Does the activation of the HSCs occur by infiltrating macrophages or is it due to an upregulation of an activator like TGF beta?
On what signal do the macrophages migrate into the liver? Macrophages produce TGF beta, could this be another reason for hepatic stellate cell activation and proliferation?
There is no simple answer to this question. It's right that TGFbeta plays a central role in liver fibrogenesis, by activating stellate cells but also by other mechanisms. However, in vitro, HSC do also activate in the absence of TGFbeta or in the presence of a TGFbeta inhibitor. This is because the stimulus derived from the stiff surface of a plastic petri dish is a very strong one. But in the liver such stiffness will only be reached in already established fibrosis so there must be other stimuli at first. The concept that first Kupffer cells become activated, secrete TGFbeta and thereby initiate HSC activation might very well be true but it will be hard to prove if this is the main mechanism in vivo. Almost every day new papers appear demonstrating that one or another factor can induce/enhance or inhibit HSC activation. Most likely this process is a concerted action of many different stimuli/cytokines acting together in vivo.
In two words (the whole process is much more complex, of course, and there are a lot of good review articles for that) - HSC may become activated directly via pathogens/various stimuli (drugs, viruses, alcohol, fat, bile salts, etc), or indirectly via various cytokines (TGFb, PDGF, HGF, TNFa etc) released from damaged liver parenchyma (activated hepatocytes or cholangiocytes) and inflammatory cells, infiltrating the liver in response to injury via chemoattraction.
There is no simple or immediate (twitter-like) response to such a question and personally I feel that the overall scenario is extremely complex and dynamic, with a lot of cells, mediators and microenvironment factors being involved, often interacting together. Just to mention few things: a) myofibroblasts as you can observe in a chronically injured human liver, can originate not only from HSC but also from portal fibroblasts and, to a less extent, from bone marrow-derived cells engrafting the injured liver; b) to the list of mediators, in addition to TGFbeta which is still likely to be the most relevant factor and other major cytokines and growth factors, you should add adipokines and reactive oxygen species and related redox signaling as well as hypoxia and HIFs; c) other putative mediators are continuously emerging including polypeptides but also microparticles and other. I would suggest to entry the field by reading some of the nice recent reviews published on such a topic in order to have a more appropriate approach to the chronic liver disease scenario.
Thank you all for your valuable feedbacks.
Dear Maurizio,
I really liked the fact that you mentioned about the apdipokine concept and the transcription factor PPAR-gamma could play a significant genetic and an epigenetic role in liver fibrosis.
I agree that liver fibrosis is a complex indication involving the role of many surrounding cells and factors like TIMPs which could inhibit MMPs leading to extracellular matrix deposition caused by stellate cells and fibroblasts/myofibrogenesis effect.There is surely even a role of inflammatory/antiinflammatory cytokines like IL1Ra,IL-6 and IL-10.
I was only wondering about the efficacious effects of mesenchymal stem cells in Liver cirrhosis.What could be a key cytokine playing an important role in the suppression and antifibrotic effects.The MSCs are known to secrete TGF beta which could also promote HSC activation or even supress the fibrosis with an antifibrotic effect?Which paracrine factor secreted by MSCs could be a target for antifibrosis?
Hepatic stellate cell activation is a complicated topic, here is the most recent review on the topic:
http://www.ncbi.nlm.nih.gov/pubmed/23903700
The mechanism of hepatic stellate cell activation most likely vary with the inducing agent; for example chemical and hepatitis virus induced fibrosis could have different initiating signals. Several lines of evidence have suggested commonalities, such as elevated TGF beta fibrotic livers. The question of the mechanism of hepatic stellate cell activation is an active research topic, which remains to be elucidated.
Each one of the previous scientist added a facet of the role of environment (inflammatory status, cytokines and their receptors, inducing agent (virsus or alcohol) in stellate cell activation. I will add the role of microbiota leading to lypopolysacharides production.
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