Remarkable heterogeneity displayed by oval cells in rat and mouse models of stem cell-mediated liver regeneration.
The experimental protocols used in the investigation of stem cell-mediated liver regeneration in rodents are characterized by activation of the hepatic stem cell compartment in the canals of Hering followed by transit amplification of oval cells and their subsequent differentiation along hepatic lineages. Although the protocols are numerous and often used interchangeably across species, a thorough comparative phenotypic analysis of oval cells in rats and mice using well-established and generally acknowledged molecular markers has not been provided. In the present study, we evaluated and compared the molecular phenotypes of oval cells in several of the most commonly used protocols of stem cell-mediated liver regeneration-namely, treatment with 2-acetylaminofluorene and partial (70%) hepatectomy (AAF/PHx); a choline-deficient, ethionine-supplemented (CDE) diet; a 3,5-diethoxycarbonyl-1,4-dihydro-collidin (DDC) diet; and N-acetyl-paraaminophen (APAP). Reproducibly, oval cells showing reactivity for cytokeratins (CKs), muscle pyruvate kinase (MPK), the adenosine triphosphate-binding cassette transporter ABCG2/BCRP1 (ABCG2), alpha-fetoprotein (AFP), and delta-like protein 1/preadipocyte factor 1 (Dlk/Pref-1) were induced in rat liver treated according to the AAF/PHx and CDE but not the DDC protocol. In mouse liver, the CDE, DDC, and APAP protocols all induced CKs and ABCG2-positive oval cells. However, AFP and Dlk/Pref-1 expression was rarely detected in oval cells.


CONCLUSIONS
Our results delineate remarkable phenotypic discrepancies exhibited by oval cells in stem cell-mediated liver regeneration between rats and mice and underline the importance of careful extrapolation between individual species.
Jelnes
Peter
P
Danish Stem Cell Research Centre, Department of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
Santoni-Rugiu
Eric
E
Rasmussen
Morten
M
Friis
Susanne Lunøe
SL
Nielsen
Jens Høiriis
JH
Tygstrup
Niels
N
Bisgaard
Hanne Cathrine
HC
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D019070:Cell Lineage / Q000502:physiology; D005260:Female; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007633:Keratins / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000502:physiology*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D010641:Phenotype; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D000509:alpha-Fetoproteins / Q000235:genetics / Q000378:metabolism
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; C489249:Abcg2 protein, rat; D015415:Biomarkers; D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; C512923:Dlk1 protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D000509:alpha-Fetoproteins; D007633:Keratins; D011770:Pyruvate Kinase