Hepatic stellate cells maintain liver homeostasis through paracrine neurotrophin-3 signaling that induces hepatocyte proliferation
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Organ size is maintained by the controlled proliferation of distinct cell populations. In the mouse liver, hepatocytes in the midlobular zone that are positive for cyclin D1 (CCND1) repopulate the parenchyma at a constant rate to preserve liver mass. Here, we investigated how hepatocyte proliferation is supported by hepatic stellate cells (HSCs), pericytes that are in close proximity to hepatocytes. We used T cells to ablate nearly all HSCs in the murine liver, enabling the unbiased characterization of HSC functions. In the normal liver, complete loss of HSCs persisted for up to 10 weeks and caused a gradual reduction in liver mass and in the number of CCND1 + hepatocytes. We identified neurotrophin-3 (Ntf-3) as an HSC-produced factor that induced the proliferation of midlobular hepatocytes through the activation of tropomyosin receptor kinase B (TrkB). Treating HSC-depleted mice with Ntf-3 restored CCND1 + hepatocytes in the midlobular region and increased liver mass. These findings establish that HSCs form the mitogenic niche for midlobular hepatocytes and identify Ntf-3 as a hepatocyte growth factor.
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HSC-depleted livers were smaller and contained smaller hepatocytes and less Ccnd1 mRNA.
“As reported previously19, HSC-depleted livers were smaller and contained smaller hepatocytes and less Ccnd1 mRNA, a potent driver of hepatocyte proliferation23 (Fig. 1a and Extended Data Fig. 1d).”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [19]
The Results section ('Sustained HSC depletion causes loss of liver mass and reduces the number of midlobular hepatocytes'; page unavailable) reports smaller livers and reduced Ccnd1 expression in HSC-depleted mice. It reports fewer midlobular hepatocytes, but does not establish that individual hepatocytes were smaller. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe JEDI depletion method revealed a role for HSCs in homeostatic hepatocyte proliferation.
“Recently, the more specific and efficient just eGFP death-inducing (JEDI) depletion method revealed a role for HSCs in homeostatic hepatocyte proliferation19.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [19]
Top altered pathways in HSC-depleted livers using iDTR or JEDI were metabolic, including drug, cytochrome P450, linoleic acid, tyrosine, tryptophan and caffeine metabolism.
“Notably, the top altered pathways in HSC-depleted livers, achieved using the iDTR system or the JEDI model19, were metabolic, including drug, cytochrome P450, linoleic acid, tyrosine, tryptophan and caffeine metabolism (Extended Data Fig. 4a and Supplementary Table 2).”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [19]
HSC mediators besides RSPO3, such as HGF, and possibly neurotrophin-3 or epiregulin, may be involved in additional aspects of HSC-hepatocyte cross-talk and together with ECs collaboratively control hepatocyte health and functions.
“Moreover, HSC mediators besides RSPO3, such as HGF, but possibly also neurotrophin-319 or epiregulin60 may be involved in additional aspects of HSC–hepatocyte cross-talk and—together with ECs29,59—collaboratively control hepatocyte health and functions.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [19]
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Fibroblast Growth Factor Enriches the Embryonic Liver Cultures for Hepatic Progenitors
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GFP-specific CD8 T cells enable targeted cell depletion and visualization of T-cell interactions
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Regulatory mechanisms of hepatic microcirculatory hemodynamics: hepatic arterial system.
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Hepatocyte generation in liver homeostasis, repair, and regeneration
Pu, W., & Zhou, B. (2022) · Cell Regeneration · doi:10.1186/s13619-021-00101-8 · Cited by 25 · see citing works
Zhang, R., Kikuchi, A. T., Nakao, T., Russell, J. O., Preziosi, M. E., Poddar, M., Singh, S., Bell, A. W., England, S. G., & Monga, S. P. (2019) · Gene Expression · doi:10.3727/105221618x15373858350141 · Cited by 15 · see citing works
Hepatic Stellate Cells and Liver Cancer
Dapito, D. H., & Schwabe, R. F. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-800134-9.00009-9 · Cited by 6 · see citing works
Correction to: Hepatocyte generation in liver homeostasis, repair, and regeneration
Pu, W., & Zhou, B. (2022) · Cell Regeneration · doi:10.1186/s13619-022-00115-w · Cited by 3 · see citing works
Flagged first, then by citations
Research works printed but not linked: 3
- [66]Dapito DH, Schwabe RF, in Stellate Cells in Health and Disease, Eds. (Elsevier, 2015), pp. 145– 162.
- [67]Oda M, Yokomori H, Han JY, Clin Hemorheol Microcirc 34, 11 (2006). 16543613
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- Authors
- Trinh, V. Q.-H., Lee, T.-F., Lemoinne, S., Ray, K. C., Ybanez, M. D., Tsuchida, T., Carter, J. K., Agudo, J., Brown, B. D., Akat, K. M., Friedman, S. L., & Lee, Y. A.
- Affiliations
- Vanderbilt University Medical Center (US)
- Icahn School of Medicine at Mount Sinai (US)
- Harvard University (US)
- Corresponding author
- Trinh, Vincent Quoc-Huy
- Lee, Ting-Fang
- Lee, Youngmin A.
- ORCID
- Venue
- Science Signaling
- Published
- 2023-05-30
- Volume
- 16
- Issue
- 787
- Pages
- eadf6696-eadf6696
- ISSN
- 1937-9145 (ISSN-L)
- 1945-0877
- PMC
- PMC10367116
- OpenAlex
- W4378782998
- Cited by
- 45
- References
- 89
- Citations by year
- 2026: 12 · 2025: 22 · 2024: 6 · 2023: 5
- FWCI
- 7.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Signaling (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Vanderbilt University
- Vanderbilt University Medical Center (P30DK058404)
- National Institutes of Health
- National Cancer Institute (P50CA236733)
- National Institute of General Medical Sciences (T32GM146636)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK056621, R01DK128289, P30DK058404, P30DK020541)
- National Center for Complementary and Integrative Health (R01AT011326)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Keywords
- hepatic stellate cells, hepatocyte proliferation, neurotrophin-3, TrkB signaling, liver homeostasis, cyclin D1, pericytes, HSC depletion, liver mass, hepatocyte growth factor
- MeSH terms
- Animals, Liver, Neurotrophin 3, Hepatocytes, Cell Proliferation, Mice, Hepatic Stellate Cells
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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