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PhD Discussions: Alba Herrero y Clement Hallopeau
Friday, March 1 @ 10:00 am–11:00 am
Molecular imaging to unveil the pathophysiology of metabolic associated fatty liver disease
Alba Herrero, Molecular Imaging for Precision Medicine group
Metabolic-associated fatty liver disease (MAFLD), a progressive liver condition rapidly rising to lead to chronic liver disease worldwide, manifests as metabolic dysregulation, leading to steatosis, fibrosis, and cirrhosis if left untreated. Beyond the liver, it induces high BMI, insulin resistance, and elevated plasma glucose amongst others. Age, genetics, and sex influence its clinical presentation, hindering biomarker detection. Currently, real-time metabolic monitoring is not readily available in clinical settings. Hyperpolarized Magnetic Resonance Spectroscopic Imaging (HP-MRSI) boosts MR signals, allowing for real-time metabolic tracking of 13C-labelled substrates, such as pyruvate, posing as a solution to this problem.
We delineated 6 study groups to evaluate the effects on liver metabolism of specific MAFLD risk factors, these being diet, sex, and genetics. Subjects were monitored throughout the experiment for signs of insulin resistance, increased plasma glucose, and BMI levels as MAFLD indicators. Analyzed with a 3T preclinical MRI scanner, and after injection of hyperpolarized [1-13C]-pyruvate, the metabolism of pyruvate was tracked in situ, probing downstream metabolic products such as lactate and alanine.
Metabolic imaging has the potential to be used in clinical settings to diagnose and track metabolic dysfunctions. Real-time monitoring of pyruvate metabolism using HP-MRSI has revealed alterations across various metabolic conditions, displaying its clinical potential.
Mechanisms of mechanical compartmentalisation in intestinal organoids
Clement Hallopeau, Integrative Cell and Tissue Dynamics group
Monolayers of intestinal organoids recapitulate the functional compartmentalisation seen in-vivo.
Crypt-like regions host stem cells, Paneth cells and transit amplifying cells, whereas villus-like regions contain differentiated cells. Measurements of traction forces in these organoids have
established that stem cells push the underlying substrate while the transit-amplifying cells pull it, defining clear mechanical and functional compartments (Pérez-González, Ceada et al, Nat Cell Bio, 2021). Crypt-villus compartmentalisation is attributed to opposed gradients in Eph/ephrin signaling, but how these gradients are linked to the mechanical pattern is unknown. To address this question, we studied the mechanical and functional compartmentalisation in organoids derived from mice lacking EphB2 and EphB3 (EphB2-/-, EphB3-/-). We found that, unlike in wild type organoids (WT), crypts of EphB2-/-EphB3-/- organoids (KO) expand at the expense of the villuslike region. This phenotype is associated to an increased proliferation of the KO crypts and a decreased expression of the stemness marker olfm4. In mechanical terms, the 3D traction pattern of the KO crypts is qualitatively similar to the WT, but forces have a decreased amplitude, suggesting a decreased tension around the KO crypts. Taken together, these data establish a link between the mechanical features and the size homeostasis of the functional compartments of the intestinal organoid, governed by Eph/ephrin signaling.
