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High-mobility group box 1 fragment ameliorates chronic pancreatitis induced by caerulein in mice

  • Original Article―Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Chronic pancreatitis (CP) is a progressive disease characterized by pancreatic fibrosis for which effective treatment options are lacking. Mesenchymal stem cells (MSCs) have shown potential for fibrosis treatment but face limitations in clinical application. The high-mobility group box 1 (HMGB1) fragment mobilizes MSCs from bone marrow into the blood and has emerged as a promising therapeutic agent for tissue regeneration in various pathological conditions. The aim of this study was to investigate the potential therapeutic effects of systemic administration of the HMGB1 fragment in a mouse model of CP.

Methods

A caerulein-induced CP mouse model was used, and the HMGB1 fragment was administered by tail vein injection. Parameters such as body weight, pancreatic tissue damage, fibrosis, inflammatory cytokine expression, and collagen-related gene expression were evaluated using various assays, including immunohistochemistry, real-time PCR, serum analysis, and single-cell transcriptome analysis. And the migration of MSCs to the pancreas was evaluated using the parabiosis model.

Results

Administration of the HMGB1 fragment was associated with significant improvements in pancreatic tissue damage and fibrosis. It suppressed the expression of inflammatory cytokines and activated platelet-derived growth factor receptor-α+ MSCs, leading to their accumulation in the pancreas. The HMGB1 fragment also shifted gene expression patterns associated with pancreatic fibrosis toward those of the normal pancreas. Systemic administration of the HMGB1 fragment demonstrated therapeutic efficacy in attenuating pancreatic tissue damage and fibrosis in a CP mouse model.

Conclusion

These findings highlight the potential of the HMGB1 fragment as a therapeutic target for the treatment of CP.

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Data availability

All sequencing data used in this study were uploaded to GEO (https://www.ncbi.nlm.nih.gov/geo/; accession number: GSE247430). Other data are included in the manuscript and/or supporting information.

Abbreviations

AP:

Acute pancreatitis

α-SMA:

α-Smooth muscle actin

CTGF:

Connective tissue growth factor

CP:

Chronic pancreatitis

CXCR4:

C-X-C chemokine receptor 4

DEG:

Differentially expressed gene

FBS:

Fetal bovine serum

GFP:

Green fluorescent protein

H&E:

Hematoxylin and eosin

HMGB1:

High-mobility group box 1

LDH:

Lactate dehydrogenase

MSC:

Mesenchymal stem cell

PDGFRα:

Platelet-derived growth factor receptor-α

PSC:

Pancreatic stellate cell

SDF-1:

Stromal cell-derived factor 1

UMAP:

Uniform manifold approximation and projection

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Acknowledgements

Shogo Kobayashi received fees from AstraZeneca and Taiho for the time and energy spent attending a meeting or giving a presentation or advice. Katsuto Tamai reports financial support was provided by Stem RIM Inc. Takashi Shimbo received a research grant from Stem RIM Inc. Katsuto Tamai has patent issued to Osaka University, StemRIM.

The authors gratefully acknowledge all members of the Department of Gastroenterological Surgery and the Department of Stem Cell Therapy Science at Osaka University, and all the staff in StemRIM Institute of Regeneration-Inducing Medicine.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan

    Daiki Hokkoku, Kazuki Sasaki, Shogo Kobayashi, Hiroki Imamura, Takeshi Kado, Keisuke Toya, Wataru Fujii, Yoshifumi Iwagami, Daisaku Yamada, Yoshito Tomimaru, Takehiro Noda, Hidenori Takahashi, Yuichiro Doki & Hidetoshi Eguchi

  2. Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan

    Takashi Shimbo, Tomomi Kitayama, Sho Yamazaki, Yukari Yamamoto, Yuya Ouchi & Katsuto Tamai

  3. StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, Suita, Osaka, Japan

    Takashi Shimbo, Yukari Yamamoto & Yuya Ouchi

  4. StemRIM Inc, Ibaraki, Osaka, Japan

    Tomomi Kitayama & Sho Yamazaki

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Correspondence to Shogo Kobayashi.

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Supplementary Information

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535_2024_2112_MOESM1_ESM.tif

Supplementary file1 HMGB1 assay of serum from normal and CP model mice. No differences were found between serum HMGB1 in normal mice and serum HMGB1 in CP model mice (n = 5 per group). *P < 0.05. CP chronic pancreatitis, HMGB1 high-mobility group box 1 (TIF 859 KB)

535_2024_2112_MOESM2_ESM.tif

Supplementary file2 RT-PCR analysis of mRNA expression of mediator of fibrosis in control and HMGB1 pancreas tissue in the4th week (n = 5 per group). †P < 0.10 compared with the control group. *P < 0.05 compared with the control group. **P < 0.01 compared with the control group. Mmp2 matrix metalloproteinase-2, Mmp9 matrix metalloproteinase-9, Tgfb1 transforming growth factor beta 1, RT-PCR reverse transcription polymerase chain reaction (TIF 917 KB)

535_2024_2112_MOESM3_ESM.tif

Supplementary file3 Serum analysis in the control and HMGB1 groups. (a–c) Serum LDH, amylase, and lipase levels in the control and HMGB1 groups in the fourth, sixth, and eighth weeks (n = 5 per group). *P < 0.05 compared with the control group. **P < 0.01 compared with the control group. HMGB1 high-mobility group box 1, LDH lactate dehydrogenas (TIF 1486 KB)

535_2024_2112_MOESM4_ESM.tif

Supplementary file4 Effect of HMGB1 fragment administration in fully developed CP model mice. (a) Schematic of HMGB1 fragment administration for the CP model mice. Caerulein was administered to C57BL/6 male mice intraperitoneally six times a day, three times a week for 8 weeks. Four weeks after the initiation of caerulein administration, HMGB1 fragments or normal saline was administered intravenously (i.v.) three times a week for 4 weeks. (b) Body weight change in the control and HMGB1 groups (n = 5 per group). (c) Percent ratio of pancreas weight to body weight in the control and HMGB1 groups (n = 5 per group). *P < 0.05 compared with the control group. **P < 0.01 compared with the control group. (d) Representative H&E staining of pancreas tissue sections from the control (upper row) and HMGB1 (lower row) groups in the sixth and eighth weeks. Scale bars, 100 μm. (e) RT-PCR analysis of mRNA expression of inflammatory cytokines in control and HMGB1 pancreas tissue in the eighth week (n = 5 per group). *P < 0.05 compared with the control group. **P < 0.01 compared with the control group. (f) Representative Sirius Red-stained tissues and stained areas in the control and HMGB1 groups (n = 5 per group). *P < 0.05 compared with the control group. Scale bars, 100 μm. (g) Quantification of hydroxyproline levels at the sixth and eighth weeks in the control and HMGB1 groups (n = 5 per group). *P < 0.05 compared with the control group. CP chronic pancreatitis, H&E hematoxylin and eosin, HMGB1 high-mobility group box 1, HYP hydroxyproline, RT-PCR reverse transcription polymerase chain reaction (TIF 49852 KB)

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Hokkoku, D., Sasaki, K., Kobayashi, S. et al. High-mobility group box 1 fragment ameliorates chronic pancreatitis induced by caerulein in mice. J Gastroenterol (2024). https://doi.org/10.1007/s00535-024-02112-z

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