Callens, S. | bioRxiv Science

bioRxiv2021

Loss of adipocyte phospholipase gene PLAAT3 causes lipodystrophy and insulin resistance due to inactivated arachidonic acid-mediated PPAR signaling

PLAAT3 is a phospholipid modifying enzyme predominantly expressed in white adipose tissue (WAT). It is a candidate drug target as Plaat3 deficiency in mice protects against picornavirus infection and diet-induced obesity. We identified four patients with homozygous loss-of-function mutations in PLAAT3, presenting with partial lipodystrophy, severe insulin resistance and dyslipidemia. PLAAT3-deficient WAT showed a failure to liberate arachidonic acid (AA) from membrane phospholipids resulting in an inactive gene network downstream of adipogenesis master regulator and anti-diabetic drug target PPARG. These findings establish PLAAT3 deficiency in humans as a novel type of partial lipodystrophy due to an AA- and PPARG-dependent defect in WAT differentiation and function.

genetics↗

bioRxiv2020

Emergent collective organization of bone cells in complex curvature fields

AO_SCPLOWBSTRACTC_SCPLOWIndividual cells and multicellular systems have been shown to respond to cell-scale curvatures in their environments, guiding migration, orientation, and tissue formation. However, it remains unclear how cells collectively explore and pattern complex landscapes with curvature gradients across the Euclidean and non-Euclidean spectra, partly owing to fabrication limitations and the lack of formal geometric considerations. Here, we show that micro-engineered substrates with controlled curvature variations induce the collective spatiotemporal organization of preosteoblasts. By leveraging mathematical surface design and a high-resolution free-form fabrication process, we exposed cells to a broad yet controlled, heterogeneous spectrum of curvature fields. We quantified curvature-induced spatial patterning at different time points and found that cells generally prefer regions with at least one negative principal curvature. We also show that multicellular cooperation enables cells to venture into unfavourably-curved territories, bridging large portions of the substrates, and collectively aligning their stress fibres. We demonstrate that this behaviour is partly regulated by cellular contractility and extracellular matrix development, underscoring the mechanical nature of curvature guidance. Our findings offer unifying perspectives on cell-geometry interactions that could be harnessed in the design of micro-engineered biomaterials, for example, for tissue engineering applications.

bioengineering↗