Human placental extract improves liver cirrhosis in mice with regulation of macrophages and senescent cells
Open accessAbstract
Cirrhosis is a disease with poor prognosis that requires the development of a novel therapeutic approach alternative to liver transplantation. In this study, we focused on the placenta and aimed to clarify the effects of human placental extract (HPE) on cirrhosis. A mouse model of carbon tetrachloride-induced cirrhosis was used to evaluate the effect of HPE administration subcutaneously and compared with the control group (n = 8 for each group). In vitro and in vivo , real time-PCR and immunostaining were performed for HPE mechanistic analysis. Spatial transcriptomics was also performed for detailed analysis of the effect of HPE on cirrhosis. HPE administration improved serum ALT levels compared to control mice. Furthermore, there was a decrease in the number of senescent cells in the liver and the mRNA levels of secrete senescence-associated secretory phenotype factors and Cdkn2a (p16) . In vitro, HPE induced macrophage polarization to the anti-inflammatory M2 phenotype. Spatial transcriptomics was also performed to analyze the underlying anti-inflammatory mechanism. The results showed that HPE strongly polarized macrophages to the M2 phenotype, especially in macrophage-rich regions in the liver. Gene expression pathway analysis using spatial transcriptomics also revealed the possibility of improving senescent cell-derived inflammation via mitochondrial function. HPE improves serum ALT levels via anti-inflammatory mechanisms in macrophages and senescent cells. HPE serves as a novel agent for cirrhosis treatment. Schematic representation of the mechanisms underlying the improvement of cirrhosis after human placental extract (HPE) administration subcutaneously in mice. (A) HPE polarizes macrophages into the anti-inflammatory M2 phenotype, especially in macrophage-rich regions of the liver, via genes of the CYP2 family. (B) HPE suppresses the senescence-associated secretory phenotype (SASP) by reducing the senescent cells. • HPE administration improved serum ALT levels in CCl 4 -induced mice cirrhotic model. • HPE polarized macrophages to M2 phenotype, especially in macrophage rich regions. • HPE suppressed senescent cells-derived inflammation in the liver of cirrhosis. • Spatial transcriptomics suggests anti-senescence and anti-inflammation of HPE.
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Improved mitochondrial function, including enhanced oxidative phosphorylation and mitochondrial biogenesis, is consistently associated with macrophage reprogramming and fibrosis resolution.
“Conversely, improved mitochondrial function -including enhanced oxidative phosphorylation and mitochondrial biogenesis- has been consistently associated with macrophage reprogramming and fibrosis resolution (28–31).”
From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [28]
The Results sections report enrichment of mitochondrial-function pathways, including mitochondrial biogenesis, in macrophage-rich liver regions and evidence of macrophage polarization after HPE treatment. They do not establish enhanced oxidative phosphorylation or a consistent association across studies. The Results and Discussion explicitly report no significant improvement in liver fibrosis, so fibrosis resolution is not supported. (LLM, conf=0.88)
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- Authors
- Ishikawa, N., Watanabe, Y., Maeda, Y., Yoshida, T., Kimura, N., Abe, H., Sakamaki, A., Kamimura, H., Yokoo, T., Kamimura, K., Tsuchiya, A., & Terai, S.
- Affiliations
- Niigata University (JP)
- Corresponding author
- Watanabe, Yusuke
- Terai, Shuji
- ORCID
- Venue
- Regenerative Therapy
- Publisher
- Elsevier BV
- Published
- 2025-03
- Volume
- 28
- Pages
- 509-516
- ISSN
- 2352-3204 (ISSN-L)
- PMC
- PMC11846928
- OpenAlex
- W4407141774
- Cited by
- 6
- References
- 34
- Citations by year
- 2026: 3 · 2025: 3
- FWCI
- 3.37
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Regenerative Therapy (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)
- Funders
- Japan Society for the Promotion of Science (21K15993, 23K24316)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- human placental extract, liver cirrhosis, carbon tetrachloride-induced cirrhosis, macrophage polarization, M2 macrophage phenotype, senescence-associated secretory phenotype, senescent cells, CDKN2A/p16, mitochondrial function, liver inflammation, ALT levels, anti-inflammatory therapy
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