Variability in responses observed in human white adipose tissue models

Abstract

Obesity is a risk factor for a myriad of diseases including diabetes, cardiovascular dysfunction, cirrhosis, and cancer, and there is a need for new systems to study how excess adipose tissue relates to the onset of disease processes. This study provides proof-of-concept patient-specific tissue models of human white adipose tissue to accommodate the variability in human samples. Our 3D tissue engineering approach established lipolytic responses and changes in insulin-stimulated glucose uptake from small volumes of human lipoaspirate, making this methodology useful for patient specific sample source assessments of treatment strategies, drug responses, disease mechanisms, and other responses that vary between patients. Mature unilocular cells were maintained ex vivo in silk porous scaffolds for up to a month of culture and imaged non-invasively with coherent anti-Stokes Raman scattering. Interestingly, differences in responsiveness between tissues were observed in terms of magnitude of lipolysis, ability to suppress lipolysis, differences in glucose uptake, and lipid droplet size. Body mass index was not a factor in determining tissue responsiveness; rather, it is speculated that other unknown variables in the backgrounds of different patients (ethnicity, athleticism, disease history, lifestyle choices, etc.) likely had a more significant effect on the observed differences. This study reinforces the need to account for the variability in backgrounds and genetics within the human population to determine adipose tissue responsiveness. In the future, this tissue system could be used to inform individualized care strategies-enhancing therapeutic precision, improving patient outcomes, and reducing clinical costs.

Adipose Tissue Fibrosis: Mechanisms, Models, and Importance

“…Human [94,95] Seeding scaffolds with whole adipose tissue, rather than isolating a specific cell type, creates a more physiologically relevant model. The scaffolds had similar numbers of cells and triglycerides after 3 months of culture compared to after seeding.…”

WAT-on-a-chip integrating human mature white adipocytes for mechanistic research and pharmaceutical applications

“…Similarly, studies using whole WAT explants are restricted to short culture durations. Additionally, inter-individual variability complicates the interpretation of study results based on samples from different donors 28 .…”

In vitro tissue-engineered adipose constructs for modeling disease

“…Interestingly, when treated with the pro-inflammatory cytokine, TNFα, adipocytes grown on 3D scaffolds secreted obesityassociated markers such as: IL1-α, osteoprotegerin (OPG), tissue inhibitor of metalloproteinases 2 (TIMP2), as well as T2DM related proteins such as IL-6, IL-8, and regulated-on-activation-normal-T-Cell-expressed-andsecreted (RANTES) [133]. In contrast to expectations and also the work by Aubin et al, TNF-α stimulation increased glucose uptake which the authors attribute to other cell types within the lipoaspirates, including endothelial cells [128,150]. These data demonstrate that adipocytes grown on a silk scaffold and subject to acute inflammation, respond in a similar manner as to what is observed in obesity and T2DM but the interactions between adipocytes and other cell types in the microenvironment are responsible for the full phenotype seen in patients.…”