Development and functional analysis of a human adipose tissue chip
Adipose tissue plays a fundamental role in the regulation of energy balance, body weight and systemic metabolism. The pathological expansion of adipose tissue in obesity is a major driver of metabolic disease and contributes to many other disease processes. Adipose tissue contains many cell types, including adipocytes, immune cells, vascular endothelium and smooth muscle cells. However, little is known about how these different cell types interact and how these interactions impact tissue function. In addition to this, our understanding of adipose biology is almost exclusively based on studies done in mice due to the lack of a physiologically relevant human tissue model system. Mouse models now face increased scrutiny and raise scientific and ethical concerns due to their questionable relevance to human physiology. To address these major challenges, we have put together a multidisciplinary team to create a bioengineered and three-dimensional human fat-on-a-chip device. The device will reconstitute key microarchitecture, cellular heterogeneity and physiological function of human subcutaneous adipose tissue. This will be done by combining culture of adipocytes and supporting cells with extracellular matrix/hydrogel, angiogenesis, and dynamic self-assembly of polymeric materials. The cells incorporated into the device will be derived from adult human stem cells or induced pluripotent stem cells which are renewable and thus amenable to genetic manipulations. We will validate our model by quantitatively analyzing physiological activities of the microengineered human adipose tissue, including adipokine production, lipolysis and glucose uptake. Finally, we will investigate the potential of this microengineered platform to model adipose tissue inflammation, including activation of macrophages. The successful outcome of this proposal will: address critical technical challenges in metabolic disease research, lead to an improved understanding of human adipose tissue biology, and provide a powerful platform to search for novel adipose-targeted therapeutics.

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