The Impacts of Lymph on the Adipogenesis of Adipose-Derived Stem Cells

Background: The pathophysiology of adipose proliferation or differentiation in extremity lymphedema has not been thoroughly studied. This study investigated the impacts of the lymph harvested from lymphedematous limbs on the adipogenesis of adipose-derived stem cells (ASCs). Methods: ASCs were isolated from the adipose tissue of normal extremities and cultured with lymph collected from Cheng lymphedema grade III to IV patients or adipogenic differentiation medium (ADM) and further subjected to differentiation and proliferation assay. The expression of adipogenesis genes was examined by real-time polymerase chain reaction to investigate the effect of lymph on ASCs. The level of adipogenic cytokines in the lymph was also evaluated. Results: The adipocytes were significantly larger in lymphedema fat tissue compared with that in normal fat tissues (P < 0.00). The adipogenesis of ASCs cultured in lymph was significantly enhanced compared with in ADM (P = 0.008) on day 10, suggesting that the adipogenesis of ASCs was promoted under the lymph-cultured environment. The expression of adipogenesis genes, peroxisome proliferator-activated receptor (P = 0.02), CAAT/enhancer-binding protein α (P = 0.008); fatty-acid binding protein (P = 0.004), and lipoprotein lipase (P = 0.003), was statistically elevated when the ASCs were cultured with lymph. The insulin content in lymph was statistically higher in lymph (P < 0.001) than in plasma. Conclusions: The adipogenesis of ASCs was promoted under the lymph-cultured environment with statistically increased adipogenesis genes of peroxisome proliferator-activated receptor, CAAT/enhancer-binding protein α, fatty-acid binding protein, and lipoprotein lipase. The excess lymph accumulated in the lymphedematous extremity contained a greater insulin/insulin-like growth factor-2. These adipogenic factors promoted the expression of early adipogenesis genes and led ASCs to undergo adipogenesis and differentiated into adipocytes. Clinical Relevance Statement: The accumulation of adipose tissue in the lymphedema region was contributed from the content of excess lymph.