IL6 supports long-term expansion of hepatocytes in vitro
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Abstract Hepatocytes are very difficult to expand in vitro. A few studies have demonstrated that chemical cocktails with growth factors or Wnt ligands can support long-term expansion of hepatocytes via dedifferentiation. However, the culture conditions are complex, and clonal expansion of hepatic progenitors with full differentiation capacity are rarely reported. Here, we discover IL6, combined with EGF and HGF, promotes long-term expansion (>30 passages in ~150 days with theoretical expansion of ~1035 times) of primary mouse hepatocytes in vitro in simple 2D culture, by converting hepatocytes into induced hepatic progenitor cells (iHPCs), which maintain the capacity of differentiation into hepatocytes. IL6 also supports the establishment of single hepatocyte-derived iHPC clones. The summation of the downstream STAT3, ERK and AKT pathways induces a number of transcription factors which support rapid growth. This physiological and simple way may provide ideas for culturing previously difficult-to-culture cell types and support their future applications.
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Induced hepatic progenitor cells proliferate for approximately 30 passages and thereafter redifferentiate to restore albumin secretion, CYP450 activity, glycogen storage, and LDL uptake, while rescuing Fah−/− mice following transplantation, supporting classification as true expansion.
“These iHPCs proliferate for approximately 30 passages and thereafter redifferentiate to restore albumin secretion, CYP450 activity, glycogen storage, and low-density lipoprotein (LDL) uptake, while also rescuing Fah−/− mice following transplantation, supporting classification as TE.”
From The Hepatocyte Expansion Paradox: A Review of In Vitro Challenges and Advances (2026) · cites this paper as [18]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredSeveral dramatic expansion results, including near-unlimited theoretical fold-expansion and multi-month clonal proliferation, have been demonstrated almost exclusively in mouse hepatocytes, whereas human systems have generally achieved more modest expansion with measurable trade-offs in redifferentiation and repopulation capacity at higher expansion levels.
“Several of the most dramatic expansion results reported to date—including near-unlimited theoretical fold-expansion and multi-month clonal proliferation—have been demonstrated almost exclusively in mouse hepatocytes [18,31], whereas human systems have generally achieved more modest expansion with measurable trade-offs in redifferentiation and repopulation capacity at higher expansion levels [4,17]”
From The Hepatocyte Expansion Paradox: A Review of In Vitro Challenges and Advances (2026) · cites this paper as [18]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredDose-response studies indicate that IL-6 initiates proliferation, but elevated IL-6 in conjunction with EGF/HGF maintains prolonged cycling.
“Dose–response studies indicate that IL-6 initiates proliferation, but elevated IL-6 in conjunction with EGF/HGF maintains prolonged cycling.”
From The Hepatocyte Expansion Paradox: A Review of In Vitro Challenges and Advances (2026) · cites this paper as [18]
Synchronized stimulation of IL-6, EGF, and HGF stimulates STAT3, ERK, and PI3K/AKT signaling pathways, facilitating transformation of adult hepatocytes into induced hepatic progenitor cells.
“The synchronized stimulation of IL-6, EGF, and HGF stimulates STAT3, ERK, and PI3K/AKT signaling pathways, facilitating the transformation of adult hepatocytes into induced hepatic progenitor cells (iHPCs) [18].”
From The Hepatocyte Expansion Paradox: A Review of In Vitro Challenges and Advances (2026) · cites this paper as [18]
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Unleashing endogenous regeneration by senolytics
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- Authors
- Guo, R., Jiang, M., Wang, G., Li, B., Jia, X., Ai, Y., Chen, S., Tang, P., Liu, A., Yuan, Q., & Xie, X.
- Affiliations
- Chinese Academy of Sciences (CN)
- Fudan University (CN)
- Nanchang University (CN)
- Corresponding author
- Xie, Xin
- ORCID
- Venue
- Nature Communications
- Published
- 2022-11-29
- Volume
- 13
- Issue
- 1
- Pages
- 7345-7345
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC9708838
- OpenAlex
- W4310240023
- Cited by
- 36
- References
- 62
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 10 · 2023: 6
- FWCI
- 4.17
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (82121005)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- interleukin-6, hepatocyte expansion, hepatocyte dedifferentiation, epidermal growth factor, hepatocyte growth factor, STAT3 signaling, ERK signaling, Akt signaling, hepatocyte differentiation, clonal expansion, primary hepatocytes
- MeSH terms
- Animals, Cell Differentiation, Clone Cells, Stem Cells, Interleukin-6, Hepatocytes, Mice
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