Biology subjects

Augustin, H.

Publications and source records attributed to Augustin, H..

6 recordsLinked to original sources

bioRxiv2026

Vascular specification from diversified mesoderm culminates in endothelial convergence

Vasculogenesis establishes the embryonic circulatory system, yet how a common vascular program emerges across multiple embryonic and extraembryonic developmental environments remains incompletely understood. Here, we reconstruct mouse vasculogenesis through integrated single-cell, spatial, lineage and perturbation analyses. We find that vascular specification emerges from distinct sources of pre-specified mesoderm through a transient Kdr+Etv2- vascular-primed state promoted by BMP signaling. Primed cells persist until E8.0- E8.5, after which they resolve into committed derivatives. Dual blood-endothelial potential is largely restricted to early vitelline progenitors, whereas embryonic and umbilical progenitors contribute predominantly to endothelial lineages. Temporal VEGF signaling perturbations validate the inferred specification sequence, placing VEGF downstream of vascular priming and demonstrating its indispensable role in vascular and primitive blood specification. Unlike most developmental lineages, endothelial derivatives converge toward a common transcriptional state while retaining transcriptional traces of their developmental origins. Together, these findings establish a mechanistically validated developmental sequence for mammalian vasculogenesis.

developmental biology↗

bioRxiv2026

Platelet C5aR1 mediates sex-specific ischemia-driven revascularization through estradiol-dependent CXCL4 release

BackgroundSex-specific differences in cardiovascular diseases remain incompletely understood at the molecular level. ObjectivesHere, we investigated the role of the platelet complement receptor C5aR1 as a sex-specific critical mediator of revascularization following hindlimb ischemia. MethodsIschemia-driven revascularization was analyzed in the hind limb ischemia (HLI) model using wild type (WT) and complement receptor-deficient male and female mice, and involved mechanisms were analyzed in platelets and megakaryocyte-shed platelets ex vivo. ResultsIn WT mice, ischemic tissue exhibited robust complement activation with C3b and C5a accumulation that correlated strongly with deposition of the anti-angiogenic factor CXCL4 (PF4). Mechanistically, C5a stimulation of platelets triggered CXCL4 secretion, and female animals with a platelet-specific deletion of C5aR1 (using PF4-Cre-C5aR1fl/fl mice) showed a significantly delayed revascularization. Female mice exhibited substantially lower platelet C5aR1 expression, and C5a-induced CXCL4 secretion was virtually abolished compared to male animals. The sex-specific difference in tissue CXCL4 deposition was not present any more in the absence of C5aR1 from platelets. We observed that megakaryocytes, which give rise to platelets, express estradiol receptors. Importantly, estradiol stimulation of megakaryocytes suppressed C5aR1 expression during pro-platelet formation, uncovering a hormone-dependent regulatory mechanism. ConclusionsThe here described estradiol-C5aR1-CXCL4 axis provides a molecular explanation for sex-specific differences in ischemic revascularization known from patient studies. Our findings establish a novel and unexpected mechanistic link between sex hormones, a complement-platelet crosstalk and the angiogenic response to ischemia with potential clinical implications for sex-specific personalized therapeutic strategies.

immunology↗

bioRxiv2022

Lung endothelium instructs dormancy of susceptible metastatic tumour cells

During metastasis, cancer cells hijack blood vessels and travel via the circulation to colonize distant sites1,2. Due to the rarity of these events, the immediate cell fate decisions of arrested circulating tumour cells (aCTC) are poorly understood and the role of the endothelium, as the interface of dissemination, remains elusive3,4. Here, we developed a novel strategy to specifically enrich for aCTC subpopulations capturing all cell states of the extravasation process and, in combination with single cell RNA-sequencing, provide a first blueprint of the transcriptional basis of early aCTC decisions. Upon their arrest at the metastatic site, tumour cells either started proliferating intravascularly or extravasated and preferably reached a state of quiescence. Endothelial-derived angiocrine Wnt factors were found to drive this bifurcation by inducing a mesenchymal-like phenotype in aCTCs instructing them to follow the extravasation-dormancy branch. Surprisingly, homogenous tumour cell pools showed an unexpected baseline heterogeneity in Wnt signalling activity and epithelial-to-mesenchyme-transition (EMT) states. This heterogeneity was established at the epigenetic level and served as the driving force of aCTC behaviour. Hypomethylation enabled high baseline Wnt and EMT activity in tumour cells leading them to preferably follow the extravasation-dormancy route, whereas methylated tumour cells had low activity and proliferated intravascularly. The data identify the pre-determined methylation status of disseminated tumour cells as a key regulator of aCTC behaviour in the metastatic niche. While metastatic niche-derived factors per default instruct the acquisition of quiescence, aCTCs unwind a default proliferation program and only deviate from it if hypomethylation in key gene families renders them responsive towards the microenvironment.

cancer biology↗

bioRxiv2019

Caspase-8 Modulates Angiogenesis By Regulating A Cell Death Independent Pathway In Endothelial Cells

During developmental angiogenesis blood vessels grow and remodel to ultimately build a hierarchical vascular network. Whether and how cell death signaling molecules contribute to blood vessel formation is still not well understood. Caspase-8 (Casp-8), a key protease in the extrinsic cell death-signaling pathway, regulates both cell death via apoptosis and necroptosis. Here we show that expression of Casp-8 in endothelial cells (ECs) is required for proper postnatal angiogenesis. EC specific Casp-8 knockout pups (Casp-8ECko) have reduced retinal angiogenesis, as the loss of Casp-8 reduced EC proliferation, sprouting and migration independent of its cell death function. Instead, the loss of Casp-8 caused hyperactivation of p38 mitogen-activated protein kinase (MAPK) downstream of receptorinteracting serine/threonine-protein kinase 3 (RIPK3) and destabilization of VE-cadherin at EC junctions. In a mouse model of oxygen-induced retinopathy (OIR), resembling retinopathy of prematurity (ROP), loss of Casp-8 in ECs is beneficial, as pathological neovascularization was reduced in Casp-8ECko pups. Taken together, we identify that Casp-8 signals in a cell-death independent manner in ECs during postnatal and pathological blood vessel formation.

developmental biology↗

bioRxiv2018

Plum is a novel regulator of synaptic function and muscle size in D. melanogaster

Alterations in the neuromuscular system underlie several neuromuscular diseases and play critical roles in the development of sarcopenia, the age-related loss of muscle mass and function. Mammalian Myostatin (MST) and GDF11, members of the TGF-{beta} superfamily of growth factors, are powerful regulators of muscle size in both model organisms and humans. Myoglianin (MYO), the Drosophila homolog of MST and GDF11, is a strong inhibitor of synaptic function and structure at the neuromuscular junction (NMJ), and a negative regulator of body weight and muscle size and function in flies. Here, we identified Plum, a cell surface immunoglobulin homologous to mammalian developmental regulators Protogenin and Nope, as a modulator of MYO function in the larval neuromuscular system. Reduction of Plum specifically in the larval body-wall muscles abolishes the previously demonstrated positive effect of attenuated MYO signalling on both muscle size and neuromuscular junction structure and function, likely by de-sequestrating the remaining MYO. In addition, downregulation of Plum on its own results in decreased synaptic strength and body weight, classifying Plum as a (novel) regulator of neuromuscular function and body (muscle) size. These findings offer new insights into possible regulatory mechanisms behind ageing- and disease-related neuromuscular dysfunctions in humans and identify potential targets for therapeutic interventions.

neuroscience↗

bioRxiv2018

A computational model of the escape response latency in the Giant Fiber System of Drosophila melanogaster

The Giant Fiber System (GFS) is a multi-component neuronal pathway mediating rapid escape response in the adult fruit-fly Drosophila melanogaster, usually in the face of a threatening visual stimulus. Two branches of the circuit promote the response by stimulating an escape jump followed by flight initiation. Our recent work demonstrated an age-associated decline in the speed of signal propagation through the circuit, measured as the stimulus-to-muscle depolarization response latency. The decline is likely due to the diminishing number of inter-neuronal gap junctions in the GFS of ageing flies. In this work, we presented a realistic conductance-based, computational model of the GFS that recapitulates our experimental results and identifies some of the critical anatomical and physiological components governing the circuit's response latency. According to our model, anatomical properties of the GFS neurons have a stronger impact on the transmission than neuronal membrane conductance densities. The model provides testable predictions for the effect of experimental interventions on the circuit's performance in young and ageing flies.

neuroscience↗