The role of aortic carboxypeptidase-like protein in adipose-derived mesenchymal stem cell adipogenesis and fibrosis

Thesis (M.A.)--Boston UniversityThe prevalence of obesity and obesity related diseases are increasing worldwide. Obesity is characterized by the pathological expansion of white adipose tissue. Previous studies on white adipose tissue of obese individuals have detected inflammation and fibrosis. These conditions may cause dysregulation of the tissue, leading to negative outcomes, including type II diabetes and metabolic syndrome. Aortic carboxypeptidase-like protein (ACLP) is a secreted extracellular matrix protein that is upregulated in fibrotic lung tissue. Importantly ACLP knockout mice are protected from experimentally induced lung fibrosis. ACLP is expressed in adipose tissue and is downregulated as stem cells undergo adipogenesis. Its overexpression increases α smooth muscle actin expression and impairs adipogenesis in preadipocyte lines; however, its role in white adipose tissue fibrosis has not been fully explored. The studies presented in this thesis aimed to investigate the hypothesis that ACLP overexpression in fibrotic white adipose tissue would promote a fibroblast to myofibroblast transition and repress adipogenesis. To determine if ACLP promotes a fibroblast to myofibroblast transition, we tested the capacity of ACLP to induce α smooth muscle actin and collagen I protein expression and increase contractility of primary stromal vascular cells. To assess the effects of ACLP on adipogenesis, we tested the ability of 10T1/2 fibroblasts and stromal vascular cells to undergo adipogenesis in collagen I gels under ACLP treatment. Results presented herein demonstrate ACLP is a potent inhibitor of adipogenesis and induces an upward trend in myofibroblast proteins and RNA expression. Significantly, these studies used murine adipose-derived cells to show the effects of ACLP, suggesting these results might be reflected in adipose tissue. These experiments support a model where ACLP potentiates adipose tissue fibrosis by inhibiting adipogenesis, resulting in fewer developing adipocytes, and stimulating myofibroblast differentiation, resulting in further collagen deposition and tissue compaction. This contribution to adipose tissue dysfunction also gives ACLP a possible role in the development of obesity related diseases, including diabetes and metabolic syndrome, identifying it as a possible target for therapeutics