Biology subjects

Sparrow, D. B.

Publications and source records attributed to Sparrow, D. B..

6 recordsLinked to original sources

bioRxiv2026

Single-Cell Multimodal Profiling Reveals Maternal Diabetes-Nkx2-5 Interaction in Congenital Heart Disease in a Genetic Model Recapitulating Human Embryopathies

The etiological complexity of congenital heart disease (CHD) arises from the interaction between genetic and environmental factors. We hypothesized that environmental exposure could potentiate a genetic susceptibility, leading to an increased incidence of specific cardiac defects. To test this hypothesis, we used betaV59M+ female mice exhibiting severe hyperglycemia (>28 mmol/L) without dyslipidemia, a model we characterized that faithfully recapitulates human diabetic embryopathy. These females were crossed with males haploinsufficient for Nkx2-5, a transcription factor essential for cardiac development and implicated in human CHD. Our results show that the combination of genetic susceptibility and a hyperglycemic maternal environment (GxE) leads to a higher frequency and severity of cardiac malformations, including ventricular septal defects specifically involving the muscular septum, univentricular morphologies, and dilation with thinning of the myocardium. These structural abnormalities were associated with transcriptional changes affecting the contractile identity of the chamber myocardium. Single-nucleus multiomic profiling (snRNA-seq and snATAC-seq) of the E9.5 cardiac region revealed that the interaction between maternal diabetes and Nkx2-5 haploinsufficiency profoundly reshapes transcriptional and chromatin accessibility landscapes. These changes affect not only metabolic pathways, but also cell cycle progression in second heart field (SHF) progenitors, likely contributing to the observed structural cardiac defects. Multiomic integration further identifies a disrupted indirect Nkx2-5-Aldh1a2 regulatory axis in posterior SHF progenitors, while demonstrating that maternal diabetes selectively affects a restricted subset of Nkx2-5-dependent regulatory elements associated with cardiomyocyte maturation. Our findings establish a comprehensive single-cell multiomic resource that will facilitate the integration of human GWAS and other genomic datasets, enabling the identification and functional interpretation of disease-associated loci.

developmental biology↗

bioRxiv2026

Molecular and Structural Basis of Cardiac Remodelling in Niemann-Pick Type C

Key Point SummaryNiemann-Pick disease type C (NPC) patients showed a high prevalence of ECG abnormalities, with additional echocardiographic evidence of altered left-ventricular structure and function. Npc1-/- mouse hearts exhibited age-associated glycosphingolipid accumulation accompanied by marked myocardial fibrosis and increased collagen deposition. Ex vivo electrophysiology revealed QT prolongation and atrioventricular conduction defects in Npc1-/- hearts, particularly under {beta}-adrenergic stress. Transcriptomic profiling identified inflammatory and fibrotic pathway activation consistent with the structural and electrophysiological abnormalities observed. Together, these findings demonstrate previously unrecognised cardiac involvement in NPC and support routine cardiac screening to improve clinical management. Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal storage disease caused by pathogenic variants in NPC1 or NPC2. Sudden death can occur due to seizures, but cardiac involvement has not been well defined. We performed 12-lead electrocardiograms (ECG) in 14 adult NPC patients (8 male, 6 female). Cardiac structure and function were examined in Npc1-/- adult mouse hearts, alongside wild-type controls. Glycosphingolipid accumulation was quantified by high-performance liquid chromatography, fibrosis and collagen deposition were quantified using Massons Trichrome (M&T) and Picrosirius Red (PR) staining. Whole-heart morphology, including chamber size and wall thickness, was assessed. Ex vivo ECG recordings assessed conduction abnormalities and arrhythmias. RNA-seq transcriptomics characterised molecular pathways altered in Npc1-/- hearts. 8/14 patients showed ECG abnormalities including abnormal QRS transitions (N=8), increased QRS amplitude (N=4), fascicular block (N=2), and abnormal T wave inversion (N=1). 13 patients also had transthoracic echocardiograms identifying mildly impaired LV systolic function (N=2) and increased wall thickness/LV mass (N=4). In Npc1-/- mice, age-related glycosphingolipid accumulation was associated with pronounced ventricular fibrotic remodelling. There was a significant increase in stained connective tissue area and connective tissue to cardiac tissue ratio in both M&T and PR staining. ECG from Langendorff-perfused Npc1-/- hearts showed QT prolongation and atrioventricular conduction abnormalities under isoprenaline stress. Transcriptomics revealed major changes in Npc1-/- hearts, consistent with histological fibrosis and linking NPC to inflammation-driven remodelling and arrhythmogenesis. These findings support routine cardiac screening in NPC patients and highlight the need for further studies to improve management and treatment.

physiology↗

bioRxiv2026

Distinct roles of the Lyve1 lineage in heart development

Lyve1Cre is widely used to study lymphatic endothelial cells, but its activity in the embryonic heart has not been comprehensively defined. Here we show that the Lyve1 lineage contributes to multiple cardiovascular cell types, including venous endothelium of the sinus venosus forming coronary vessels, endocardial cells generating complementary coronary territories and valve structures, lymphatic endothelial cells required for cardiac lymphatic development, and tissue-resident macrophages within the embryonic myocardium. Functional perturbations demonstrated that Notch1 gain-of-function in Lyve1+ lineages disrupted vascular development, while Prox1 deletion caused severe edema, blood-filled lymphatics, and perinatal lethality. Mid-gestation mutants exhibited underdeveloped, blood-filled lymphatics despite intact blood vasculature, and by late gestation cardiac lymphatics were depleted. These findings reveal distinct cardiovascular roles of the Lyve1 lineage and establish Lyve1Cre as a versatile but non-specific tool, underscoring the need for careful interpretation when investigating heart development and regenerative processes.

developmental biology↗

bioRxiv2024

Lysosomal calcium signalling contributes to the acute α-adrenergic response via calcium-stimulated adenylyl cyclase 1 and 8

Inositol trisphosphate (IP3), a calcium (Ca2+)-mobilizing second messenger, releases Ca2+ from the sarcoplasmic reticulum (SR) via IP3 receptors and modulates adenylyl cyclase (AC) activity in atrial myocytes. Lysosomes participate in Ca2+ homeostasis by mobilising Ca2+ in response to Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP). We postulate that both downstream activation of Ca2+ sensitive AC (AC1 and AC8) and lysosomal Ca2+ signalling in response to IP3R activation contribute to atrial myocyte function and pacemaking. Ectopic application of phenylephrine (PE) increased chronotropy and inotropy and this response was reduced in the presence of NAADP pathway inhibitors (BZ-194 and SAN4825) and Bafilomycin A1. PE increased cyclic adenosine 3-5 monophosphate (cAMP) activity in neonatal rat atrial myocytes (NRAMs) and this was inhibited by NAADP pathway inhibitors. This inhibition was not observed in neonatal rat ventricular myocytes (NRVMs), revealing specificity of this response to NRAMs. We investigated expression of AC1 and AC8 as a possible explanation to these observations. Genetic perturbation of AC1 and AC8 by double-knockout of Adcy1 and Adcy8 in a mouse model showed a decrease in positive chronotropic and inotropic response upon cumulative dose of PE in atrial tissue, reduced PE stimulated amplitude of Ca2+ transient in isolated atrial myocytes and presented decreased cytosolic cAMP levels in response to PE in neonatal atrial myocytes that was not inhibited by NAADP pathway inhibitors. Our data identifies a link between NAADP and -adrenergic signalling pathways in atrial myocytes, highlighting that lysosomal Ca2+ is an important component of -adrenergic stimulation in the cardiac atria and warrants further investigation.

physiology↗

bioRxiv2021

Maternal iron deficiency impacts the placental arterial network.

Placental vascular gene networks in mammals have been largely unexplored due to a lack of well validated molecular markers to identify them. This is required to study how they form in development, and how they are impacted by embryonic or maternal defects, which in-turn adversely affects the forming heart and vasculature. Such defects are known to be a consequence of maternal iron deficiency (ID), the most common nutrient deficiency world-wide. Here we employed marker analysis to characterise the arterial/arteriole and venous/venule endothelial cells (ECs) during normal placental development, and in the context of maternal ID. We reveal for the first time that placental ECs are unique compared with their embryonic counterparts. In the developing embryo, arterial ECs express Neuropilin1 (Nrp1), Delta-like ligand 4 (Dll4) and Notch1, while developing venous ECs express Neuropilin2 (Nrp2), Apj (Aplnr) and Ephrinb4 (Ephb4). However, in the E15.5 placenta, Nrp1 and Notch1 were restricted to arteries, but not continuing arteriole ECs. The arterial tree exclusively expressed Dll4. Nrp2 showed pan-EC expression at E15.5, while Ephb4 was not present at this stage. However, we found the placental venous vascular tree could be distinguished from the arterial tree by high versus low Endomucin (EMCN) and Apj (Aplnr) expression respectively. Using EMCN, we reveal that the placental arterial, but not venous, vascular tree is adversely impacted by maternal ID, with reduced area, total length and number of junctions of all vessels without affecting the EMCN high vessels. Defects to the embryonic cardiovascular system can therefore have a significant impact on blood flow delivery and expansion of the placental arterial tree.

developmental biology↗

bioRxiv2020

Maternal iron deficiency perturbs embryonic cardiovascular development

Congenital heart disease (CHD) is the most common type of birth defect, with a global prevalence of 0.9% of live births1. Most research in the last 30 years has focused on finding genetic causes of CHD. However, despite the association of over 100 genes with CHD, mutations in these genes only explain ~30% of cases2. Many of the remaining cases of CHD are caused by in utero exposure to environmental factors3. Here we have identified a completely new environmental teratogen causing CHD: maternal iron deficiency. In humans, iron deficiency anaemia is a major global health problem. 38% of pregnant women worldwide are anaemic4, and at least half of these are due to iron deficiency, the most prevalent micronutrient deficiency. We describe a mouse model of maternal iron deficiency anaemia that causes severe cardiovascular defects in her offspring. We show that these defects likely arise from increased retinoic acid signalling in iron deficient embryos, probably due to reduced activity of the iron-dependent retinoic acid catabolic CYP26 enzymes. The defects can be prevented by maternal iron administration early in pregnancy, and are also greatly reduced in offspring of mothers deficient in both iron and the retinoic acid precursor vitamin A. Finally, one puzzling feature of many genetic forms of CHD in humans is the considerable variation in penetrance and severity of defects. We show that maternal iron deficiency acts as a significant modifier of heart and craniofacial phenotype in a mouse model of Down syndrome. Given the high incidence of maternal iron deficiency, peri-conceptional iron monitoring and supplementation could be a viable strategy to reduce the prevalence and severity of CHD in human populations worldwide.

developmental biology↗