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Mesenchymal stem cells cultured under hypoxic conditions had a greater therapeutic effect on mice with liver cirrhosis compared to those cultured under normal oxygen conditions
Open accessAbstract
Mesenchymal stem cells (MSCs) can be easily expanded. They can be acquired from medical waste such as adipose and umbilical cord tissues, are influenced by culturing conditions, and exert anti-inflammatory, antioxidant, anti-fibrotic, and angiogenic effects. We analyzed the multi-directional effects of MSCs cultured under hypoxic conditions and their underlying mechanisms in the treatment of liver cirrhosis in a mouse model. Human bone marrow-derived MSCs cultured under hypoxic (5% O2; hypoMSCs) and normoxic (21% O2; norMSCs) conditions were compared by cap analysis of gene expression (CAGE) with or without serum from liver cirrhosis patients. The therapeutic effects of MSCs, including serum liver enzyme induction, fibrosis regression, and hepatic oxidative stress, were evaluated by injecting 1 × 106, 2 × 105, or 4 × 104 MSCs/mouse into the tail veins of mice with carbon tetrachloride (CCl4)-induced liver cirrhosis. Intravital imaging was performed with a two-photon excitation microscope to confirm the various MSC migration paths to the liver. CAGE analysis revealed that the RNA expression levels of prostaglandin E synthase (Ptges) and miR210 were significantly higher in hypoMSCs than in norMSCs. In vivo analysis revealed that both hypoMSCs and norMSCs reduced serum alanine aminotransferase, oxidative stress, and fibrosis compared to that in control mice in a dose-dependent manner. However, hypoMSCs had stronger therapeutic effects than norMSCs. We confirmed this observation by an in vitro study in which hypoMSCs changed macrophage polarity to an anti-inflammatory phenotype via prostaglandin E2 (PGE2) stimulation. In addition, miR210 reduced the rate of hepatocyte apoptosis. Intravital imaging after MSC administration showed that both cell types were primarily trapped in the lungs. Relatively a few hypoMSCs and norMSCs migrated to the liver. There were no significant differences in their distributions. The therapeutic effect of hypoMSCs was mediated by PGE2 and miR210 production and was greater than that of norMSCs. Therefore, MSCs can be manipulated to improve their therapeutic efficacy in the treatment of liver cirrhosis and could potentially serve in effective cell therapy. MSCs produce several factors with multidirectional effects and function as “conducting cells” in liver cirrhosis.
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Culturing MSCs in hypoxic conditions enhances their secretory, anti-apoptosis, and anti-fibrotic properties compared to the typically used 20% O2.
“Furthermore, culturing MSCs in hypoxic conditions also enhanced their secretory, anti-apoptosis, and anti-fibrotic properties than the typically used 20% O2 [356].”
From Mechanisms, efficacy, and future perspectives of cellular-based therapies for liver fibrosis/cirrhosis: focusing on mesenchymal stromal cells (2025) · cites this paper as [356]
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References 26 · Cited by 43
Research works printed but not linked: 24
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Metadata
- Authors
- Kojima, Y., Tsuchiya, A., Ogawa, M., Nojiri, S., Takeuchi, S., Watanabe, T., Nakajima, K., Hara, Y., Yamashita, J., Kikuta, J., Takamura, M., Ishii, M., & Terai, S.
- Affiliations
- Niigata University (JP)
- Nihon Pharmaceutical Co., Ltd. (Japan) (JP)
- The University of Osaka (JP)
- Corresponding author
- Tsuchiya, Atsunori
- Terai, Shuji
- ORCID
- Venue
- Regenerative Therapy
- Publisher
- Elsevier BV
- Published
- 2019-12
- Volume
- 11
- Pages
- 269-281
- ISSN
- 2352-3204 (ISSN-L)
- PMC
- PMC6813562
- OpenAlex
- W2974844443
- Cited by
- 43
- References
- 26
- Citations by year
- 2025: 10 · 2024: 2 · 2023: 11 · 2022: 5 · 2021: 8 · 2020: 6 · 2019: 1
- FWCI
- 2.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Regenerative Therapy (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- Funders
- Nihon Superior
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
- Keywords
- mesenchymal stem cells, hypoxic culture, liver cirrhosis, prostaglandin E2, miR-210, prostaglandin E synthase, macrophage polarization, hepatocyte apoptosis, liver fibrosis, oxidative stress, cell therapy, carbon tetrachloride-induced liver injury, intravital imaging
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