The DOI matches its Crossref record; 148 of the 148 references it cites were found in a registry or an index.
Cellular plasticity balances the metabolic and proliferation dynamics of a regenerating liver
Open accessPublished version of a preprint
Abstract
The adult liver has an exceptional ability to regenerate, but how it maintains its specialized functions during regeneration is unclear. Here, we used partial hepatectomy (PHx) in tandem with single-cell transcriptomics to track cellular transitions and heterogeneities of ∼22,000 liver cells through the initiation, progression, and termination phases of mouse liver regeneration. Our results uncovered that, following PHx, a subset of hepatocytes transiently reactivates an early-postnatal-like gene expression program to proliferate, while a distinct population of metabolically hyperactive cells appears to compensate for any temporary deficits in liver function. Cumulative EdU labeling and immunostaining of metabolic, portal, and central vein–specific markers revealed that hepatocyte proliferation after PHx initiates in the midlobular region before proceeding toward the periportal and pericentral areas. We further demonstrate that portal and central vein proximal hepatocytes retain their metabolically active state to preserve essential liver functions while midlobular cells proliferate nearby. Through combined analysis of gene regulatory networks and cell–cell interaction maps, we found that regenerating hepatocytes redeploy key developmental regulons, which are guided by extensive ligand-receptor-mediated signaling events between hepatocytes and nonparenchymal cells. Altogether, our study offers a detailed blueprint of the intercellular crosstalk and cellular reprogramming that balances the metabolic and proliferative requirements of a regenerating liver.
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“Numerous changes in mRNA abundance and splicing occur within the first 3 weeks of life (Bhate et al. 2015; Chembazhi et al. 2021; Liang et al. 2022), as hematopoiesis and proliferative activity are reduced, and gene products involved in metabolism are induced (Zaret 2002; Gordillo et al. 2015).”
From ESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation (2025) · cites this paper as Chembazhi et al. 2021
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Several studies suggest that hepatocyte proliferation leads to metabolic remodelling and that hepatocytes across the liver can adapt dynamically to changes during regeneration106,107,[131], [132], [133], [134], [135]”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [106]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“During pan-zonal regeneration induced by partial hepatectomy, hepatocytes across the liver underwent transient fetal reprogramming to acquire proliferative potential.106,107”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [106]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Transient changes in hepatocyte identity are required when hepatocytes re-enter the cell cycle in response to injury, while others increase metabolic function to maintain hepatic metabolism.25,104,106,107,134”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [106]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Importantly, single-cell transcriptomic analysis identified distinct clusters among 18,272 hepatocytes corresponding to quiescent (5328 hepatocytes), transition (5137 hepatocytes), proliferating (6769 hepatocytes), and hypermetabolic (1038 hepatocytes) states after PHx.6”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [6]
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“Taken together, our data indicate that CAR coordinates metabolic adaptation, particularly by constraining BA homeostasis, and is an important factor for the hypermetabolic hepatocytes, which support regeneration by meeting increased metabolic demands.6”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [6]
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In the citing paper
“Following partial hepatectomy, a subset of hepatocytes transiently acquired an early-postnatal-like gene expression programme to proliferate, while other hepatocytes became metabolically hyperactive to compensate for any temporary deficits in liver function.106”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [106]
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“A recent single-cell study characterized the functional heterogeneity within hepatocytes after PHx and identified a subset of hypermetabolic hepatocytes that compensate for the transient loss of metabolic function during regeneration.6”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [6]
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Citations
Cites
Integrating single-cell transcriptomic data across different conditions, technologies, and species
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Fast, sensitive and accurate integration of single-cell data with Harmony
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Trapnell, C., Cacchiarelli, D., Grimsby, J., Pokharel, P., Li, S., Morse, M., Lennon, N. J., Livak, K. J., Mikkelsen, T. S., & Rinn, J. L. (2014) · Nature Biotechnology · doi:10.1038/nbt.2859 · Cited by 7,314
Scenic: single-cell regulatory network inference and clustering.
Aibar, S., González-Blas, C. B., Moerman, T., Huynh-Thu, V. A., Imrichova, H., Hulselmans, G., Rambow, F., Marine, J.-C., Geurts, P., Aerts, J., et al. (2017) · Nature Methods · doi:10.1038/nmeth.4463 · Cited by 6,520
Reversed graph embedding resolves complex single-cell trajectories
Qiu, X., Mao, Q., Tang, Y., Wang, L., Chawla, R., Pliner, H. A., & Trapnell, C. (2017) · Nature Methods · doi:10.1038/nmeth.4402 · Cited by 5,070
Burden of liver diseases in the world
Asrani, S. K., Devarbhavi, H., Eaton, J., & Kamath, P. S. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2018.09.014 · Cited by 3,783
Organoid Models and Applications in Biomedical Research
Xinaris, C., Brizi, V., & Remuzzi, G. (2015) · The Nephron journals/Nephron journals · doi:10.1159/000433566 · Cited by 3,519
Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics
Street, K., Risso, D., Fletcher, R. B., Das, D., Ngai, J., Yosef, N., Purdom, E., & Dudoit, S. (2018) · BMC Genomics · doi:10.1186/s12864-018-4772-0 · Cited by 3,159
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Mid-zone hepatocytes trade proliferation for survival via Atf4-Chop axis in early acute liver injuryPreprint
Zhu, Y., Deng, C., Chen, B., He, J., Liu, Y., Lei, S., Lu, W., Peng, C., & Shan, Z. (2026) · eLife · doi:10.7554/elife.108646.3
Feng, G., Wang, X., Li, P., Wang, Y., Wan, H., Dong, K., Deng, H., 邹愚, Hu, Y., Jiang, S., et al. (2026) · JHEP Reports · doi:10.1016/j.jhepr.2026.102077
Metadata
- Authors
- Chembazhi, U. V., Bangru, S., Hernaez, M., & Kalsotra, A.
- Affiliations
- University of Illinois Urbana-Champaign (US)
- Corresponding author
- Kalsotra, Auinash
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2021-03-01
- Volume
- 31
- Issue
- 4
- Pages
- 576-591
- ISSN
- 1088-9051 (ISSN-L)
- 1549-5469
- PMC
- PMC8015853
- OpenAlex
- W3133820991
- Cited by
- 102
- References
- 147
- Citations by year
- 2026: 13 · 2025: 19 · 2024: 22 · 2023: 26 · 2022: 9 · 2021: 10
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genome Research (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- NIH (R01HL126845, R01AA010154, T32-EB019944)
- Muscular Dystrophy Association (MDA514335)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- liver regeneration, partial hepatectomy, hepatocyte proliferation, cellular plasticity, cell-to-cell communication, non-parenchymal cells, developmental gene regulatory networks, single-cell transcriptomics
- MeSH terms
- Cell Plasticity, Animals, Hepatectomy, Liver, Liver Regeneration, Hepatocytes, Cell Proliferation, Mice, Single-Cell Analysis, Transcriptome
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