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Mesenchymal origin of hepatic stellate cells, submesothelial cells, and perivascular mesenchymal cells during mouse liver development
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UNLABELLED: The knowledge concerning fetal hepatic stellate cells (HSCs) is scarce, and their cell lineage and functions are largely unknown. The current study isolated fetal liver mesenchymal cells from a mouse expressing beta-galactosidase under the control of Msx2 promoter by fluorescence-activated cell sorting (FACS) and surveyed marker genes by microarray analysis. Based on the location and immunostaining with conventional and newly disclosed markers, we have identified three distinct populations of fetal liver mesenchymal cells expressing both desmin and p75 neurotrophin receptor (p75NTR): HSCs in the liver parenchyma; perivascular mesenchymal cells expressing alpha-smooth muscle actin (alpha-SMA); and submesothelial cells associated with the basal lamina beneath mesothelial cells and expressing activated leukocyte cell adhesion molecule (ALCAM) and platelet-derived growth factor receptor alpha. A transitional cell type from the submesothelial cell phenotype to fetal HSCs was also identified near the liver surface. Mesothelial cells expressed podoplanin and ALCAM. Ki-67 staining showed that proliferative activity of the submesothelial cells is higher than that of mesothelial cells and transitional cells. Using anti-ALCAM antibodies, submesothelial and mesothelial cells were isolated by FACS. The ALCAM(+) cells expressed hepatocyte growth factor and pleiotrophin. In culture, the ALCAM(+) cells rapidly acquired myofibroblastic morphology and alpha-SMA expression. The ALCAM(+) cells formed intracellular lipid droplets when embedded in collagen gel and treated with retinol, suggesting the potential for ALCAM(+) cells to differentiate to HSCs. Finally, we demonstrated that fetal HSCs, submesothelial cells, and perivascular mesenchymal cells are all derived from mesoderm by using MesP1-Cre and ROSA26 reporter mice. CONCLUSION: Fetal HSCs, submesothelial cells, and perivascular mesenchymal cells are mesodermal in origin, and ALCAM(+) submesothelial cells may be a precursor for HSCs in developing liver.
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“The STM gives rise to the liver mesenchyme, which in the adult liver encompasses the mesothelium, the external cellular lining of the liver, and hepatic stellate cells (HSCs), the sinusoidal pericytes”
From Single-Cell Transcriptomics Reveals Early Emergence of Liver Parenchymal and Non-parenchymal Cell Lineages (2020) · cites this paper as Asahina et al., 2009
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Metadata
- Authors
- Asahina, K., Tsai, S. Y., Li, P., Ishii, M., Maxson, R. E., Sucov, H. M., & Tsukamoto, H.
- Affiliations
- University of Southern California (US)
- Corresponding author
- Asahina, Kinji
- Venue
- Hepatology
- Published
- 2009-03
- Volume
- 49
- Issue
- 3
- Pages
- 998-1011
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC2673117
- OpenAlex
- W2091764094
- Cited by
- 238
- References
- 29
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 6 · 2023: 15 · 2022: 6 · 2021: 15 · 2020: 11 · 2019: 15 · 2018: 18 · 2017: 12 · 2016: 13 · 2015: 20 · 2014: 19 · 2013: 15 · 2012: 17
- FWCI
- 9.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (R24 AA12885, P50-AA11999, R24AA012885, P50AA011999)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Keywords
- hepatic stellate cells, fetal liver development, mesodermal origin, ALCAM, mesothelial cells, cell lineage, myofibroblast differentiation, lipid droplets, hepatocyte growth factor, pleiotrophin, alpha-smooth muscle actin, podoplanin, Ki-67 proliferation index, mouse liver
- MeSH terms
- Podoplanin, Animals, Cell Differentiation, Cells, Cultured, Desmin, Endothelium, Vascular, Epithelial Cells, Female, Lac Operon, Liver, Male, Membrane Glycoproteins, Mice, Transgenic, Receptors, Nerve Growth Factor, Homeodomain Proteins, Activated-Leukocyte Cell Adhesion Molecule, Organogenesis, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Hepatic Stellate Cells, Mesenchymal Stem Cells
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