that activated pancreatic stellate cells (PSCs) are critical for the formation of extracellular matrix (ECM) in pancreatic fibrosis in C P3. PSCs have morphological and functional similarities to hepatic stellate cells (HSCs), which play a major role in liver fibrogenesis[6]. Hic-5-deficient mice show significantly reduced mouse liver fibrosis and HSC activation. Hic-5 enhanced the activation of HSCs by regulating TGF-β1-dependent Smad[2] and Hic-5 siRNA reduced liver fibrosis in carbon tetrachloride (CCL4)-treated mice. Hic-5 has been reported to be essential for matrix ECM deposition and remodeling in vivo[10]

Methods

Results

Conclusion