COLLAGEN STIFFNESS AND ARCHITECTURE REGULATE FIBROTIC GENE EXPRESSION IN ENGINEERED ADIPOSE TISSUE
April 14, 2020
Adipose tissue (AT) has a dynamic extracellular matrix (ECM) surrounding adipocytes that allows for remodeling during metabolic fluctuations. During the progression of obesity, AT has increased ECM deposition, stiffening, and remodeling, resulting in a pro‐fibrotic dysfunctional state. Here, the incorporation of ethylene glycol‐bis‐succinic acid N‐hydroxysuccinimide ester (PEGDS) allows for control over 3D collagen hydrogel stiffness and architecture to investigate its influence on adipocyte metabolic and fibrotic function. Upon stiffening and altering ECM architecture, adipocytes did not alter their expression of key adipokines, leptin, and adiponectin. However, they do increase actin cytoskeletal fiber formation, pro‐fibrotic gene expression, ECM deposition, and remodeling within a stiffer, 3D collagen hydrogel. For example, COL6A3 gene expression is upregulated approximately twofold, resulting in increased deposition of pericellular collagen VI alpha 3 surrounding adipocytes. Furthermore, inhibition of actin contractility results in a reversal of pro‐fibrotic gene expression and ECM deposition, indicating that adipocytes are mediating mechanical cues through actin cytoskeletal networks. This study demonstrates that ECM stiffness and architecture plays a critical regulatory role in adipocyte fibrotic function and contributes to the overall pro‐fibrotic dysfunctional state of AT during the progression of obesity and AT fibrosis.
ENDOTHELIAL CELL CROSSTALK IMPROVES BROWNING BUT HINDERS WHITE ADIPOCYTE MATURATION IN 3D ENGINEERED ADIPOSE TISSUE
March 26, 2020
Vasculature is central to the development of adipose tissue (AT) engineered models. It is a key part of AT function and long-term maintenance, but the crosstalk between adipocytes and endothelial cells is not well understood. Here, we directly co-culture the two cell types at varying ratios in a 3D Type I collagen gel. Constructs were evaluated for adipocyte maturation and function and vascular network organization. Further, these constructs were treated with forskolin, a beta-adrenergic agonist, to stimulate lipolysis and browning. Adipocytes in co-cultures were found to be less mature than an adipocyte-only control, shown by smaller lipid droplets and downregulation of key adipocyte-related genes. The most extensive vascular network formation was found in the 1:1 co-culture, supported by vascular endothelial growth factor (VEGF) upregulation. After forskolin treatment, the presence of endothelial cells was shown to upregulate PPAR coactivator 1 alpha (PGC-1α) and leptin, but not uncoupling protein 1 (UCP1), suggesting a specific crosstalk that enhances early stages of browning.
BIOENGINEERING AND METABOLISM VOICES
March 5, 2019
To explore the world where technology fuses with the life sciences, we asked a diverse group of scientists to tell us about bioengineering innovations that impact metabolism and physiology. From miniaturized models of physiological systems to smart drugs with feedback control, we take a journey with them through the frontiers of biomedicine.