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Review
. 2008 Jan;88(1):125-72.
doi: 10.1152/physrev.00013.2007.

Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver

Scott L Friedman  1
Affiliations
Review

Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver

Scott L Friedman. Physiol Rev. 2008 Jan.

Abstract

The hepatic stellate cell has surprised and engaged physiologists, pathologists, and hepatologists for over 130 years, yet clear evidence of its role in hepatic injury and fibrosis only emerged following the refinement of methods for its isolation and characterization. The paradigm in liver injury of activation of quiescent vitamin A-rich stellate cells into proliferative, contractile, and fibrogenic myofibroblasts has launched an era of astonishing progress in understanding the mechanistic basis of hepatic fibrosis progression and regression. But this simple paradigm has now yielded to a remarkably broad appreciation of the cell's functions not only in liver injury, but also in hepatic development, regeneration, xenobiotic responses, intermediary metabolism, and immunoregulation. Among the most exciting prospects is that stellate cells are essential for hepatic progenitor cell amplification and differentiation. Equally intriguing is the remarkable plasticity of stellate cells, not only in their variable intermediate filament phenotype, but also in their functions. Stellate cells can be viewed as the nexus in a complex sinusoidal milieu that requires tightly regulated autocrine and paracrine cross-talk, rapid responses to evolving extracellular matrix content, and exquisite responsiveness to the metabolic needs imposed by liver growth and repair. Moreover, roles vital to systemic homeostasis include their storage and mobilization of retinoids, their emerging capacity for antigen presentation and induction of tolerance, as well as their emerging relationship to bone marrow-derived cells. As interest in this cell type intensifies, more surprises and mysteries are sure to unfold that will ultimately benefit our understanding of liver physiology and the diagnosis and treatment of liver disease.

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Figures

Fig. 1
Fig. 1
Growth of the hepatic stellate cell field in 25 years. This graph illustrates the number of citations per year between 1980 and 2005 in Medline using the search terms of either hepatic stellate cell, Ito cell, lipocyte, fat storing cell, or perisinusoidal cell.
Fig. 2
Fig. 2
Morphology of hepatic stellate cells in normal liver. A: diagram of the hepatic sinusoid demonstrating the relative orientation of stellate cells (in blue, indicated with arrows) within the sinusoidal architecture. B: higher resolution drawing of stellate cells situated within the subendothelial space. [From Friedman and Arthur (169).]
Fig. 3
Fig. 3
Ultrastructure of cultured stellate cells. Primary rat hepatic stellate cells cultured for 7 days on either uncoated plastic (left panel) or Matrigel (right panel). Cells on plastic become activated and are flat, with well-developed endoplasmic reticulum (ER) and some lipid droplets (L). In contrast, cells on Matrigel (GM, gel matrix) remain quiescent with condensed nuclear chromatin (N) and a high density of vitamin A-containing lipid droplets. Acellular debris (D) and secreted matrix (M) are trapped within the Matrigel surrounding the cell (bar = 10 μm). [From Friedman et al. (173).]
Fig. 4
Fig. 4
Cultured hepatic stellate cells in primary culture. A: high-power phase (left panel) and fluorescence (right panel) micrograph of primary cultured rat stellate cells, demonstrating cytoplasmic vitamin A droplets that fluorescence when excited by ultraviolet light (bar = 20 μm). B: low-power fluorescence micrograph of rat hepatic stellate cells in primary culture on plastic for 1 wk, photographed under ultraviolet light (bar = 80 μm). [From Friedman et al. (174).]
Fig. 5
Fig. 5
Immunoregulatory roles of stellate cells (see text).
Fig. 6
Fig. 6
Sources of myofibroblasts in liver injury. Multiple sources of fibrogenic myofibroblasts are likely in liver injury depending on the site and nature of the injury. While resident stellate cells appear to be the most likely source, periportal fibroblasts may be especially prominent in biliary injury, whereas bone marrow and possible epithelial-mesenchymal transition may contribute as well.
Fig. 7
Fig. 7
Pathways of stellate cell activation and resolution. Following liver injury, hepatic stellate cells undergo “activation,” which connotes a transition from quiescent vitamin A-rich cells into proliferative, fibrogenic, and contractile myofibroblasts. The major phenotypic changes after activation include proliferation, contractility, fibrogenesis, matrix degradation, chemotaxis, retinoid loss, and WBC chemoattraction. Key mediators underlying these effects are shown. The fate of activated stellate cells during resolution of liver injury is uncertain but may include reversion to a quiescent phenotype and/or selective clearance by apoptosis. [From Friedman (165).]
Fig. 8
Fig. 8
Mechanisms of transcriptional regulation of stellate cell activation (see text).
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References

    1. Adachi M, Osawa Y, Uchinami H, Kitamura T, Accili D, Brenner DA. The forkhead transcription factor FoxO1 regulates proliferation and transdifferentiation of hepatic stellate cells. Gastroenterology. 2007;132:1434–1446. - PubMed
    1. Adachi T, Togashi H, Suzuki A, Kasai S, Ito J, Sugahara K, Kawata S. NAD(P)H oxidase plays a crucial role in PDGF-induced proliferation of hepatic stellate cells. Hepatology. 2005;41:1272–1281. - PubMed
    1. Adrian JE, Poelstra K, Scherphof GL, Molema G, Meijer DK, Reker-Smit C, Morselt HW, Kamps JA. Interaction of targeted liposomes with primary cultured hepatic stellate cells: involvement of multiple receptor systems. J Hepatol. 2006;44:560–567. - PubMed
    1. Akita K, Okuno M, Enya M, Imai S, Moriwaki H, Kawada N, Suzuki Y, Kojima S. Impaired liver regeneration in mice by lipopolysaccharide via TNF-alpha/kallikrein-mediated activation of latent TGF-beta. Gastroenterology. 2002;123:352–364. - PubMed
    1. Aleffi S, Petrai I, Bertolani C, Parola M, Colombatto S, Novo E, Vizzutti F, Anania FA, Milani S, Rombouts K, Laffi G, Pinzani M, Marra F. Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells. Hepatology. 2005;42:1339–1348. - PubMed

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