Abstract
Increasing evidence provides support that mammalian liver contains stem/progenitor cells, but their molecular phenotype, embryological derivation, biology and their role in liver cell turnover and regeneration remain to be further clarified. In this study, we report the isolation, characterization and reproducible establishment in line of a resident liver stem cell (RLSC) with immunophenotype and differentiative potentiality distinct from other previously described liver precursor/stem cells. RLSCs, derived from fetal and neonatal murine livers as well as from immortalized hepatocytic MMH lines and established in lines, are Sca+, CD34−, CD45−, α-fetoprotein+ and albumin−. This molecular phenotype suggests a non-hematopoietic origin. RLSC transcriptional profile, defined by microArray technology, highlighted the expression of a broad spectrum of ‘plasticity-related genes’ and ‘developmental genes’ suggesting a multi-differentiative potentiality. Indeed, RLSCs spontaneously differentiate into hepatocytes and cholangiocytes and, when cultured in appropriate conditions, into mesenchymal and neuro-ectodermal cell lineages such as osteoblasts/osteocytes, chondrocytes, astrocytes and neural cells. RLSC capability to spontaneously differentiate into hepatocytes, the lack of albumin expression and the broad differentiative potentiality locate them in a pre-hepatoblast/liver precursor cells hierarchical position. In conclusion, RLSCs may provide a useful tool to improve liver stem cell knowledge and to assess new therapeutic approaches for liver diseases.
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Abbreviations
- α−FP:
-
α-fetoprotein
- BC:
-
basal conditions
- CC:
-
chondrogenic conditions
- dpc:
-
days post coitum
- GFAP:
-
glyal fibrillar acid protein
- HC:
-
hepatocyte conditions
- MetE14:
-
cyto-Met transgenic embryo 14 dpc
- MetNBD6:
-
cyto-Met transgenic mouse 6 days newborn
- MMH:
-
met murine hepatocyte
- NC:
-
neurogenic conditions
- OC:
-
osteogenic conditions
- RLSC:
-
resident liver stem cell
- wtE14:
-
wild type embryo 14 dpc
- ZO-1:
-
zonula occludens 1
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Financial supports: Associazione Italiana per la Ricerca sul Cancro; Ministero della Salute; Ministero dell’Università e della Ricerca Scientifica.
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Conigliaro, A., Colletti, M., Cicchini, C. et al. Isolation and characterization of a murine resident liver stem cell. Cell Death Differ 15, 123–133 (2008). https://doi.org/10.1038/sj.cdd.4402236
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DOI: https://doi.org/10.1038/sj.cdd.4402236
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