Tryptase-Positive Mast Cells Promote Adipose Fibrosis in Secondary Lymphedema through PDGF

Abstract

Lymphedema is a chronic and progressive condition that causes physical disfigurement and psychological trauma due to the accumulation of lymphatic fluid in the interstitial space. Once it develops, lymphedema is difficult to treat because it leads to the fibrosis of adipose tissue. However, the mechanism behind this remains unclear. The purpose of this study was to investigate the involvement of mast cells (MCs) in the adipose tissues of patients with lymphedema. We found that fibrosis spread through blood vessels in the adipose tissues of lymphedema patients, and the expression of the collagen I and III genes was significantly increased compared to that of those in normal adipose tissue. Immunostaining of vimentin and α-smooth muscle actin showed that fibroblasts were the main cellular components in severely fibrotic regions. Toluidine blue staining confirmed a significant increase in the number of MCs in the adipose tissues of lymphedema patients, and immunostaining of serial sections of adipose tissue showed a significant increase in the number of tryptase-positive cells in lymphedema tissues compared with those in normal adipose tissues. Linear regression analyses revealed significant positive correlations between tryptase and the expressions of the TNF-α, platelet-derived growth factor (PDGF)-A, and PDGFR-α genes. PDGF-A–positive staining was observed in both fibroblasts and granules of tryptase-positive MCs. These results suggest that MC-derived tryptase plays a role in the fibrosis of adipose tissue due to lymphedema directly or in cooperation with other mediators.

Breast reconstruction and breast cancer-related lymphedema: insights and perspectives

“…Pathohistological studies have identified hyperplasia of collagen fibers and smooth muscle cells, causing thickening of the lymphatic vessels. This contributes to the hardening of the lymphatics, compromising their peristaltic ability and [26][27][28] , lastly, exacerbating the accumulation of lymph. In summary, the pathophysiology of lymphedema results from an inappropriate circle of stasis, causing an imbalance in the interstitial fluids, lymphatic vessel remodeling and function, and adipose tissue deposition.…”