Biology subjects

Heymans, A.

Publications and source records attributed to Heymans, A..

11 recordsLinked to original sources

bioRxiv2026

Unraveling the metabolic landscape of alkaptonuria through a human-relevant in vitro liver disease model

Alkaptonuria (AKU) is a rare inherited metabolic disorder of tyrosine catabolism caused by a deficient homogentisate 1,2-dioxygenase (HGD) enzyme. This results in the accumulation of homogentisic acid (HGA), driving a progressive multisystem pathology characterized by debilitating early-onset osteoarthritis due to connective tissue degeneration. While previous in vitro studies have primarily relied on exogenous HGA exposure in osteoarticular cell models, the direct metabolic consequences of endogenous HGD deficiency within its native hepatic context remain poorly understood. Here, we established the first human-relevant HGD knockout hepatic in vitro model using a universal in-house-developed homology-directed repair approach. Integrative multi-omic analysis revealed that HGD deficiency induces widespread metabolic rewiring extending beyond disrupted tyrosine catabolism. HGD-deficient hepatocytes exhibited elevated oxidative stress accompanied by impaired mitochondrial respiration and a pseudohypoxic metabolic adaptation toward increased glycolytic dependency. Despite this glycolytic shift, the cells displayed reduced anabolic and translational activity alongside attenuated proliferation, consistent with a chronic stress-adaptive survival state rather than a proliferative metabolic phenotype. This study provides systems-level insights into the pathophysiology of AKU and establishes a versatile platform for mechanistic and therapeutic investigation.

cell biology↗

bioRxiv2026

Liver-directed AAV gene therapy metabolically corrects AKU in Hgd deficient mice

BackgroundAlkaptonuria (AKU) is a rare autosomal recessive metabolic disorder caused by deficiency of homogentisate 1,2-dioxygenase (HGD), resulting in systemic accumulation of homogentisic acid (HGA), ochronosis, and progressive multisystem disease. Although nitisinone (NTBC) lowers HGA levels, it does not correct the underlying genetic defect and induces hypertyrosinemia, highlighting the need for curative treatment approaches. We evaluated liver-directed adeno-associated virus (AAV)-mediated HGD gene therapy as a potential treatment for AKU. MethodsHgd-deficient (Hgd-/-) mice received liver-directed AAV2/8 vectors expressing codon-optimized human HGD under a liver-specific promoter. Reporter vectors were first used to assess hepatic biodistribution and transduction efficiency. Therapeutic efficacy was subsequently evaluated following AAV2/8-HGD administration (1 x 1012 vg/mouse). HGD expression was assessed by DNAscope, Western blotting, and RT-qPCR. Metabolic correction was determined using targeted LC-MS/MS and untargeted LC-HRMS metabolomics and compared with NTBC-treated Hgd-/- mice. ResultsReporter studies demonstrated liver-predominant transduction, with dose-dependent hepatocyte transduction reaching 89-93% at the highest dose. AAV2/8-HGD treatment produced robust hepatic HGD expression, with codon-optimized human HGD transcript levels approximately 33-fold higher than endogenous murine Hgd expression. Twelve weeks after treatment, plasma and urinary HGA levels were significantly reduced, with plasma HGA restored to near wild-type concentrations. Untargeted metabolomics further demonstrated marked reductions in HGA-derived phase I and II metabolites and revealed significant modulation of tricarboxylic acid cycle metabolism, consistent with partial restoration of metabolic homeostasis. Compared with NTBC-treated mice, AAV2/8-HGD achieved comparable plasma HGA reduction without elevation of upstream tyrosine pathway metabolites. ConclusionsLiver-directed AAV2/8-HGD gene therapy achieved substantial biochemical correction in Hgd-/- mice and restored metabolic flux without inducing hypertyrosinemia. These findings provide proof-of-concept supporting AAV-mediated HGD replacement as a promising long-term therapeutic strategy for AKU.

genetics↗

bioRxiv2026

Mechanical coordination of counter-gradient growth maintains organ curvature in apical hooks

How growing tissues convert mechanical tension into signals that stabilize form remains a central question in morphogenesis. Curved organ shapes in plants arise from differential growth, yet how such curvature is actively maintained while organs continuously grow remains poorly understood. In etiolated seedlings, the apical hook provides a tractable model to dissect this process, as its curvature is stably maintained over extended periods despite ongoing cell expansion. Using quantitative imaging and computational modeling, we show that antagonistic growth gradients at apical and basal regions are both necessary and sufficient to maintain hook curvature, with cuticle integrity being critical for establishing these counter-gradients. Mechanical cues linked to cuticle structure, coupled with apoplastic reactive oxygen species (ROS), coordinate cellular growth anisotropy, and disruptions in cuticle biosynthesis trigger defective hook development. These findings reveal that the apical hook curve maintenance is not a simple switch between growth promotion and repression, but a highly dynamic, tightly regulated process where mechanical and biochemical signals coordinate organ-scale morphogenesis, fundamentally reshaping how we understand developmental growth.

plant biology↗

bioRxiv2026

Secondary Growth and Exodermal Barriers Shape Local Root Hydraulics: Modeling Insights in Tomato

Root water uptake efficiency depends on root system architecture and anatomical features of individual root segments. Beyond cell wall, membrane, and plasmodesmata hydraulic properties, root anatomy critically influences profiles of radial conductivity and axial conductance. While these structural factors have been well-characterized in monocotyledons, their role in dicotyledons--where developmental anatomy, secondary growth, and hydrophobic barrier dynamics differ--remains poorly understood. Here, we integrate structural and functional models to assess how dicotyledon-specific anatomy, hydrophobic depositions (suberin/lignin in exo-/endodermis), and aquaporin contribution influence root hydraulics. Using tomato (Solanum lycopersicum L., cv. Moneymaker) as a dicotyledon model, our simulations show that: - Exodermal suberin has negligible effects on radial conductivity when a lignin cap is present, and exodermal barriers are less effective than endodermal ones. - Secondary growth and dicotyledon-specific anatomy are essential for sustaining high axial conductance, ensuring efficient water uptake across soil profiles and maintaining root system hydraulic conductance.

plant biology↗

bioRxiv2025

Outer epidermal edges mediate cell-cell adhesion for tissue integrity in plants

Cell-cell adhesion in plants is generally thought to be primarily mediated by the middle lamella, a supposedly thin adhesive layer of the cell wall. Here, we challenge this view. Through computational simulation we found that outer edges of cellular interfaces of the epidermis are hotspot for cell separating tensile stress. Characterization of the ultrastructure of those edges in planta revealed that they are locally thickened regions that harbor cellulose lamellae and pectin-based structural continuity across adjacent cells. We confirmed their dominant role for adhesion by studying mutants where those edges are defective and through direct mechanical testing. This reveals the key role of outer epidermal cell edges, rather than the middle lamella, in mediating cell-cell adhesion for tissue integrity in plants.

plant biology↗

bioRxiv2024

Rhamnogalacturonan-II dimerization deficiency impairs the coordination between growth and adhesion maintenance in plants

Cell adhesion is a fundamental feature of multicellular organisms. In plants, cell adhesion is mediated by the cell wall, but the control and maintenance of cell adhesion during growth and development remains poorly understood1. Here we uncover the role of a component of the cell wall, rhamnogalacturonan-II (RG-II) and its capacity to crosslink in the presence of Boron2, as a key regulator of plant cell adhesion maintenance. We show that RG-II dimerization deficiency leads to cell adhesion defects. Importantly, the analysis of mur1 mutants with RG-II dimerization defects uncovers a cell adhesion pathway that is distinct from that identified by the analysis of pectin deficient mutants3. We found that mutations in two cell wall integrity sensors, RESISTANCE TO FUSARIUM OXYSPORUM 1 and RECEPTOR-LIKE PROTEIN 44, as well as supplementation with the hormone brassinosteroid can partially rescue the adhesion defects associated with RG-II dimerization deficiency. We also show that adhesion defects associated with RG-II dimerization deficiency are related to increased epidermal tension as well as decreased homogalacturonan levels in the cell wall, which can also be rescued by supplementation with brassinosteroid. Overall, we propose that RG-II dimerization defects alter cell adhesion directly (reduced crosslinks) but also indirectly through cell wall integrity sensing, brassinosteroid signalling, cell wall remodelling and cell layer growth coordination. Thus, our results uncover the involvement of cell wall integrity sensors and hormonal signalling in the coordination between growth and adhesion maintenance in plants, which is a key feature for complex multicellularity. Highlights- RG-II dimerization is required for cell-cell adhesion in plants. - Cell wall integrity sensors and brassinosteroid signalling mediate cell adhesion downstream of RG-II dimerization. - Cell detachments due to defective RG-II dimerization are caused by weakened middle lamella and higher tissue tension.

plant biology↗

bioRxiv2023

Evidence that variation in root anatomy contributes to local adaptation in Mexican native maize

Mexican native maize (Zea mays ssp. mays) is adapted to a wide range of climatic and edaphic conditions. Here, we focus specifically on the potential role of root anatomical variation in this adaptation. In light of the investment required to characterize root anatomy, we present a machine learning approach using environmental descriptors to project trait variation from a relatively small training panel onto a larger panel of genotyped and georeferenced Mexican maize accessions. The resulting models defined potential biologically relevant clines across a complex environment and were used subsequently in genotype-environment association. We found evidence of systematic variation in maize root anatomy across Mexico, notably a prevalence of trait combinations favoring a reduction in axial conductance in cooler, drier highland areas. We discuss our results in the context of previously described water-banking strategies and present candidate genes that are associated with both root anatomical and environmental variation. Our strategy is a refinement of standard environmental genome wide association analysis that is applicable whenever a training set of georeferenced phenotypic data is available.

plant biology↗

bioRxiv2021

Evidence for a multicellular symplasmic water pumping mechanism across vascular plant roots

With global warming, climate zones are projected to shift poleward, and the frequency and intensity of droughts to increase, driving threats to crop production and ecosystems. Plant hydraulic traits play major roles in coping with such droughts, and process-based plant hydraulics (water flowing along decreasing pressure {Psi}p or total water potential {Psi}tot gradients) has newly been implemented in land surface models. An enigma reported for the past 35 years is the observation of water flowing along increasing water potential gradients across roots. By combining the most advanced modelling tool from the emerging field of plant micro-hydrology with pioneering cell solute mapping data, we found that the current paradigm of water flow across roots of all vascular plants is incomplete: it lacks the impact of solute concentration (and thus negative osmotic potential {Psi}o) gradients across living cells. This gradient acts as a water pump as it reduces water tension without loading solutes in plant vasculature (xylem). Importantly, water tension adjustments in roots may have large impacts in leaves due to the tension-cavitation feedback along stems. Here, we mathematically demonstrate the water pumping mechanism by solving water flow equations analytically on a triple-cell system. Then we show that the simplistic upscaled equations hold in 2- and 3-D maize, grapevine and Arabidopsis complex hydraulic anatomies, and that water may flow "uphill" of water potential gradients toward xylem as observed experimentally. Besides its contribution to the fundamental understanding of plant water relations, this study lays new foundations for future multidisciplinary research encompassing plant physiology and ecohydrology, and has the ambition to mathematically capture a keystone process for the accurate forecasting of plant water status in crop models and LSMs. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/439789v1_ufig1.gif" ALT="Figure 1"> View larger version (85K): org.highwire.dtl.DTLVardef@a7db9borg.highwire.dtl.DTLVardef@42bb32org.highwire.dtl.DTLVardef@1100204org.highwire.dtl.DTLVardef@1f45a48_HPS_FORMAT_FIGEXP M_FIG C_FIG Highlights- We provide a scale-consistent solution of water flow equations across root tissues - Symplasmic osmotic potential gradients are missing in the current theory of root water uptake - The model solves the empirical enigma of root water uptake uphill of water potential gradients

physiology↗

bioRxiv2020

Connecting the dots between root cross-section images and modelling tools to create a high resolution root system hydraulic maps in Zea mays.

Root hydraulic properties play a central role in the global water cycle, agricultural systems productivity, and ecosystem survival as they impact the global canopy water supply. However, the available experimental methods to quantify root hydraulic conductivities, such as the root pressure probing, are particularly challenging and their applicability on thin roots and small root segments is limited. There is a gap in methods enabling easy estimations of root hydraulic conductivities across a diversity of root types and at high resolution along root axes. In this case study, we analysed Zea mays (maize) plants of the var. B73 that were grown in pots for 14 days. Root cross-section data were used to extract anatomical measurements. We used the Generator of Root Anatomy in R (GRANAR) model to generate root anatomical networks from anatomical features. Then we used the Model of Explicit Cross-section Hydraulic Anatomy (MECHA) to compute an estimation of the root axial and radial hydraulic conductivities (kx and kr, respectively), based on the generated anatomical networks and cell hydraulic properties from the literature. The root hydraulic conductivity maps obtained from the root cross-sections suggest significant functional variations along and between different root types. Predicted variations of kr along the root axis were strongly dependent on the maturation stage of hydrophobic barriers. The same was also true for the maturation rates of the metaxylem. The different anatomical features, as well as their evolution along the root type add significant variation to the kr estimation in between root type and along the root axe. Under the prism of root types, anatomy, and hydrophobic barriers, our results highlight the diversity of root radial and axial hydraulic conductivities, which may be veiled under low-resolution measurements of the root system hydraulic conductivity. While predictions of our root hydraulic maps match the range and trend of measurements reported in the literature, future studies could focus on the quantitative validation of hydraulic maps. From now on, a novel method, which turns root cross-section images into hydraulic maps will offer an inexpensive and easily applicable investigation tool for root hydraulics, in parallel to root pressure probing experiments. One-Sentence summaryThe use of cross-section images and modelling tools to generate a map the axial and radial hydraulic conductivity along different root types for the maize cultivar B73.

plant biology↗

bioRxiv2019

MARSHAL, a novel tool for virtual phenotyping of maize root system hydraulic architectures

Functional-structural root system models combine functional and structural root traits to represent the growth and development of root systems. In general, they are characterized by a large number of growth, architectural and functional root parameters, generating contrasted root systems evolving in a highly nonlinear environment (soil, atmosphere), which makes unclear what impact of each single root system on root system functioning actually is. On the other end of the root system modelling continuum, macroscopic root system models associate to each root system instance a set of plant-scale, easily interpretable parameters. However, as of today, it is unclear how these macroscopic parameters relate to root-scale traits and whether the upscaling of local root traits are compatible with macroscopic parameter measurements. The aim of this study was to bridge the gap between these two modelling approaches by providing a fast and reliable tool, which eventually can help performing plant virtual breeding.\n\nWe describe here the MAize Root System Hydraulic Architecture soLver (MARSHAL), a new efficient and user-friendly computational tool that couples a root architecture model (CRootBox) with fast and accurate algorithms of water flow through hydraulic architectures and plant-scale parameter calculations, and a review of architectural and hydraulic parameters of maize.\n\nTo illustrate the tools potential, we generated contrasted maize hydraulic architectures that we compared with architectural (root length density) and hydraulic (root system conductance) observations. Observed variability of these traits was well captured by model ensemble runs We also analyzed the multivariate sensitivity of mature root system conductance, mean depth of uptake, root system volume and convex hull to the input parameters to highlight the key parameters to vary for efficient virtual root system breeding. MARSHAL enables inverse optimisations, sensitivity analyses and virtual breeding of maize hydraulic root architecture. It is available as an R package, an RMarkdown pipeline, and a web application.\n\nOne-sentence summaryWe developed a dynamic hydraulic-architectural model of the root system, parameterized for maize, to generate contrasted hydraulic architectures, compatible with field and lab observations and that can be further analyzed in soil-root system models for virtual breeding.\n\nAuthors contributionsF.M., X.D., M.J. and G.L. designed the study and defined its scope; F.M. and G.L. developed the model while associated tools were created by A.H. and G.L.; F.M. ran the model simulations and analyzed the results together with M.J and G.L.; F.M. and M.J. wrote the first version of this manuscript; all co-authors critically revised it.

plant biology↗

bioRxiv2019

GRANAR, a new computational tool to better understand the functional importance of root anatomy

Root hydraulic conductivity is an important determinant of plant water uptake capacity. In particular, the root radial conductivity is often thought to be a limiting factor along the water pathways between the soil and the leaf. The root radial conductivity is itself defined by cell scale hydraulic properties and anatomical features. However, quantifying the influence of anatomical features on the radial conductivity remains challenging due to complex, and time-consuming, experimental procedures.\n\nWe present a new computation tool, the Generator of Root ANAtomy in R (GRANAR) that can be used to rapidly generate digital versions of root anatomical networks. GRANAR uses a limited set of root anatomical parameters, easily acquired with existing image analysis tools. The generated anatomical network can then be used in combination with hydraulic models to estimate the corresponding hydraulic properties.\n\nWe used GRANAR to re-analyse large maize (Zea mays) anatomical datasets from the literature. Our model was successful at creating virtual anatomies for each experimental observation. We also used GRANAR to generate anatomies not observed experimentally, over wider ranges of anatomical parameters. The generated anatomies were then used to estimate the corresponding radial conductivities with the hydraulic model MECHA. This enabled us to quantify the effect of individual anatomical features on the root radial conductivity. In particular, our simulations highlight the large importance of the width of the stele and the cortex.\n\nGRANAR is an open-source project available here: http://granar.github.io\n\nOne-Sentence summaryGenerator of Root ANAtomy in R (GRANAR) is a new open-source computational tool that can be used to rapidly generate digital versions of root anatomical networks.

plant biology↗