| Project/Area Number |
20K08327
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 53010:Gastroenterology-related
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| Research Institution | Kanazawa University |
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Principal Investigator |
Nasti Alessandro 金沢大学, 医薬保健学総合研究科, 特任准教授 (20830871)
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| Co-Investigator(Kenkyū-buntansha) |
関 晃裕 金沢大学, 附属病院, 助教 (00733859)
酒井 佳夫 金沢大学, 医学系, 協力研究員 (80401925)
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| Project Period (FY) |
2020-04-01 – 2025-03-31
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| Project Status |
Granted (Fiscal Year 2023)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | NASH / SS / ADSC / uncultured ADSCs / SVF / Immune therapy / adipose tissue (AT) |
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| Outline of Research at the Start |
Nonalcoholic steatohepatitis (NASH) is a liver disease with no established treatment. Adipose tissue-derived stromal cells (ADSCs) are able to repair damaged tissues by means of immunomodulation and secretive ability; we will study the repairing of NASH cirrhosis by using NASH mice-derived ADSCs.
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| Outline of Annual Research Achievements |
Non-alcoholic fatty liver disease (NAFLD) affects millions of people worldwide, often leading to non-alcoholic steatohepatitis (NASH), fibrosis, and eventually cirrhosis. Despite its prevalence, effective treatments remain elusive due to limited understanding of the complex molecular mechanisms driving NAFLD progression. Adipose-derived stem cells (ADSCs) is a candidate for treating liver diseases, since ADSCs promote tissue repair and modulate immune responses. We established a murine model of NASH using high-fat diet feeding and assessed the effect of ADSC administration on liver histopathology and gene expression profiles. We discovered that ADSCs activated Notch signaling in the cirrhotic liver of NASH mice, resulting in enhanced HES1 expression - a downstream target of Notch - and increased numbers of HES1-expressing hepatocytes. To corroborate these findings, we performed immunohistochemistry analyses, revealing robust Notch receptor and ligand induction upon ADSC exposure. Given the known roles of Notch signaling in regulating cellular functions such as proliferation, differentiation, and apoptosis, we confirmed that ADSC-mediated Notch activation might influence liver regeneration and cell survival during NASH progression. Indeed, ADSC treatment promoted liver regeneration, evidenced by increased alpha-fetoprotein (AFP) expression - a marker of hepatic progenitor cells - in the livers of NASH animals. Furthermore, we showed that ADSCs mitigated apoptosis in NASH-cirrhotic liver tissue, marked by substantially fewer TUNEL-positive cells following ADSC intervention.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
Overall, this data provides novel insight into the therapeutic potential of ADSC therapy in managing NASH-associated liver injury. Notch signaling, as a critical mediator of ADSC-driven benefits, offers exciting prospects for refining current treatment paradigms and developing targeted interventions for patients afflicted by NAFLD and related disorders. Further investigation is warranted to fully understand the intricate interplay between ADSCs and Notch signaling in the context of liver physiology and pathophysiology. Although Covid-19 pandemic and the 2024 Noto Peninsula Earthquake slowed down the progression of the experiments in the FY2020-FY2023 period, the overall project is progressing smoothly.
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| Strategy for Future Research Activity |
For FY2024, we plan to use ADSCs as treatment for NASH, understanding the proven mechanism of reduced apoptosis in hepatocyte cell line, and how this effect might be dependent on Notch signaling.
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