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has attracted a lot of attention. But as we have seen, the effects of TGF-β are more global than just blood
vessel damage and there is a more compelling candidate.

TGF-β and HGF- the Yin/Yang of fibrosis [28]
HGF has been referred to as a direct antagonist to TGF-β induced fibrosis. HGF and TGF-β have been
called the “Ying and Yang of Fibrosis” [Figure 7]. HGF directly inhibits the production of TGF-β and blocks
the intracellular pathways from the TGF-β Receptor to nucleus at various points. In both kidney and liver
injury models, levels of HGF relative to TGF-β coincide with the development of fibrosis versus its
resolution. HGF has been proposed as a therapeutic possibility to treat fibrosis.

But if counteracting the effects of TGF-β is enough to arrest the progress of fibrosis, is it enough to
regenerate tissue? We know that in the liver, many growth factors and extrinsic factors such as portal blood
flow rates can influence rates of regeneration, but without HGF, there is no liver regeneration. Thus, at least
[29]
in the liver, the primordial regenerating organ, HGF is indispensable . Likewise, HGF receptor activation
is indispensable for wound healing .
[30]
HGF is a single inactive polypeptide secreted by mesenchymal cells and cleaved in the extracellular space
[31]
by serine proteases into its active form. Like TGF-β, it is widely distributed in the extracellular matrix of
most tissues. Its receptor is HGFR (hepatocyte growth factor receptor), which used to be known as the “C-
Met” and was thought to be an oncogene. The receptor is expressed mainly by epithelial and endothelial
cells. The receptor has a complex structure. The intracellular moiety has multiple branching points at which
specific phosphorylation events trigger specific intracellular pathways. Like TGF-β, HGF is very important
in embryogenesis. Throughout embryogenesis , HGF helps cells bud off from developing tissues and move
[32]
towards and shape the complex architecture of prospective organs. It does promote EMT, like TGF-β.
However, whereas TGF-β directs the cell to fibroblast differentiation, HGF allows the epithelial ductal cell or
endothelial cell to proliferate and differentiate. HGF can direct cells to aggregate and form tubular
structures with branching capabilities, which is important in creating both ducts and vessels. HGF also
stimulates the production of MMPs active against collagen type3 (the most dominant in the interstitial
tissue matrix). This helps migration and refashions the tissue matrix to accommodate the regenerating
structures. Its function is similar in adult tissues after injury or during wound healing when lingering cells
migrate into injury sites to restore and regenerate pre-existing structures. These activities - motility, cell
survival, and proliferation embody a biological suite that is called the “invasive growth program” .
[33]

HGF vs. TGF-β
The metaphor of HGF and TGF-β being the Yin/Yang of fibrosis in the context of fibrosis is perhaps
incomplete as it does not account for the “invasive growth program” (regenerative response). Furthermore,
the “invasive growth program” (regenerative phase) and the fibrotic (remodeling) phase are two of the
major three response patterns of the body, with the inflammatory pathway being the third. The story of
HGF versus RIF is the drama of healing unfolding in a dramatic, “reversed” way.

For example, in the case of RIF, there is such a uniform TGF-β amplified signal that the response unfolds
deterministically from inflammation to its sclerotic end, like a biological winter. HGF can stimulate a
regenerative response in RIF tissue that reprograms the entire tissue bed. Stem cells display their full
armamentarium to create functioning structures of life where there were scars. The following are ways in
which the “invasive growth program” counters “the master regulator of fibrosis.”