Gliotoxin-mediated apoptosis of activated human hepatic stellate cells

Hepatocyte Transplantation Activates Hepatic Stellate Cells With Beneficial Modulation of Cell Engraftment in the Rat *

“…To demonstrate whether HSC activation directly affected cell engraftment, we performed "lossof-function" studies by depleting activated HSC with gliotoxin. [12][13][14] In contrast to results in animals with liver injury, 12 we observed by oil-red-O or desmin stainings that gliotoxin did not deplete HSC in the healthy rat liver. No other method is available to deplete quiescent HSC.…”

“…7,41 For instance, MMP-2 and TIMP-1 were expressed in HSC, and not hepatocytes, after turpentine-induced acute liver injury. 43 Finally, our studies with gliotoxin, which induces apoptosis in activated HSC, [12][13][14] showed impaired transplanted cell engraftment. These findings cannot be accounted for by gliotoxin toxicity in transplanted cells, because gliotoxin did not cause hepatotoxicity in the doses used here and in previous studies, 12 and did not impair cell engraftment when used by itself.…”

Hepatic stellate cells primed with cytokines upregulate inflammation in response to peptidoglycan or lipoteichoic acid

“…This included the expression of smooth muscle a-actin, glial fibrillary acidic protein (GFAP), and Type I collagen, as previously well characterized by Schnabl et al [26][27][28] Telomerasepositive HSCs were seeded on uncoated plastic tissue culture dishes and cultured in DMEM (Life Technologies, Grand Island, NY) supplemented with 10% heat inactivated FBS and standard antibiotics in a 95% air and 5% CO 2 humidified atmosphere at 371C. For RT-PCR experiment of TLR2 and CD14, primary human HSCs were isolated by a two-step collagenase perfusion from surgical specimens of a normal human liver or a HCV-induced human cirrhotic liver as described previously.…”

Mechanisms of alcohol‐induced hepatic fibrosis

“…47 The key to translating the important discovery of the activated-HSC-apoptosis model of fibrosis recovery into a clinical entity of therapeutic value in diseases such as ALD is to design strategies that selectively kill activated HSCs without affecting macrophages and hepatocytes that are critical for recovery and regeneration. For example, gliotoxin is capable of inducing apoptosis not only of HSCs but also of hepatocytes at higher concentrations, 48 thus limiting its clinical usefulness. On the other hand, activated HSCs selectively express the low affinity neurotro-phic receptor p75 and undergo apoptosis in response to nerve growth factor stimulation.…”