Molecular analysis and differentiation capacity of adipose-derived stem cells from lymphedema tissue.

Breast cancer remains one of the most prevalent cancers in women, with an estimated 200,000 new cases of invasive breast cancer and over 50,000 cases of in situ breast cancer expected annually.1 Despite improved early detection and evolving strategies to minimize surgical intervention for diagnosis and treatment of axillary disease associated with breast cancer, many women are still plagued by the disabling complication of upper limb lymphedema. Conservative treatment using massage and compression therapy remains the mainstay for lymphedema; however, these treatments do not offer lasting relief of the condition because they fail to address the underlying pathologic accumulation of excess adipose tissue.2 Several investigators have reported the use of liposuction to treat upper extremity lymphedema, providing an opportunity to examine whether the stromal fraction of lymphedema-associated adipose tissue differs from nonaffected subcutaneous adipose tissue.3 We hypothesize that the stromal vascular fraction of lymphedema tissue has important differences compared with that of healthy subcutaneous fat with regard to gene expression and differentiation capacity. The complication of lymphedema develops gradually as the lymphatic vessels are unable to drain the appropriate amount of lymph and proteins. The remaining lymphatic channels become dilated and overloaded, rendering the valves incompetent.2 Eventually, the entire extremity is affected, and even the most distal vessels become dilated. Concurrently, mononuclear phagocytotic cells and mesenchymal tissue lose their ability to transport proteins, causing these to accumulate. Excess protein creates an osmotic gradient, drawing in additional fluid. Over time, the extremity enlarges and becomes painful and weak. Traditional therapeutic approaches assumed that the enlarged extremity in lymphedema was mainly the cause of excess lymph fluid, and thus noninvasive treatments were focused on compression and enhancing lymph flow. After the first operation on an affected arm, however, surgeons realized that the majority of this excess tissue was adipose tissue and not just edematous tissue.4,5 Therefore, it appears clear that lipoaspiration is needed to address the excess adipose component associated with the chronic lymphedematous arm. Within the stromal vascular fraction of adipose tissue, scientists have identified a group of cells known as adipose-derived stromal cells. As in other mesenchymal populations, adipose-derived stem cells have the capacity to differentiate into skeletal muscle, smooth muscle, fat, cartilage, connective tissues, tendon, and bone.6–9 The adipogenic potential of adipose-derived stem cells has been the focus of many studies, and several articles have been published on the in vitro adipogenic differentiation of adipose-derived stem cells, although we are not aware of studies assessing whether differences in adipose-derived stem cells account for the increased adiposity seen in lymphedema patients.10–12 Similarly, several studies have demonstrated the vasculogenic capacity of adipose-derived stem cells; however, it is unknown whether lymphedema-derived adipose-derived stem cells differ in their vasculogenic potential.13–17 In this study, we set out to characterize functional differences in the adipose-derived stem cells from lymphedematous and healthy adipose tissue, as this might enhance our understanding of the involved molecular mechanisms and provide further insight into the underlying abnormality.