Biology subjects

Beck, H. C.

Publications and source records attributed to Beck, H. C..

5 recordsLinked to original sources

bioRxiv2026

A Meta-Analysis of 515 Human Proteomes Defines the Core Composition and Contaminants of Plasma Extracellular Vesicles isolates

Plasma extracellular vesicles (EVs) are promising liquid biopsy biomarkers, yet their proteomic profiling remains confounded by co-isolated lipoproteins and soluble complexes. Here, we resolve this heterogeneity through a meta-analysis of 515 human plasma EV proteomes. We demonstrate that the reproducible core proteome is dominated by soluble host-response modules rather than unique vesicular markers. Deconvolution analysis resolved the isolate into distinct biological sources, distinguishing the hepatic secretome and immune complexes from vesicular signals. Crucially, canonical tetraspanins (CD9, ADAM10) clustered with platelet and erythrocyte proteins, indicating that the bulk tetraspanin signal derives from hematopoietic ectosome shedding. In contrast, ESCRT machinery (TSG101, ALIX) formed a distinct, lower-abundance cluster, physically separating endosomal biogenesis from membrane shedding. We provide a modular atlas that mathematically distinguishes the functional matrix of coisolates from vesicular cargo, establishing a new framework for interpreting biological origin in plasma EV proteomics.

systems biology↗

bioRxiv2023

SorCS2 modulates neurovascular coupling via glutamatergic and calcium signaling in astrocytes

AO_SCPLOWBSTRACTC_SCPLOWSorCS2 is involved in trafficking of membrane receptors and transporters. SorCS2 is implicated in brain disorders, but the mechanism remains uncertain. We hypothesized that SorCS2 expression is important for neurovascular coupling. Brains from P8 and 2-month-old wild type mice were stained for SorCS2 and compared to SorCS2 knockouts (Sorcs2-/-). Changes in cerebral perfusion in response to sensory stimulation, i.e., neurovascular coupling, were compared in vivo. Neurovascular coupling was also assessed ex vivo in brain slices loaded with calcium-sensitive dye. Proteomics of astrocytes was analyzed for ingenuity pathways. SorCS2 was strongly expressed in astrocytic endfeet of P8 mice but only in few astrocytes from 2-month-old brains. Sorcs2-/- mice demonstrated reduced neurovascular coupling. This was associated with reduced astrocytic calcium response to neuronal excitation in Sorcs2-/- mice. No difference in cerebral artery caliber nor in endothelial function was seen between wild type and Sorcs2-/- mice. Proteomics indicated reduced glutamatergic signaling and suppressed calcium signaling in Sorcs2-/- astrocytes. We suggest that SorCS2 expression is important for neurovascular coupling due to modulation of glutamatergic and calcium signaling in astrocytes.

neuroscience↗

bioRxiv2023

Ccn2 deficiency causes smooth muscle cell de-differentiation and severe atherosclerosis in hyperlipidemic mice

Cellular communication network factor 2 (CCN2/CTGF) is a matricellular protein with an established role in fibrotic diseases and cancers, and therapies targeting CCN2 is currently in Phase II and III clinical trials for idiopathic pulmonary fibrosis, pancreatic cancer and Duchenne Muscular Dystrophy. Recent studies have highlighed a protective role of CCN2 in aortic aneurysm disease, but its role in atherosclerosis remains to be investigated. We identified arteries as having the highest relative expression of CCN2 across 54 human tissues. In aortas, CCN2 was among the highest expressed genes, and in situ hybridization of human internal thoracic arteries revealed vascular smooth muscle cells (SMCs) as its principal source. Hypothesizing a role for CCN2 in SMC phenotype maintenance and athero-protection, we investigated inducible Ccn2 knockout (Ccn2{Delta}/{Delta}) mice in normo- and hyper-lipidemic settings. Induction of hyperlipidemia by single intravenous injection of 1{middle dot}1011 viral genomes of rAAV8-D377Y-mPcsk9 combined with 24 weeks of western type diet resulted in severe enlargement (3-5-fold increase of relative aorta mass compared to wildtype littermates, p < 0.0001) and whitening of Ccn2{Delta}/{Delta} aortas. Oil Red O-staining of en face prepared thoracic aortas showed a marked increase in atherosclerosis in Ccn2{Delta}/{Delta} mice as compared to wildtype littermates (75% vs. 10% Oil Red O-positive aortic area, p < 0.0001). Transcriptomic profiling of cultivated SMCs derived from aortas of normolipidemic mice showed signatures of dedifferentiation (reduced expression of e.g. Myocd, Acta2 and Myh11) and modulation toward a synthetic, pro-inflammatory phenotype of Ccn2{Delta}/{Delta} SMCs. These effects were verified in vivo and in CCN2-silenced human aortic SMCs. Taken together, we find that CCN2 plays a critical athero-protective role in artery tissues, likely through maintaining SMCs in a differentiated, contractile phenotype.

pathology↗

bioRxiv2021

LAMP2A regulates the loading of proteins into exosomes.

Exosomes are extracellular vesicles of endosomal origin released by virtually all cell types across metazoans. Exosomes are active vehicles of intercellular communication and can transfer lipids, RNAs and proteins between different cells, tissues or organs. However, the mechanisms that regulate the selective loading of cytosolic proteins into these vesicles are still largely unknow. Here we describe a mechanism whereby proteins containing a pentapeptide sequence, biochemically related to the KFERQ-motif, are loaded into a subpopulation of exosomes in a process that is dependent on the membrane protein LAMP2A. Moreover, this mechanism is independent of the ESCRT machinery components TSG101 and VPS4b and dependent on HSC70, CD63, Alix, Syntenin-1, Rab31 and ceramides. The transcription factor and master regulator of hypoxia HIF1A is loaded into exosomes by this mechanism to transport hypoxia signaling to normoxic cells. Additionally, by tagging fluorescent proteins with KFERQ-like sequences we were able to follow inter-organ transfer of exosomes in zebrafish larvae. Our findings identify LAMP2A as a key component in exosome biogenesis while opening new avenues for exosome engineering by allowing the loading of bioactive proteins by tagging them with KFERQ-like motifs.

cell biology↗

bioRxiv2021

Messages From the Small Intestine Carried by Extracellular Vesicles in Prediabetes: a Proteomic Portrait

Extracellular vesicles (EVs) mediate communication in physiological and pathological conditions. In the pathogenesis of type 2 diabetes, inter-organ communication plays an important role in its progress and metabolic surgery leads to its remission. Moreover, gut dysbiosis is emerging as a diabetogenic factor. However, it remains unclear how gut senses metabolic alterations and whether this is transmitted to other tissues via EVs. Using a diet induced-prediabetic mouse model, we observed that protein packaging in gut derived EVs (GDE), specifically small intestine, is increased in prediabetes. Proteins related to lipid metabolism and to oxidative stress management were more abundant in prediabetic GDE compared to healthy controls. On the other hand, proteins related to glycolytic activity, as well as those responsible for the degradation of polyubiquitinated composites, were depleted in prediabetic GDE. Together, our findings show that protein packaging in GDE is markedly modified during prediabetes pathogenesis. Thus, suggesting that prediabetic alterations in small intestine are translated into modified GDE proteome, which are dispersed into the circulation where they can interact with and influence the metabolic status of other tissues. This study highlights the importance of the small intestine as a tissue that propagates prediabetic metabolic dysfunction throughout the body and the importance of GDE as the messenger.

pathology↗