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Rodriguez. Plast Aesthet Res 2023;10:67 https://dx.doi.org/10.20517/2347-9264.2023.73 Page 9 of 18

Blood vessel degradation
By upregulating MMP9 (type IV collagenase), TGF-β causes the degradation of collagens type 4 (basal
lamina) and 7 (reticular lamina), which are prominent constituents of basement membranes. This effect is
significant because it facilitates the migration of the endothelial cell to the extravascular space but also
affects the structural integrity of the blood vessel. Together with the endothelial cell changes, these TGF-β
effects on blood vessels help explain the increased permeability of irradiated vessels and structural
abnormalities such as ectasia. Dr. Rigotti’s electron micrographs [Figure 5] in his landmark article illustrate
these phenomena clearly. MMP 9 itself also cleaves L-TGF-β, making more TGF-β available.

Constitutive fibrosis
TGF-β also stimulates the production of collagen type III, the type found in ground substance. But in
addition to the increased synthesis of collagen type III, there is also increased synthesis of TIMPs
(temporary inhibitors of metallo proteinases). TIMPS inhibit collagen lysis. TGF-β also downregulates
MMP1, which degrades native fibrillary collagen. The end result is a net overproduction of collagen
[23]
(increased synthesis, decreased breakdown) .

TGF-β also stimulates the production of CTGF (connective tissue growth factor), a growth factor with a role
in wound healing but which is seen in virtually all fibrotic states.

Once the specific cell behaviors triggered by TGF-β are well understood, a re-examination of Dr. Rigotti’s
electron micrographs highlights the influence of TGF-β in RIF. In Figure 6, the authors observe lysosomes
[2]
on an adipocyte and scattered intracellular debris. Both observations are linked to TGF-β directed apoptosis.
The lysosomes are secreted by macrophages and contain lysosomal enzymes that digest apoptotic cells and
create fragmented cellular debris in preparation for macrophage uptake.

The accumulation of collagen in the interstitial space is the result of TGF-β stimulation of Collagen type3,
and inhibition of its breakdown by stimulation of TIMPs that inhibit collagenases active against collagen
type3.

The duplication of the capillary vessel lamina and the separation between the endothelial cell and the
pericyte are both the result of TGF-β stimulation of MMP2 and MMP9, both collagenases active against
collagen type IV, the predominant collagen in basement membrane and basal lamina. This disruption in the
basement membrane is usually the first step in the TGF-β directed EMT and EnMT, where disruption of the
attachments to basement membrane prepares the endothelial cell to migrate out of the vessel and proceed to
fibroblast differentiation. The Weiber-Palade bodies in the endothelial cell contain chiefly Von Willebrand
factor and Interleukin-8 (IL_8). IL-8 is an inflammatory cytokine that can be induced by oxidative stress. In
this setting, the weiber-palade bodies are related to the radiation oxidative stress but not necessarily to the
TGF-β response.

HOW DO FAT GRAFTS HEAL RADIATION INJURY?
The role of TGF-β has been understood by specialists in radiobiology for at least two decades. After the
events of 9/11, the Federal government launched an initiative to counteract both ARI and RIF and dedicated
$150 million to the effort. Lines of inquiry were directed at molecular antagonists to TGF-β, unfortunately
without success .
[21]

Yet in 2001, Jackson et al. published a case report of successful treatment of RIF using fat grafting to the
thigh of a woman who had had a limb-sparing rhabdomyosarcoma excision 20 years prior . He reported a
[1]