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Page 2 of 18 Rodriguez. Plast Aesthet Res 2023;10:67 https://dx.doi.org/10.20517/2347-9264.2023.73

INTRODUCTION
Things that we have learned in medical school and residency about RIF (radiation induced fibrosis) include
aphorisms such as “surgery is permanent, but radiation is permanent AND progressive”. This presumes that
radiation affects individual cells by causing damage to the cellular DNA, and that damaged radiated tissues
do not heal well because of malfunctioning vasculature. Therefore, there is no cure for radiation damage
except for the substitution of damaged tissue with healthy vascularized tissue (pedicled or free tissue
[1]
transfer). The first report that avascular fat grafts restored RIF tissue to normalcy , and the demonstration
[2]
by electron micrographs of regenerated tissues in fat-grafted areas , directly contradict our preconceived
notions of radiation damage and how it can be reversed. In this article, Dr. Rigotti intimated that the healing
effect of fat grafts on RIF is mediated by “stem cells”. How these “stem cells” resident in fat graft heal
radiated tissue is the subject of this review.

This article provides a simplified overview of how fat grafts regenerate RIF-damaged tissue based on
published data. It is not an exhaustive review of molecular pathways but provides a general understanding
of the principal cytokine dynamics of radiation damage, regeneration, and reversal of RIF. The cornerstone
principles to understand are (A) RIF is an organized tissue response mediated principally by TGF-β
(transforming growth factor beta) and (B) Fat Grafts reverse this damage in a process mediated by HGF
(hepatocyte growth factor).

RADIATION INJURY AND RIF
Radiation damage can be broadly divided into two categories- acute radiation syndrome (ARS) and the
more chronic RIF. Although the precipitating agent is the same, they are different processes and not
necessarily linked.

ARS is a type of inflammatory process that has its own set of cytokine and immune effector cells. When
severe, it can progress to a “cytokine storm” that ends in systemic inflammatory response syndrome (SIRS).
Although discussion of ARS is outside of the scope of this article, the reader is directed to other excellent
[3,4]
reviews .
RIF, in contrast, is a fibrotic tissue response mediated by specific cytokines (mainly TGF-β) and immune
effector cells (fibroblasts) . Regardless, both ARS and RIF have in common the fact that they are mediated
[5]
by cytokines and immune effector cells. In this article, we will focus on RIF.

This recent concept of damage mediated by cytokine messengers and effector cells has been referred to as
Radiation-induced bystander effect (RIBE) and is different than the previous consensus known as the
[6]
“target cell theory”. This theory held that the central event of Ionizing Radiation is damage to the cell DNA,
and that the damage determined the cell’s fate at the time of cell division.

Target cell theory
According to this theory, ionizing radiation damages the DNA of individual cells. Each type of cell responds
differently to a given dose of radiation depending on the effectiveness of its repair mechanisms against
radiation damage. The repair may be effective, may end up in a mutation of the DNA, or it may be
ineffective. The amount of damage is expressed as the cell goes into its mitotic cycle when the cell may (A)
survive intact; (B) survive in a mutated state; or (C) may die [Figure 1]. Rapidly dividing cells, such as tumor
cells, are more susceptible to radiation damage, but slowly replicating tissues can also express radiation
damage later in time as the cells go into mitosis.