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Rodriguez. Plast Aesthet Res 2023;10:67 https://dx.doi.org/10.20517/2347-9264.2023.73 Page 13 of 18

Differentiation
TGF-β locks cells into the G phase of cell division cycle. This means the cell goes on to maturation and
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senescence, and the replication option is closed off. HGF, on the other hand, restores the cell’s ability to go
into the G phase of the cell division cycle and repopulate depleted cell lines.
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Cell survival
TGF-β triggers specific apoptotic pathways in cells. HGF, on the contrary, triggers specific anti-apoptotic
pathways.

Putting it all together [Figure 8]

(1) When the tissue is irradiated, ROS break up the Ligand-TGF-β bond of Latent TGF-β and active TGF-β
is released throughout the matrix in the irradiated area.

(2) TGF-β is bound to its receptor. It is a “sticky” bond, so the effect is prolonged, i.e., SMAD’s 2and 3
shuttle several times between receptor and nucleus several times per single receptor activation.

(3) An intracellular messenger (SMAD complex) is activated, goes into the nucleus, and results in
3-4
transcription of a suite of gene products.

(4) These gene products affect cell behavior change as detailed below. These changes include (A) breakdown
of blood vessel basement membranes; (B) this, in turn, facilitates migration of epithelial cells and
endothelial cells, and terminal differentiation (EMT and EnMT), which results in depletion of epithelial and
endothelial cells driving cells to the fibroblast/myofibroblast lineage (C) Apoptosis (D) deposition of
collagen (E) upregulation of TGF-β itself. The result is the familiar clinical and microscopic picture of RIF:
A hypocellular field dominated by fibroblasts/myofibroblasts and heavy collagen deposition with loss of
normal tissue function.

(5) When the fat graft is injected, stem cells residing in SVF release HGF.

(6) HGF is bound to HGFR.

(7) (C-met oncogene). HGFR unleashes a variety of intracellular pathways and cellular interactions with
macrophages and other immune cell types that enable the “Mitotic growth Program”. This HGF
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regenerative program is, feature by feature, the antithesis of the TGF-β fibrotic program.

(8) Feature by Feature comparison of HGF “mitotic growth program” vs. TGF-β Fibrosis instruction set. (A)
HGF, like TGF-β, both cause EMT and EnMT. However, TGF-β drives cells to fibrocyte terminal
differentiation, and the cell is blocked from DNA synthesis and duplication. On the other hand, HGF places
cells in the S phase of the cell cycle, where DNA replication occurs, and the cell can undergo mitosis; (B)
HGF, in conjunction with other cytokines such as VEGF or EGF, directs differentiation to different cell
types, whereas TGF-β, by virtue of G1 cycle arrest, produces terminal differentiation; (C) Whereas TGF-β
signals apoptosis, HGF signals anti-apoptosis; (D) HGF, to facilitate cell migration and refashion tissue
matrix, stimulates collagen lysis. TGF-β results in fibrillary collagen deposition and a fibrotic matrix that can
interfere with organ function; (E) HGF is a potent stimulator of angiogenesis (even independently of
VEGF), whereasTGF-β impairs blood vessels by depletion of endothelial cells and disruption of basement
membranes; (F) Finally, HGF itself causes downregulation of TGF-β. On the other hand, TGF-β upregulates
itself.