Regulation of Mesenchymal Progenitor Cell Fate and Adipose Tissue Remodeling

University Of Pennsylvania, Philadelphia PA

Investigators

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Abstract

SUMMARY Metabolic diseases are rising around the world as changing diets have led to striking increases in obesity rates. Co-morbidities including coronary artery disease and type 2 diabetes drive massive increases in medical costs and are leading causes of death worldwide. Adipose tissue is crucial for safely sequestering lipids to protect other organs as obesity progresses. Unhealthy expansion of adipose tissue due to genetic or environmental factors leads to increased inflammation and drives the progression of metabolic disease. Therefore, understanding the adipose tissue remodeling process in response is crucial for the development of novel therapies to promote metabolic health and reduce chronic inflammation. Mesenchymal progenitor cells (MPCs) are a heterogeneous cell population in adipose tissue that respond to environmental and metabolic cues to regulate various processes including adipogenesis, immune cell activity and fibrosis. We have found that during obesity progression, MPCs undergo a cell fate switch into cells with properties similar to cancer associated fibroblasts (CAFs). This CAF-like population expresses hallmark CAF genes including the transcription factor SOX4 and the pleotropic growth factor Midkine (MDK) that likely regulate adipogenesis and inflammation in adipose tissue. Importantly, both SOX4 and MDK levels correlate with type 2 diabetes status in humans. Our central hypothesis is that the induction inflammatory CAF-like cells in adipose tissue promotes maladaptive inflammation and decreases proper adipose tissue function. Specific Aim 1 investigates the role of the transcription factor SOX4 in driving MPC phenotype switching and adipose tissue remodeling during the development of obesity and insulin resistance. Specific Aim 2 investigates the role of MDK in regulating immune cell activity and adipose tissue function. Overall, these studies will provide insight into how adipose tissue remodels during the development of obesity, leading to an unhealthy metabolic profile and systemic inflammation that can drive the progression of cardiometabolic complications and other pathologies. Understanding these processes may uncover new therapeutic strategies for metabolic disease.