Multiscale modeling of tissue-engineered fat: Is there a deformation-driven positive feedback loop in adipogenesis?

Mechanotransduction plays a role in adipose tissues by transducing the environmental mechanical signals. It is recognized that dynamic or cyclic mechanical strains suppress adipogenesis, but static strains activate the adipogenic signaling pathways. This phenomenon needs to be investigated further, given its potential use in tissue engineering of fat. We used in vitro cultures as model systems for studying differentiation and function of adipocytes. Additionally, using the finite element method, we developed here sets of multiscale models (MSM), which represent single or multiple adipocytes embedded in scaffolds, stimulated mechanically in a static regime. Based on in vitro adipocyte culture work, these models were employed to study the hypothesis that the loading state of the plasma membrane (PM) in adipocytes is influenced by neighboring cells, which could reflect positive feedback loops of en mass adipose cell differentiation. We demonstrate that under static loading, tensile strains at the PM increase with the stage of cell maturation. Furthermore, when the cell density was sufficient (above 19 cells per 100 μm³), progressive differentiation in some of the cells caused higher magnitudes of tensile strains in the PMs of other nearby cells. MSM are currently the only feasible means to correlate continuum (macrolevel) construct deformations to subcellular-level PM stretches in distorted cells. These macro-to-micro mechanobiology relationships, revealed through MSM, point to stimulations that promote the formation of lipid droplet accumulations and the increase of adipogenesis. Such models are a cost-effective useful platform for achieving better understanding of these deformation-driven cell processes toward optimized design of tissue-engineered fat constructs.