Inflammatory Cytokine TNFα Promotes the Long-Term Expansion of Primary Hepatocytes in 3D Culture
Open accessAbstract
In the healthy adult liver, most hepatocytes proliferate minimally. However, upon physical or chemical injury to the liver, hepatocytes proliferate extensively in vivo under the direction of multiple extracellular cues, including Wnt and pro-inflammatory signals. Currently, liver organoids can be generated readily in vitro from bile-duct epithelial cells, but not hepatocytes. Here, we show that TNFα, an injury-induced inflammatory cytokine, promotes the expansion of hepatocytes in 3D culture and enables serial passaging and long-term culture for more than 6 months. Single-cell RNA sequencing reveals broad expression of hepatocyte markers. Strikingly, in vitro-expanded hepatocytes engrafted, and significantly repopulated, the injured livers of Fah-/- mice. We anticipate that tissue repair signals can be harnessed to promote the expansion of otherwise hard-to-culture cell-types, with broad implications.
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Organoids of murine intestines, livers, and pancreas were successfully transplanted into mice, and the transplanted organoids could restore organ dysfunction.
“Organoids of murine intestines31, livers35,125,126 and pancreas69,146 were successfully transplanted into mice, and the transplanted organoids could restore organ dysfunction.”
From Organoids (2022) · cites this paper as [125]
The Results section, “In vitro expanded hepatocytes engraft Fah-deficient mice” (page unavailable), reports transplantation of mouse hepatocyte 3D colonies into a liver-failure model and substantial engraftment. It reports functional markers in the engrafted cells, but does not establish that liver dysfunction was restored. The intestinal and pancreatic examples have separate citations in the citing sentence and are not attributed to this paper. (LLM, conf=0.84)
Experimental — accuracy not yet measuredBoth cholangiocyte and hepatocyte organoids have been established from mouse and human liver tissue.
“In the case of the liver, both cholangiocyte (ductal cell of the bile duct)35,36 and hepatocyte organoids125,126 have been established, both from mouse and human tissue samples.”
From Organoids (2022) · cites this paper as [125]
The Introduction and Methods describe hepatocyte organoids established from primary mouse hepatocytes. They do not report establishing hepatocyte organoids from human liver tissue. The paper also mentions earlier bile-duct-derived liver organoids, but this citation is attached to the hepatocyte portion of the citing sentence. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn hepatocyte organoids, hepatocyte functions are preserved, yet liver tissue architecture does not match native tissue where hepatocytes are arranged in cords.
“In the example of hepatocyte organoids125, hepatocyte functions are preserved, yet the liver tissue architecture does not match the native tissue where hepatocytes are arranged in cords.”
From Organoids (2022) · cites this paper as [125]
The Results section, “Characterization of hepatocyte cultures” (page unavailable), reports that the 3D cultures retained functional properties in long-term culture. It describes the colonies as compact structures with pseudo-glandular rosettes, but does not explicitly compare their architecture with native hepatocyte cords. That architectural contrast is therefore not established by our copy. (LLM, conf=0.85)
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 [31]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredCompact 3D liver models enhanced with TNFα sustain long-term hepatocyte culture, including serial passaging and expansion over several months.
“Compact 3D liver models enhanced with tumor necrosis factor-α (TNFα) have demonstrated the capacity to sustain long-term hepatocyte culture, encompassing serial passaging and expansion over several months, and thus illustrate the importance of precisely regulated inflammatory signaling in facilitating hepatocyte plasticity and viability [31].”
From The Hepatocyte Expansion Paradox: A Review of In Vitro Challenges and Advances (2026) · cites this paper as [31]
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Chen, B., Du, C., Wang, M., Guo, J., & Liu, X. (2024) · Medical Review · doi:10.1515/mr-2023-0047 · Cited by 30 · see citing works
Cell therapy for liver disorders: past, present and future
Ortuño‐Costela, M. D. C., Pinzani, M., & Vallier, L. (2025) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-025-01050-2 · Cited by 32 · see citing works
- Authors
- Peng, W. C., Logan, C. Y., Fish, M., Anbarchian, T., Aguisanda, F., Álvarez-Varela, A., Wu, P., Jin, Y., Zhu, J., Li, B., Grompe, M., Wang, B., & Nusse, R.
- Affiliations
- Howard Hughes Medical Institute (US)
- Stanford University (US)
- Oregon Health & Science University (US)
- University of California, San Francisco (US)
- Corresponding author
- Peng, Weng Chuan
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-11
- Volume
- 175
- Issue
- 6
- Pages
- 1607-1619.e15
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6497386
- OpenAlex
- W2902626180
- Cited by
- 331
- References
- 78
- Citations by year
- 2026: 33 · 2025: 43 · 2024: 48 · 2023: 40 · 2022: 49 · 2021: 59 · 2020: 39 · 2019: 19 · 2018: 1
- FWCI
- 18.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- California Institute for Regenerative Medicine
- NIH (S10OD020141)
- Stanford Child Health Research Institute
- Burroughs Wellcome Fund
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- TNF-α, hepatocyte expansion, primary hepatocytes, 3D cell culture, liver regeneration, hepatocyte engraftment, liver injury, hepatocyte markers, long-term culture
- MeSH terms
- Animals, Antigens, Differentiation, Cell Line, Transformed, Humans, Liver, Time Factors, Tumor Necrosis Factor-alpha, Mice, Knockout, Spheroids, Cellular, Cell Culture Techniques, Hepatocytes, Cell Proliferation, Hep G2 Cells, Human Umbilical Vein Endothelial Cells
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