The Promotion of Adipogenesis in a Rat Model of Radiation Induced Fibrosis of the Mammary Fat Pad

Background/Purpose: Radiofibrosis of breast tissue ultimately compromises breast tissue reconstruction by interfering with tissue viability and healing; autologous fat transfer has recently been shown to reduce radiotherapy-related tissue injury, thought to be attributed to the presence of adipose-derived pluripotent stem cells^1,2. We have identified a novel gene HMMR/RHAMM, whose expression decreases adipogenesis and increases fibrosis. We have developed RHAMM peptide mimetics (NP-110) to block RHAMM signalling, and it is thought that the injection of such a peptide will promote adipogenesis and decrease fibrosis in mammary tissue in rats.

Methods: High frequency ultrasound was used to assess volume through thickness measurements and 3D reconstruction of mammary fat pads in 20 retired breeder female rats that were non-irradiated, irradiated, treated, and not-treated with peptide NPI-110 at days 0, 7, 14, and 21. Rats were euthanized at Day 21, and mammary fat pad tissues were processed for expression of fibrotic and adipogenetic markers using real-time polymerase chain reaction and immunohistochemistry.

Results: Volume estimates of fat pad and expression of fibrotic markers such as Collagen-1, Collagen-3, and TGFß-1, and adipogenetic markers such as PPARγ, adiponectin and perilipin were ameliorated by peptide NP-110 and radiotherapy when quantified via qPCR and immunohistochemistry. NPI-110 significantly reduced skin inflammation and radiofibrosis, the latter assessed by collagen fibril deposition via picrosirius red staining, and increased mRNA expression of adipogenic markers.

Conclusion: Results from this study may aid in therapies in the human patient population which decrease the significant morbidity associated with a very challenging and common clinical problem – reconstruction in previously radiated beds in general, and breast cancer specifically. 

1. Rigotti G, Rigotti G, Marchi A, et al. Clinical treatment of radiotherapy tissue damage by lipoaspirate transplant: a healing process mediated by adipose-derived adult stem cells. Plast Reconstr Surg. 2007;119:1409-22-4.

2. Di Santolo MS, Sagnelli M, Tortora G, et al. The utility of the high resolution ultrasound technique in the evaluation of autologous adipose tissue lipofilling, used for the correction of post-surgical, post-traumatic and post-burn scars. Radiol Medica. 2016;121(6):521-527.