Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

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.

The niche of stellate cells within rat liver #

“…It is widely accepted that these HSC-derived myofibroblast-like cells contribute to liver fibrosis. 2 Controversies exist about the embryonic origin of HSCs, because they express proteins of all three germ layers. 3 Bone marrow stem cells are able to generate cells of all germ layers, and it was suggested that the bone marrow might be a source of stellate cells in adult vertebrate liver.…”

Effects of aging on liver microcirculatory function and sinusoidal phenotype

“…HSC are vitamin A storing cells located in the space of Disse, surrounding LSEC, and represent the liver pericytes. At last, KC, the resident macrophages of the liver, are located at the luminal side of the endothelial lining (Fernández‐Iglesias & Gracia‐Sancho, 2017; Friedman, 2008; Ju & Tacke, 2016). …”

Chip-based liver equivalents for toxicity testing – organotypicalness versus cost-efficient high throughput

“…A thorough review on the origin of these cells, their function in normal liver, and in liver injury and repair can be found elsewhere. 39 Kupffer cells are another important cell type which preferentially reside in the sinusoid of the periportal zone and form almost 80% of the macrophage population. They present antigens and release numerous signalling molecules, which at peak reactivity can lead to hepatic injury.…”