Identification and Characterization of Vitamin A-storing Cells in Fetal Liver: Implications for Functional Importance of Hepatic Stellate Cells in Liver Development and Hematopoiesis

¹ University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599
² Departments of Cell and Molecular Physiology and Biomedical Engineering; Program in Molecular Biology and Biotechnology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599

^* To whom correspondence should be addressed. E-mail: hiroshi{at}vmas.kitasato-u.ac.jp.

	Abstract

Hepatic stellate cells (HpSTCs) are major regulators of hepatic fibrogenesis in adults. However, their early development in fetal liver is largely unknown. To characterize fetal HpSTCs in the liver in which hepatic development and hematopoiesis occur in parallel, we determined the phenotypic characteristics of HpSTCs from rat fetal livers utilizing a strategy focused on vitamin A. Storage of vitamin A in the cytoplasm is a unique characteristic of HpSTCs, permitting identification of them by vitamin A-specific autofluorescence (vA⁺) when excited with UV light utilizing flow cytometry. A characteristic vA⁺ cell population was identified as early as 13-day post coitum liver and having a surface phenotype of RT1A^- ICAM-1⁺ VCAM-1⁺ 3-integrin⁺. Although non-specific autofluorescent cells were found with the antigenic profile of RT1A^- ICAM-1⁺ VCAM-1⁺, they were 3-integrin^- and proved to be hepatoblasts, bipotent hepatic parenchymal progenitors. In addition to expression of classical HpSTC markers, the vA⁺ cells were able to proliferate continuously in a serum-free hormonally defined medium containing leukemia inhibitory factor, which was found as a key factor for their replication. These results demonstrated that the vA⁺ cells are fetal HpSTCs with extensive proliferative activity. Furthermore, the vA⁺ cells strongly express hepatocyte growth factor, stromal derived factor-1, and Hlx, homeobox transcriptional factor, indicating that they play important roles for hepatic development and hematopoiesis. The ability to isolate and expand fetal HpSTCs enable further investigations into their roles in early liver development and facilitate identification of possibly novel signals of potential relevance for liver diseases.

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