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Cited by 194Liver physiology and pathologyCongenital heart defects researchOrgan Transplantation Techniques and Outcomes

In Vivo Lineage Tracing of Polyploid Hepatocytes Reveals Extensive Proliferation during Liver Regeneration

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Matsumoto, Tomonori, Wakefield, Leslie, Tarlow, Branden David, Grompe, Markus·2020·Cell Stem Cell
DOI 10.1016/j.stem.2019.11.014PMC PMC7204404
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Abstract

The identity of cellular populations that drive liver regeneration after injury is the subject of intense study, and the contributions of polyploid hepatocytes to organ regeneration and homeostasis have not been systematically assessed. Here, we developed a multicolor reporter allele system to genetically label and trace polyploid cells in situ. Multicolored polyploid hepatocytes undergo ploidy reduction and subsequent re-polyploidization after transplantation, providing direct evidence of the hepatocyte ploidy conveyor model. Marker segregation revealed that ploidy reduction rarely involves chromosome missegregation in vivo. We also traced polyploid hepatocytes in several different liver injury models and found robust proliferation in all settings. Importantly, ploidy reduction was seen in all injury models studied. We therefore conclude that polyploid hepatocytes have extensive regenerative capacity in situ and routinely undergo reductive mitoses during regenerative responses.

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  • Recent studies have demonstrated that hepatocytes are primarily maintained by the proliferation of pre-existing hepatocytes during liver homeostasis and regeneration.

    “recent studies have demonstrated that hepatocytes are primarily maintained by the proliferation of pre-existing hepatocytes during liver homeostasis and regeneration14–19”

    From Multimodal decoding of human liver regeneration (2024) · cites this paper as [16]

    The Results section ('Polyploid hepatocytes undergo multiple rounds of cell division in several liver injury models'; page unavailable) reports proliferation of pre-existing hepatocytes across several injury models, supporting their role in regeneration. The Discussion says the bulk of polyploid hepatocytes participate in regeneration, but the passages do not establish that proliferation primarily maintains hepatocytes during homeostasis or that it is the predominant source across all regeneration. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Polyploid hepatocytes marked by a multicolour reporter system appeared to be as proliferative as diploid hepatocytes in mouse models of hepatocyte transplantation and liver regeneration.

    “However, polyploid hepatocytes marked by a multicolour reporter system appeared to be as proliferative as diploid hepatocytes in mouse models of hepatocyte transplantation and liver regeneration.137”

    From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [137]

    The Results sections on transplanted polyploids and liver injury models report extensive proliferation of multicolour-labelled polyploid hepatocytes in mice. The Discussion says they expanded despite competing diploid hepatocytes, but the cited passages do not establish that polyploid and diploid hepatocytes were equally proliferative. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Polyploidization is implicated in maintaining genomic stability, buffering metabolic demands, and enhancing stress resistance.

    “Importantly, polyploidization is not only a form of cellular growth but is also implicated in maintaining genomic stability, buffering metabolic demands, and enhancing stress resistance.”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [81]

    The Introduction (page unavailable) hypothesizes that polyploid hepatocytes may enhance metabolism and be less affected by genotoxic damage; the Discussion (page unavailable) describes stress-adapted, injury-resistant progeny. These passages support possible metabolic and stress-related benefits, but they do not establish that polyploidization buffers metabolic demands or maintains genomic stability. The Discussion also warns that prolonged chromosomal instability may increase cancer risk. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • While diploid hepatocytes dominate the early proliferative response following major hepatectomy, polyploid hepatocytes contribute to regeneration through selective division and hypertrophy, particularly when proliferation is delayed or impaired.

    “While diploid hepatocytes have been shown to dominate the early proliferative response following major hepatectomy, polyploid hepatocytes contribute to regeneration through selective division and hypertrophy, particularly under conditions where proliferation is delayed or impaired[80,81].”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [81]

    Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable, 1 not checked. Expand the claim to see per-atom verdicts.

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Authors
Matsumoto, T., Wakefield, L., Tarlow, B. D., & Grompe, M.
Affiliations
  • Oregon Health & Science University (US)
  • Stanford Medicine (US)
Corresponding author
Grompe, Markus
ORCID
Venue
Cell Stem Cell
Publisher
Elsevier BV
Published
2020-01
Volume
26
Issue
1
Pages
34-47.e3
ISSN
  • 1875-9777 (ISSN-L)
  • 1934-5909
DOI
10.1016/j.stem.2019.11.014
PMC
PMC7204404
OpenAlex
W2996555649
Cited by
194
References
57
Citations by year
2026: 17 · 2025: 12 · 2024: 31 · 2023: 41 · 2022: 29 · 2021: 39 · 2020: 25
FWCI
14.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell stem cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • Kanae Foundation for the Promotion of Medical Science
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
  • Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
Keywords
liver regeneration, hepatocyte proliferation, ploidy reduction, chromosome missegregation, liver injury
MeSH terms
Humans, Liver, Liver Regeneration, Polyploidy, Hepatocytes, Cell Proliferation

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