Biology subjects

Joyal, J.-S.

Publications and source records attributed to Joyal, J.-S..

8 recordsLinked to original sources

bioRxiv2026

Developmental senescence orchestrates hyaloid vessel regression in the postnatal eye

The mammalian eye develops in concert with coordinated growth and remodeling of three vascular networks: the hyaloid vasculature, the choroid and retinal plexus. While retinal and choroidal systems support visual function in the mature eye, the hyaloid network plays a vital yet temporary role supporting the developing lens and inner retina. Regression of the hyaloid network is essential for optical clarity, yet the mechanisms guiding the process remain incompletely understood. Using single-cell RNA sequencing, we show that postnatal mouse hyaloid cells are broadly senescent. Hyaloid vascular smooth muscle, endothelial and immune cells display cell-cycle arrest marked by Cdkn1a with the expression of SASP factors. Genetic ablation of Cdkn1a impedes normal hyaloid regression, demonstrating that developmental senescence is essential for vascular remodeling and functions alongside apoptosis and macrophage-mediated clearance. These findings identify an unrecognized senescence-driven mechanism orchestrating hyaloid involution during ocular development, broadening the understanding of vascular remodeling in the eye.

cell biology↗

bioRxiv2024

Corticosteroids prevent pathological angiogenesis yet compromise reparative vascular remodeling in the retina

Tissue inflammation is often broadly associated with cellular damage, yet sterile inflammation also plays critical roles in beneficial tissue remodeling. In the central nervous system (CNS), this is observed through a predominantly innate immune response in retinal vascular diseases such as age-related macular degeneration, diabetic retinopathy and retinopathy of prematurity. Here we set out to elucidate the dynamics of the immune response during progression and regression of pathological neovascularization in retinopathy. In a mouse model of oxygen-induced retinopathy, we report that broad spectrum corticosteroid drugs such as dexamethasone suppress initial formation of pathological pre-retinal neovascularization in early stages of disease, yet blunt successive waves of reparative inflammation and hence prevent beneficial vascular remodeling. Using genetic depletion of distinct components of the innate immune response, we demonstrate that CX3C chemokine receptor 1 (CX3CR1)-expressing microglia contribute to angiogenesis. Conversely, myeloid cells expressing Lyz-M (lysozyme 2) are recruited to sites of damaged blood vessels and pathological neovascularization where they partake in a reparative process that ultimately restores circulatory homeostasis to the retina. Hence, the Janus-faced properties of anti-inflammatory drugs should be considered when treating retinal vascular disease and particularly in stages associated with persistent neovascularization.

immunology↗

bioRxiv2023

Metabolic Reprogramming of the Neovascular Niche Promotes Regenerative Angiogenesis in Proliferative Retinopathy

Healthy blood vessels supply neurons to preserve metabolic function. In blinding ischemic proliferative retinopathies (PRs), pathological neovascular tufts often emerge in lieu of needed physiological neuroretina revascularization. We show that metabolic shifts in the neurovascular niche define this angiogenic dichotomy between healthy and diseased blood vessel growth. Fatty acid oxidation (FAO) metabolites accumulated in human and murine retinopathy samples. Neovascular tufts with a distinct single-cell transcriptional signature highly expressed FAO enzymes. The deletion of Sirt3, an FAO regulator, shifted the neurovascular niche metabolism from FAO to glycolysis and suppressed tuft formation. This metabolic transition increased Vegf expression in astrocytes and reprogrammed pathological EC to a physiological phenotype, hastening vascular regeneration of the ischemic retina. Our findings identify SIRT3 as a metabolic switch in the neurovascular niche, offering a new therapeutic target for optimizing ischemic tissue revascularization. HighlightsO_LIPathological EC favor FAO over glycolysis. C_LIO_LIUnique signature for pathological EC found in proliferative retinopathy model. C_LIO_LISirt3 deletion shifts astrocytes and EC metabolism from FAO to glycolysis. C_LIO_LIMetabolic reprogramming of the vascular niche enhances physiological revascularization. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/566898v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@70020eorg.highwire.dtl.DTLVardef@19719acorg.highwire.dtl.DTLVardef@1168ddeorg.highwire.dtl.DTLVardef@1bc25e0_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

Inhibition of Type I PRMTs Reforms Muscle Stem Cell Identity Enhancing their Therapeutic Capacity

In skeletal muscle, muscle stem cells (MuSC) are the main cells responsible for regeneration upon injury. In diseased skeletal muscle, it would be therapeutically advantageous to replace defective MuSCs, or rejuvenate them with drugs to enhance their self-renewal and ensure long-term regenerative potential. One limitation of the replacement approach has been the inability to efficiently expand MuSCs ex vivo, while maintaining their stemness and engraftment abilities. Herein, we show that inhibition of type I protein arginine methyltransferases (PRMTs) with MS023 increases the proliferative capacity of ex vivo cultured MuSCs. Single cell RNA sequencing (scRNAseq) of ex vivo cultured MuSCs revealed the emergence of subpopulations in MS023-treated cells which are defined by elevated Pax7 expression and markers of MuSC quiescence, both features of enhanced self-renewal. Furthermore, the scRNAseq identified MS023-specific subpopulations to be metabolically altered with upregulated glycolysis and oxidative phosphorylation (OxPhos). Transplantation of MuSCs treated with MS023 had a better ability to repopulate the MuSC niche and contributed efficiently to muscle regeneration following injury. Interestingly, the preclinical mouse model of Duchenne muscular dystrophy had increased grip strength with MS023 treatment. Our findings show that inhibition of type I PRMTs increased the proliferation capabilities of MuSCs with altered cellular metabolism, while maintaining their stem-like properties such as self-renewal and engraftment potential.

molecular biology↗

bioRxiv2022

Disrupting peroxisomes alters lipid metabolism in melanoma and uncovers a novel therapeutic vulnerability in combination with MAPK-targeted therapies

Melanomas reprogram their metabolism to rapidly adapt to therapy-induced stress conditions, allowing them to persist and ultimately develop resistance. We report that a subpopulation of melanoma cells tolerate MAPK pathway inhibitors (MAPKi) through a concerted metabolic reprogramming mediated by peroxisomes and UDP-glucose ceramide glycosyltransferase (UGCG). Compromising peroxisome biogenesis, by repressing PEX3 expression, potentiates the pro-apoptotic effects of MAPKi via an induction of ceramides, an effect limited by UGCG-mediated ceramide metabolism. Co-targeting PEX3 and UGCG selectively eliminates a subset of metabolically active, drug-tolerant CD36+ melanoma persister cells, thereby sensitizing melanoma to MAPKi and delaying resistance. Increased levels of peroxisomal genes and UGCG are found in patient-derived MAPKi-relapsed melanomas, and simultaneously inhibiting PEX3 and UGCG restores MAPKi sensitivity in multiple models of therapy resistance. Finally, triple therapy comprised of a newly identified inhibitor of the PEX3-PEX19 interaction, a UGCG inhibitor and a MAPKi demonstrates potent anti-tumor activity in pre-clinical melanoma models, thus representing a promising approach for melanoma treatment. HighlightsO_LIInhibiting peroxisome biogenesis uncovers a metabolic vulnerability in melanoma C_LIO_LICD36+ persister melanoma cells tolerate MAPK-targeted therapy through peroxisome/UGCG mediated metabolic rewiring C_LIO_LIDual blockade of PEX3 and UGCG potentiates melanoma response to MAPK-targeted therapies and restores therapeutic sensitivity in MAPKi-resistant tumors C_LIO_LINNC 55-0396 is a PEX3-PEX19 binding inhibitor with potent anti-tumor activity in melanoma C_LI

cancer biology↗

bioRxiv2022

Developmental role of macrophages modelled in human pluripotent stem cell derived intestinal tissue

Macrophages populate the embryo early in gestation but their role in the developmental process remains largely unknown. In particular, specification and function of macrophages in intestinal development remain unexplored. To study this event in human developmental context, we derived and combined human intestinal organoid and macrophages from pluripotent stem cells. Macrophages migrated into the organoid, proliferated, and occupied the emerging micro-anatomical niches of epithelial crypts and ganglia. They also acquired a similar transcriptomic profile to fetal intestinal macrophages and displayed tissue macrophage behaviors, such as recruitment to tissue injury. Using this model, we show that macrophages reduce glycolysis in mesenchymal cells and limit tissue growth without affecting tissue architecture, in contrast to the pro-growth effect of enteric neurons. In short, we engineered an intestinal tissue model populated with macrophages, and we suggest that resident macrophages contribute to regulation of metabolism and growth of the developing intestine.

developmental biology↗

bioRxiv2022

Nuclear Location Bias of HCAR1 Drives Cancer Malignancy through Numerous Routes

The involvement of G-Protein-Coupled Receptors (GPCR) location bias in diverse cellular functions and their misregulation in pathology is an underexplored territory. HCAR1, a GPCR for lactate is linked to cancer progression, mainly due to Warburg effect, but its mechanism of action remains elusive. Here, we show HCAR1 has a nuclear localization, capable of signaling intranuclearly to induce nuclear-ERK and AKT phosphorylation concomitant with higher cancer cell proliferation and survival. We determine its nuclear interactome, proving its involvement in protein-translation and DNA-damage repair. Nuclear HCAR1 (N-HCAR1) directly interacts with chromatin/DNA promoting expression of genes involved in cellular migration. Notably, we show N-HCAR1 particularly regulates a broader transcriptomic signature than its PM counterpart, emphasizing on the facts that functional output of N-HCAR1 is larger than PM localized HCAR1. Our study presents several unprecedented processes by which a GPCR through location-biased activity regulate various cellular functions and how cancer cells exploit these.

cell biology↗

bioRxiv2020

Leveraging complex interactions between signaling pathways involved in liver development to robustly improve the maturity and yield of pluripotent stem cell-derived hepatocytes

Pluripotent stem cell (PSC)-derived hepatocyte-like cells (HLC) have shown great potential as an alternative to primary human hepatocytes (PHH) for in vitro modeling. Several differentiation protocols have been described to direct PSC towards the hepatic fate, although the resulting HLC have shown more a fetal than adult phenotype. Here, by leveraging recent knowledge of the signaling pathways involved in liver development, we describe a robust, scalable protocol that allows to consistently generate high-quality HLC from both ESC and iPSC. Such HLC are comparable to adult PHH in terms of key mature liver functions and proved suitable to assess drug hepatotoxicity, as a proof of concept of their potential as a physiologically representative alternative for in vitro modeling.

developmental biology↗