Biology subjects

Deprest, J.

Publications and source records attributed to Deprest, J..

5 recordsLinked to original sources

bioRxiv2026

Intra-Abdominal Bowel Dilation in Experimental Gastroschisis is Associated with a Modifiable Transcriptomic Program of Intestinal Dysfunction

STRUCTURED ABSTRACTO_ST_ABSObjectiveC_ST_ABSTo characterize intestinal transcriptional profiles in gastroschisis, their temporal evolution, and response to fetal intervention. Summary Background DataGastroschisis causes significant intestinal dysfunction, with intra-abdominal bowel dilation clinically shown to correlate with worse outcomes. While inflammation and neurovascular impairment have been implicated, genome-wide transcriptional characterization of disease severity remains lacking. MethodsUsing a fetal ovine model of complex gastroschisis, in which all gastroschisis animals demonstrated significant intra-abdominal bowel dilation at term, bulk RNA sequencing was performed on proximal small intestinal tissue from mid-gestation and term fetuses across three groups: normal, gastroschisis, and prenatally repaired gastroschisis. Differential gene expression (FDR [≤] .05, |log2 fold change| [≥] 1.5) and pathway enrichment analyses were performed, with targeted interrogation of extracellular matrix (ECM), enteric nervous system (ENS), angiogenic, and inflammatory pathways. ResultsAt mid-gestation, gastroschisis intestine showed minimal transcriptional differences (150 differentially expressed genes [DEGs]) and some bowel dilation. By term, dysregulation was substantial (2,423 DEGs) alongside significant dilation. Normal ontogenetic intestinal maturation patterns were altered, with fewer expected developmental gene changes and discordant pathway regulation. ECM pathway aberrations emerged early and persisted, while ENS, angiogenic, and inflammatory pathways were only dysregulated at term. Fetal repair was associated with normalization of gene expression at term (29 DEGs vs controls). ConclusionIntestinal transcriptional changes in experimental gastroschisis parallel progressive bowel dilation, consistent with a mechanical stress contribution to intestinal injury. Prenatal repair normalizes both dilation and gene expression, indicating a dynamic and potentially modifiable transcriptional program that supports the rationale for early fetal intervention. Mini AbstractIn a fetal ovine model, progressive bowel dilation in gastroschisis parallels transcriptomic dysregulation of ECM remodeling, neurovascular impairment, and inflammation which is normalized by prenatal repair.

developmental biology↗

bioRxiv2026

A Reproducible Fetal Lamb Model of Complex Gastroschisis with Temporal Characterization of Bowel Changes

ObjectiveTo establish a fetal lamb model of complex gastroschisis and characterize the impact on the intestines over time. Summary Background DataGastroschisis is a congenital abdominal wall defect and in its complex form is associated with serious morbidity. Robust large-animal models may help understanding are lacking. MethodsAt gestational day 75, gastroschisis was induced by creating a 1-cm abdominal wall defect reinforced by a silicone ring. Fetuses were assessed either at term or at mid-gestation (13-21 days post-induction). The primary outcome was complex gastroschisis occurrence, defined by bowel stenosis, atresia, volvulus, perforation or necrosis; otherwise classified as simple. At mid-gestation, occurrence was compared between early (13-16 days) and late (17-21 days) intervals. Secondary outcomes included prenatal ultrasound findings, in vivo bowel motility and morphology, ex-vivo bowel contractility, amniotic fluid composition, and histology across complex, simple, and normal groups. ResultsGastroschisis was induced in 32 fetuses. At term (n=14), all survivors (7/14; 50%) had complex gastroschisis, with impaired bowel motility, altered enteric neural contractile responses and smooth muscle remodeling. At mid-gestation (n=18), complex gastroschisis occurred more frequently in the late than in the early group (71% vs. 11%; p=0.035). Mid-gestation gastroschisis fetuses showed greater intra-abdominal bowel dilatation on ultrasound and higher amniotic fluid digestive enzyme levels compared with non-operated littermates, with the greatest dilation observed in complex gastroschisis. ConclusionsThis model consistently reproduces complex gastroschisis in term survivors. After induction, complex gastroschisis occurrence increases with disease duration and is accompanied by structural and functional bowel changes.

developmental biology↗

bioRxiv2025

The craniofacial shape of modern humans embodies genomic signatures of evolution, diversity, and clinical conditions

Human craniofacial morphology is a hallmark of our species diversity and evolutionary history, shaped by adaptation, introgression, and global dispersal. Cranial globularization and chin emergence are well-documented morphological transformations whose genetic basis remains poorly understood, whereas Neandertal introgression is primarily documented through genomic evidence. How these evolutionary phenomena relate to craniofacial variation in present-day humans remains largely unresolved. Here, we leverage 3D craniofacial data from over 50,000 UK Biobank participants and employ a multivariate, multiscale genome-wide association approach to define axes of variation aligned with inter-population allele frequency shifts, evolutionary processes, and clinical conditions. We identify continuous craniofacial trends within our cohort that mirror global patterns of genetic diversity, indicating that facial differences between human populations arise at the phenotypic axes already present within a single population. We further demonstrate that modern human-derived alleles underlie the origins of the human chin by reducing midfacial projection relative to other hominins and reveal the persistent effects of Neandertal introgression on craniofacial diversity today. We also model genetically informed endophenotypes for orofacial clefts, obstructive sleep apnoea, and myopia. These findings provide insights into our species evolutionary history and endophenotypes of clinical conditions and establish a framework for contextualizing craniofacial diversity into biologically meaningful axes of variation relevant to diverse scientific disciplines.

genetics↗

bioRxiv2024

Prenatal VEGF Nano-Delivery Reverses Congenital Diaphragmatic Hernia-Associated Pulmonary Abnormalities

RationaleCongenital diaphragmatic hernia (CDH) results in lung hypoplasia. In severe cases, tracheal occlusion (TO) can be offered to promote lung growth. However the benefit is limited, and novel treatments are required to supplement TO. Vascular endothelial growth factor (VEGF) is downregulated in animal models of CDH and could be a therapeutic target, but its role in human CDH is not known. ObjectivesTo investigate whether VEGF supplementation could be a suitable treatment for CDH-associated lung pathology. MethodsFetal lungs from CDH patients were used to determine pulmonary morphology and VEGF expression. A novel human ex vivo model of fetal lung compression recapitulating CDH features was developed and used to determine the effect of exogenous VEGF supplementation (Figure 1A). A nanoparticle-based approach for intra-pulmonary delivery of VEGF was developed by conjugating it on functionalized nanodiamonds (ND-VEGF) and was tested in experimental CDH in vivo. O_FIG O_LINKSMALLFIG WIDTH=138 HEIGHT=200 SRC="FIGDIR/small/581170v1_fig1.gif" ALT="Figure 1"> View larger version (77K): org.highwire.dtl.DTLVardef@2ba882org.highwire.dtl.DTLVardef@4413d2org.highwire.dtl.DTLVardef@17155aborg.highwire.dtl.DTLVardef@1af7c73_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1C_FLOATNO (A) Schematic of the study design based on the analysis of the early-stage CDH fetal lung sections to assess early hypoplasia and VEGF impairment. In parallel, a human compression-based CDH model will be developed to validate the CDH phenotype and test a therapeutical approach to rescue lung hypoplasia. (B) H&E analysis of 18 and 22 pcw post-mortem CDH human lung tissue reveals impaired epithelial development compared to control healthy tissue at matching developmental stages. Scale bar 100m. (C) Morphometric analysis of CDH and healthy lung tissue at 18-22 pcw reveals decreased values of volume densities of air space (Vair%) and corresponding higher values of volume densities of alveolar septa (Vsep%) in CDH tissues compared to healthy tissue at the same developmental stages. A similar trend can be observed for the mean linear intercept of air space (Lma%) and its corresponding mean linear intercept of septal thickness (Lmw%). (D) Histologic analysis of VEGFA, KDR, Ki67 and NKX2-1 markers in normal and CDH fetal lung tissue at 18 and 22 pcw. Scale bar 100m. (E) Quantification of epithelial VEGFA and KDR expression reported in D shows a significant decrease for both markers in CDH compared to healthy samples. Correspondingly, the percentage of Ki67-positive epithelial cells is significantly lower in CDH compared to healthy samples, with no significant differences in the number of NKX2-1-positive cells. ***<p=0.001. (F) Immunofluorescence analysis of ECAD in normal and CDH fetal lung tissue at 18 and 22 pcw. Scale bar 100m. (G) Quantification of epithelial nuclear density based on results in Figure F shows no significant differences between CDH and healthy tissue. C_FIG Measurements and Main ResultsVEGF expression was downregulated in distal pulmonary epithelium of human CDH fetuses in conjunction with attenuated cell proliferation. The compression model resulted in impaired branching morphogenesis similar to CDH and downregulation of VEGF expression in conjunction with reduced proliferation of terminal bud epithelial progenitors; these could be reversed by exogenous supplementation of VEGF. Prenatal delivery of VEGF with the ND-VEGF platform in CDH fetal rats resulted in lung growth and pulmonary arterial remodelling that was complementary to that achieved by TO alone with appearances comparable to healthy controls. ConclusionsThis innovative approach could have a significant impact on the treatment of CDH.

bioengineering↗

bioRxiv2023

Single cell-guided prenatal derivation of primary epithelial organoids from the human amniotic and tracheal fluids.

Despite advances in prenatal diagnosis, it is still difficult to predict severity and outcomes of many congenital malformations. New patient-specific prenatal disease modelling may optimise personalised prediction. We and others have described the presence of mesenchymal stem cells in amniotic fluid (AFSC) that can generate induced pluripotent stem cells (iPSCs). The lengthy reprogramming processes, however, limits the ability to define individual phenotypes or plan prenatal treatment. Therefore, it would be advantageous if fetal stem cells could be obtained during pregnancy and expanded without reprogramming. Using single cell analysis, we characterised the cellular identities in amniotic fluid (AF) and identified viable epithelial stem/progenitor cells of fetal intestinal, renal and pulmonary origin. With relevance for prenatal disease modelling, these cells could be cultured to form clonal epithelial organoids manifesting small intestine, kidney and lung identity. To confirm this, we derived lung organoids from AF and tracheal fluid (TF) cells of Congenital Diaphragmatic Hernia (CDH) fetuses and found that they show differences to non-CDH controls and can recapitulate some pathological features of the disease. Amniotic Fluid Organoids (AFO) allow investigation of fetal epithelial tissues at clinically relevant developmental stages and may enable the development of therapeutic tools tailored to the fetus, as well as to predicting the effects of such therapies.

cell biology↗