Biology subjects

Mancini, P.

Publications and source records attributed to Mancini, P..

4 recordsLinked to original sources

bioRxiv2024

Evolvoid: A genetic algorithm for shaping optimal cellular constructs

We describe an in-silico pipeline, Evolvoid, based on Genetic Algorithms (GAs) for identifying the optimal morphologies of cell-laden constructs. Driven by an ad hoc selection rule (i.e., the so-called fitness function (FF)), Evolvoid iteratively identifies the characteristics (i.e., the genome) of the survival of the fittest individual of a given population throughout generations. The FF is based on universally observed biophysical laws, representing the optimal trade-off between i) high cell viability and robustness to changes in environmental oxygen and ii) a low surface energy. The Shannon entropy is used to evaluate genome complexity, with the most complex fittest individuals showing quantitative and qualitative biological resemblance to in vitro constructs. Evolvoid paves the way for the development of "lab on a laptop": high-fidelity and cost-effective digital twins of cellular constructs which could augment or even substitute costly in vitro models.

bioengineering↗

bioRxiv2022

Cellular redox metabolism is modulated by the distinct localization of cyclic nucleotide phosphodiesterase 5A isoforms

3-5 cyclic nucleotide phosphodiesterases (PDEs) are a family of evolutionary conserved cAMP and/or cGMP hydrolysing enzymes, components of transduction pathways regulating crucial aspects of cell life. Among them, cGMP-specific PDE5, being a regulator of vascular smooth muscle contraction, is the molecular target of several drugs used to treat erectile dysfunction and pulmonary hypertension. Production of full-length murine PDE5A isoforms in the milk-yeast Kluyveromyces lactis showed that the quaternary assembly of MmPDE5A1 is a mixture of dimers and tetramers, while MmPDE5A2 and MmPDE5A3 only assembled as dimers. We showed that the N-terminal peptide is responsible for the tetramer assembly of MmPDE5A1, while that of MmPDE5A2 for its mitochondrial localization. Overexpression of the three isoforms alters at different levels the cAMP/cGMP equilibrium as well as the NAD(P)+/NAD(P)H balance and induces a metabolic switch from oxidative to fermentative. In particular, the mitochondrial localization of MmPDE5A2 unveiled the existence of a cAMP-cGMP signaling cascade in this organelle, for which we propose a metabolic model that could explain the role of PDE5 in some cardiomyopathies and some of the side effects of its inhibitors.

cell biology↗

bioRxiv2021

The dorsal blastopore lip is a source of signals inducing PCP in the Xenopus neural plate

Coordinated polarization of cells in the tissue plane, known as planar cell polarity (PCP), is associated with a signaling pathway critical for the control of morphogenetic processes. Although the segregation of PCP components to opposite cell borders is believed to play a critical role in this pathway, whether PCP derives from egg polarity or preexistent long-range gradient, or forms in response to a localized cue remains a challenging question. Here we investigate the Xenopus neural plate, a tissue that has been previously shown to exhibit PCP. By imaging Vangl2 and Prickle3, we show that PCP is progressively acquired in the neural plate and requires a signal from the posterior region of the embryo. Tissue transplantations indicated that PCP is triggered in the neural plate by a planar cue from the dorsal blastopore lip. The PCP cue did not depend on the orientation of the graft and was distinct from neural inducers. These observations suggest that neuroectodermal PCP is not instructed by a preexisting molecular gradient, but induced by a signal from the dorsal blastopore lip. HighlightsO_LIThe Xenopus neural plate progressively acquires PCP in a posterior-to-anterior direction. C_LIO_LIThe dorsal blastopore lip is likely the source of the PCP-instructing signal for the Xenopus neural plate. C_LIO_LIThe PCP cue is distinct from neural inducers and has a planar mode of transmission. C_LI

developmental biology↗

bioRxiv2019

Endosome-Mediated Epithelial Remodeling Downstream of Hedgehog/Gli Is Required for Tracheoesophageal Separation

The trachea and esophagus arise from the separation of a common foregut tube during early fetal development. Mutations in key signaling pathways such as Hedgehog (HH)/Gli can disrupt tracheoesophageal (TE) morphogenesis and cause life-threatening birth defects (TEDs), however the underlying cellular mechanisms are unknown. Here we use mouse and Xenopus to define the HH/Gli-dependent processes orchestrating TE morphogenesis. We show that downstream of Gli the Foxf1+ splanchnic mesenchyme promotes medial constriction of the foregut at the boundary between the presumptive Sox2+ esophageal and Nkx2-1+ tracheal epithelium. We identify a unique boundary epithelium co-expressing Sox2 and Nkx2-1 that fuses to form a transient septum. Septum formation and resolution into distinct trachea and esophagus requires endosome-mediated epithelial remodeling involving the small GTPase Rab11, and localized extracellular matrix degradation. These are disrupted in Gli-deficient embryos. This work provides a new mechanistic framework for TE morphogenesis and informs the cellular basis of human TEDs.\n\nHighlight bullet pointsO_LIThe Sox2+ esophagus and Nkx2-1+ trachea arise from the separation of a single foregut tube through a series of cellular events conserved in mouse and Xenopus\nC_LIO_LITracheoesophageal morphogenesis initiates with HH/Gli-dependent medial constriction of the gut tube mesenchyme at the Sox2-Nkx2-1 border\nC_LIO_LIThe foregut epithelial walls fuse forming a transient septum co-expressing Sox2 and Nkx2-1\nC_LIO_LIDownstream of HH/Gli Rab11-dependent endosome-mediated epithelial remodeling and localized extracellular matrix degradation separate the esophagus and trachea\nC_LIO_LIHH/Gli mutations reveal the cellular basis of tracheoesophageal birth defects\nC_LI

developmental biology↗