Abstract
BackgroundThe transformation of hepatic stellate cell (HSC) to myofibroblast is a key event during liver fibrogenesis. However, the differentiation trajectory of HSC-to-myofibroblast transition and the switching genes during this process remains not well understood.MethodsWe applied single-cell sequencing data to reconstruct a single-lineage pseudotime trajectory of HSC transdifferentiation in vitro and analyzed the gene expression patterns along the trajectory. GeneSwitches was used to identify the order of critical gene expression and functional events during HSC activation.ResultsA novel cell state during HSC activation was revealed and the HSCs belonging to this state may be an important origin of cancer-associated fibroblasts (CAFs). Combining single-cell transcriptomics with GeneSwitches analyses, we identified some distinct switching genes and the order at which these switches take place for the new state of HSC and the classic culture-activated HSC, respectively. Based on the top switching genes, we established a four-gene combination which exhibited highly diagnostic accuracy in predicting advanced liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) or hepatitis B (HBV).ConclusionOur study revealed a novel cell state during HSC activation which may be relevant to CAFs, and identified switching genes that may play key roles in HSC transdifferentiation and serve as predictive markers of advanced fibrosis in patients with chronic liver diseases.
Highlights
Hepatic fibrosis is a common wound-healing response to diverse chronic liver diseases
The pathogenesis of hepatic fibrosis is mostly featured by excessive accumulation of extracellular matrix (ECM) in the liver [1], which is mainly derived from activated hepatic stellate cell (HSC)
The results showed that genes such as Npm1, Rack1, Mif, Cstb, Arpc2, and Krtcap2 were expressed much higher in HSC-derived cancer-associated fibroblasts (CAFs) than those in activated HSCs from bile duct-ligated (BDL) or DDC model (Fig. 4)
Summary
Hepatic fibrosis is a common wound-healing response to diverse chronic liver diseases. The pathogenesis of hepatic fibrosis is mostly featured by excessive accumulation of extracellular matrix (ECM) in the liver [1], which is mainly derived from activated hepatic stellate cell (HSC). HSCs are activated and transformed into proliferative, fibrogenic and contractile myofibroblasts, which are characterized by expressing high level of Acta (smooth muscle actin alpha 2). HSC activation is recognized as a pivotal event during liver fibrogenesis [2, 3]. HSC zonation has been proposed as a determinant of the liver fibrogenesis response [4]. The transformation of hepatic stellate cell (HSC) to myofibroblast is a key event during liver fibrogenesis. The differentiation trajectory of HSC-to-myofibroblast transition and the switching genes during this process remains not well understood
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