Biology subjects

Cordero, J. B.

Publications and source records attributed to Cordero, J. B..

5 recordsLinked to original sources

bioRxiv2025

Intestinal Tissue Mechanics Regulate Angiogenesis and Stem Cell Proliferation via Vascular Piezo

The vasculature is a prominent component of developmental and adult tissue microenvironments. How tissue specific characteristics and environmental states influence vascular biology and function, remains largely understudied. Using the fruit fly Drosophila melanogaster midgut and its associated vascular-like tracheal system, we discover reciprocal, mechanochemical interorgan communication between the adult intestine and its vascular microenvironment, which influences vascular and stem cell adaptations during intestinal regeneration. Mechanistically, apoptotic epithelial cells contribute to biomechanical remodelling of the regenerating midgut, which is associated with activation of Piezo in a subset of gut tracheal cells. Piezo drives activation of the mechanosensitive transcription factor Yorkie/YAP, leading to tracheal remodelling and intestinal stem cell proliferation. Furthermore, we identify a conserved role of mammalian vascular Piezo1 influencing remodelling of the intestinal crypt vasculature, and intestinal regeneration upon DNA damage and inflammation in mice. Our cross-species in vivo study reveals the presence of biomechanically distinct compartments in the regenerative intestine and identifies mechanosensory interorgan signalling, which contributes to intestinal regeneration through the vascular-stem cell niche. Furthermore, our work highlights the importance of studying tissue- and context-specific vascular biology to better understand intestinal compartmentalization, plasticity, and the complexity of tissue/vasculature interactions within a living organ.

developmental biology↗

bioRxiv2024

Non-gonadal PIWI protein, Aubergine, regulates regenerative stem cell proliferation and tumourigenesis in the Drosophila adult intestine.

The PIWI-interacting RNA (piRNA) biosynthesis pathway is best studied for its role suppressing Drosophila germline transposable elements. Piwi, the founding member of the pathway, is involved in adult intestinal stem cell (ISC) homeostasis. Whether a broader role of the PIWI pathway exists in the intestine, remains unknown. Here, we characterise a role of the PIWI family protein Aubergine (Aub) in ISCs. While dispensable for basal ISC self-renewal, upregulation of Aub by damage-induced reactive oxygen species drives regenerative ISC proliferation through increased protein synthesis, including translation of ISC factors Myc and Sox21a. Unexpectedly, such roles of Aub in ISCs appear uncoupled from its piRNA regulatory function. Additionally, Aub and mammalian PIWIL1, mediate tumorigenic intestinal growth in Drosophila and human organoids, respectively. Our results reveal regulated protein translation as a fundamental aspect of regenerative ISC function and discover a central role of Aub in such process.

developmental biology↗

bioRxiv2024

Neuroendocrine Control of Intestinal Regeneration Through the Vascular Niche in Drosophila.

Robust and controlled intestinal regeneration is essential for the preservation of organismal health and wellbeing and involves reciprocal interactions between the intestinal epithelium and its microenvironment. While knowledge of regulatory roles of the microenvironment on the intestine is vast, how distinct perturbations within the intestinal epithelium may influence tailored responses from the microenvironment, remains understudied. Here, we present previously unknown signaling between enteroendocrine cells (EE), vasculature-like trachea (TTCs), and neurons, which drives regional and global stem cell proliferation during adult intestinal regeneration in Drosophila. Injury-induced ROS from midgut epithelial cells promotes the production and secretion of Dh31, the homolog of mammalian Calcitonin Gene-Related Peptide (CGRP), from anterior midgut EE cells. Dh31 from EE cells and neurons signal to Dh31 receptor within TTCs leading to cell autonomous production of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF)-like Pvf1. Tracheal derived Pvf1 induces remodeling of the tracheal stem cell niche and regenerative ISC proliferation through autocrine and paracrine Pvr/MAPK signalling, respectively. Interestingly, while EE Dh31 exerts broad control of ISC proliferation throughout the midgut, functions of the neuronal source of the ligand appear restricted to the posterior midgut. Altogether, our work has led to the discovery of a novel enteroendocrine/neuronal/vascular signaling network controlling global and domain specific ISC proliferation during adult intestinal regeneration.

developmental biology↗

bioRxiv2021

Dynamic adult tracheal plasticity drives stem cell adaptation to changes in intestinal homeostasis.

Coordination of stem cell function by local and niche-derived signals is essential to preserve adult tissue homeostasis and organismal health. The vasculature is a prominent component of multiple stem cell niches. However, its role in adult intestinal homeostasis remains largely understudied. Here, we uncover a previously unrecognised crosstalk between adult intestinal stem cells (ISCs) in Drosophila and the vasculature-like tracheal system, which is essential for intestinal regeneration. Following damage to the intestinal epithelium, gut-derived reactive oxygen species (ROS) activate tracheal HIF-1 and bidirectional FGF/FGFR signaling, leading to reversible remodelling of gut-associated terminal tracheal cells and ISC proliferation following damage. Unexpectedly, ROS-induced adult tracheal plasticity involves downregulation of the tracheal specification factor trachealess (trh) and upregulation of IGF2 mRNA-binding protein (IGF2BP2/Imp). Our results reveal a novel intestine/vasculature interorgan communication program, which is essential to adapt stem cells response to the proliferative demands of the intestinal epithelium.

developmental biology↗

bioRxiv2020

RAL GTPases mediate EGFR/MAPK signalling-driven intestinal stem cell proliferation and tumourigenesis upstream of RAS activation.

RAS-like (RAL) GTPases function in Wnt signalling-dependent intestinal stem cell proliferation and regeneration. Whether RAL proteins work as canonical RAS effectors in the intestine, and the mechanisms of how they contribute to tumourigenesis remain unclear. Here, we show that RAL GTPases are necessary and sufficient to activate EGFR/MAPK signalling in the intestine, via induction of EGFR internalisation. Knocking down Drosophila RalA from intestinal stem and progenitor cells leads to increased levels of plasma membrane-associated EGFR and decreased MAPK pathway activation. Importantly, in addition to impacting stem cell proliferation during damage-induced intestinal regeneration, this role of RAL GTPases impacts on EGFR-dependent tumorigenic growth in the intestine and in human mammary epithelium. However, the effect of oncogenic RAS in the intestine is independent from RAL function. Altogether, our results reveal previously unrecognised cellular and molecular contexts where RAL GTPases become essential mediators of adult tissue homeostasis and malignant transformation.

cancer biology↗