Biology subjects

Rust, R.

Publications and source records attributed to Rust, R..

At least 19 recordsLinked to original sources

bioRxiv2026

Focal neuronal loss and cell replacement in a connectome model of fly steering

Focal neuronal loss after stroke, traumatic brain injury or spinal cord injury can disrupt circuits and result in persistent motor deficits. Which cells and connections must be restored to recover a specific behavior is difficult to establish experimentally. Here we use a connectome-constrained spiking model of the fruit-fly nervous system and decode motor-neuron output to simulate visually guided steering. After loss of 4,000 neurons, path straightness ranged from 0.04 to 0.95 depending on lesion location. At a fixed sensorimotor site, a 2,000-neuron lesion reduced simulated displacement to 6.5% of intact. Across 100 stochastic simulation realizations of the connectome, replacing 100 cells with their original connections increased displacement to 62.5% of intact when motor-control pathways were prioritized, compared with 10.1% after random selection of 100 cells and 48.5% after random selection of 1,000 cells. When connections were instead inferred from cell type, the same 100 intended replacements reached 60.0% of intact with matched identities and 6.7% with non-target identities, indicating that cell identity and type-dependent integration are required for recovery. Our model generates testable predictions for genetic ablation experiments in fruit flies and identifies candidate cellular and circuit requirements for motor repair that can inform cell replacement therapies and future models of mammalian locomotion.

neuroscience↗

bioRxiv2026

Progranulin haploinsufficiency remodels the cerebral microvasculature and neurovascular unit

Progranulin (PGRN) deficiency is a major genetic cause of frontotemporal dementia (FTD), yet its impact on cerebrovascular function remains understudied. Here, we show that PGRN deficiency contributes to cerebral microvascular perfusion and induces alterations within the neurovascular unit. In vivo two-photon imaging revealed increased capillary stalling and in cerebral blood flow (CBF), driven in part by increased leucocyte-capillary interactions and elevated endothelial ICAM-1 expression. Transcriptomic profiling of isolated cerebral microvessels demonstrated coordinated upregulation of immune and extracellular matrix pathways alongside suppression of angiogenic and stress-response programs, indicative of endothelial activation. Cross-species analyses identified partial conservation of these vascular signatures in endothelial cells from human FTD-GRN patients, associated with dysregulated angiogenic and inflammatory signaling. Despite altered tight junction organization and reduced solute carrier transporter expression, blood-brain barrier (BBB) permeability remained largely intact, suggesting functional rather than structural BBB disruption, as well as. These vascular changes were accompanied by broad alterations in the morphology of astrocytes, pericytes, and microglial cells. Here we determined a novel role for progranulin in cerebrovascular homeostasis and established microvascular dysfunction as a key driver of FTD-GRN pathophysiology.

neuroscience↗

bioRxiv2026

Shared and disease-specific human brain vascular signatures in Alzheimer's disease, frontotemporal dementia, and Huntington's disease

The blood-brain barrier (BBB) plays a central role in brain function and is increasingly implicated in neurodegenerative disease. Major neurodegenerative disorders, including Alzheimers disease (AD), frontotemporal dementia (FTD), and Huntingtons disease (HD), share overlapping pathological features. Yet, the extent to which these diseases converge or diverge at the level of BBB-associated cell types remains poorly understood. Here, we performed a comparative analysis of vessel-enriched human brain transcriptomic datasets across AD, FTD, and HD to define shared and disease-specific neurovascular alterations. We identify a partially conserved transcriptional signature of vascular dysfunction across all three diseases, alongside disease-specific changes in endothelial, pericyte, and perivascular cell populations. Endothelial remodeling was most prominent in capillary and venous segments, highlighting segment-specific vulnerability along the arteriovenous axis. Notably, we identified two molecularly distinct human pericyte subtypes across all three datasets and found a consistent reduction in the matrix-type pericytes (M-peri) fraction, suggesting a selective decline. Cell-cell communication analysis further revealed reorganized endothelial-pericyte signaling networks, with prominent alterations in extracellular matrix-associated pathways, including LAMININ, COLLAGEN, FN1, and NCAM, together with changes in contact-dependent and vascular signaling pathways such as NOTCH and VEGF. Together, our findings define shared and disease-specific neurovascular mechanisms across major neurodegenerative disorders and highlight BBB-associated pathways as central features of neurodegeneration, providing a framework for future diagnostic and therapeutic strategies.

neuroscience↗

bioRxiv2026

Tracking claim changes from preprint to publication across 72,644 biomedical studies using large language models

Preprints now disseminate a large share of biomedical research before peer review. Because they have not yet passed peer review, some scientists regard preprint claims as unverified or potentially unreliable, yet how much those claims change before publication has so far been quantified only in smaller cohorts, with results that vary by field and topic. Here, we compiled every bioRxiv preprint posted between 2018 and 2025 that we could match by DOI to a peer-reviewed published version, yielding 72,644 preprint-publication pairs. Using a large language model (Claude Sonnet 4.6), we parsed every preprint-publication abstract pair into one primary and two secondary claims, and classified each pair for content change (unchanged, minor, major) and hedging shift (more cautious, more confident, unchanged). On a validation subsample, the model agreed with two independent domain experts about as well as the experts agreed with each other (Cohens kappa 0.63 to 0.66). The primary claim was unchanged in 39.9% of abstracts, minorly revised in 50.0%, and substantially revised in only 10.2%. Hedging shifts were uncommon and asymmetric, with twice as many claims becoming more cautious as more confident (8.4% vs 4.2%). Major revisions were more frequent after long peer review (14.1% in the slowest versus 7.0% in the fastest tertile of review time) and declined over the study period (17.0% in 2019 to 5.7% in 2024). Over the same period, biomedical papers that were never posted as preprints were retracted at roughly twice the rate of those that were. Together, these data show that the move from preprint to peer-reviewed publication leaves the central claims of most biomedical abstracts intact, indicating that preprints are a reliable source of biomedical research.

scientific communication and education↗

bioRxiv2026

Vascular and synaptic proteomes reveal blood-brain barrier disruption and postsynaptic remodeling in human temporal lobe epilepsy

Blood-brain barrier (BBB) dysfunction and mesial temporal lobe epilepsy (MTLE) are considered to be engaged in a pathological feedback loop, with the consequent worsening of both conditions. However, the molecular landscape of the disruptions at the synapse and the blood-brain barrier during MTLE remains poorly characterized. Here, we perform quantitative proteomics on paired brain microvessel and vessel-depleted postsynaptic density (PSD) enriched fractions isolated from the epileptic hippocampus and ipsilateral temporal pole of patients with drug-resistant MTLE. The microvessel fraction (1,541 proteins; 439 differentially expressed proteins (DEPs)) reveals loss of tight-junction and endothelial adhesion proteins together with pericyte markers, concurrent with a significant increase of fibrinogen, plasminogen, complement C3, GFAP, and enrichment for complement and coagulation cascades. The PSD enriched fraction (7,450 proteins; 1,881 DEPs) shows the consequences of BBB leakage with an increase of protein infiltration, alongside inflammatory and extracellular-matrix proteins, together with disruption of the pre- and postsynaptic signaling machinery and loss of GABAergic interneurons. Cross-referencing healthy-brain expression confirms that the dysregulation of the processes reflects disease-associated changes rather than regional differences. Immunohistochemistry confirms microvascular remodeling, pericyte loss, parenchymal fibrinogen extravasation, microglial activation and presynaptic marker depletion in the epileptic hippocampus. Ligand-receptor mapping reveals dysregulation of the neurovascular ECM-adhesion interface, with upregulated parenchymal ECM ligands and downregulated vascular integrin receptors. Network-proximity analyses nominate candidate disease-modifying compounds for reversing the combined vascular and synaptic MTLE signature. Together, these findings establish a molecular map of vascular and synaptic dysfunction in human MTLE.

neuroscience↗

bioRxiv2026

Neural graft elimination via dual safety switch compromises therapeutic recovery after stroke

Safety switch systems are increasingly incorporated into stem cell therapies to enable selective graft elimination in the event of adverse outcomes. Yet how removing transplanted cells affects the underlying pathology remains largely unexplored. Here, we show that iPSC-derived neural stem cells (NSCs) co-transduced with herpes simplex virus thymidine kinase (HSV-TK) and inducible caspase-9 (iC9) are more efficiently ablated by combined ganciclovir (GCV) and chemical inducer of dimerization (CID) treatment than either single switch alone, under both proliferating and differentiating conditions. Using bioluminescence imaging to track graft survival longitudinally, we demonstrate that dual safety switch NSC (DS-NSC) grafts are selectively eliminated by GCV and CID administration in immunodeficient mice following photothrombotic stroke. The combination treatment initiated on day 8 post-transplantation resulted in reduced graft volume, lower NSC proliferation, and persistently reduced bioluminescence signal compared to mice receiving only solvent. Histological analysis revealed that combination treatment was associated with larger stroke lesions, higher IBA1 fluorescence intensity, and reduced vascular density in the ischemic border zone. Mice receiving GCV and CID showed persistently elevated contralateral hindlimb error rates on a ladder walk task from day 28 post-stroke onward compared to solvent-treated mice. These findings demonstrate that while DS-NSC elimination is feasible, the pharmacological activation of the safety switch system is associated with impaired functional stroke recovery.

neuroscience↗

bioRxiv2026

Targeting integrin αvβ3 by chimeric antigen receptor neural stem cell (CAR-NSC) therapy for stroke

Stroke remains a leading cause of adult disability due to the brains limited regenerative capacity. Although stem cell therapies show favorable safety and feasibility profiles in early clinical trials, poor spatial retention and limited engagement with peri-infarct salvageable tissue constrain efficacy. Here, we engineered human induced pluripotent stem cell-derived neural stem cells (NSC) with a chimeric antigen receptor (CAR)-like architecture to enable targeted recognition of injury-associated cues. Specifically, cells were modified to express a membrane-anchored single chain variable fragment (scFv) targeting integrin v{beta}3, a receptor selectively upregulated in peri-infarct vasculature after stroke. Engineered CAR-NSC retained progenitor identity and selectively bound recombinant integrin v{beta}3 in vitro. Following focal transplantation into a photothrombotic stroke mouse model, CAR-NSC displayed broader dispersion within peri-infarct tissue and covered a greater proportion of the ischemic lesion compared to non-binding control-CAR-NSC. CAR-NSC grafts extended longer neurites that aligned more closely with the lesion border. In addition, CAR-NSC transplantation reduced microglial activation and was associated with increased vascular density and blood-brain barrier integrity in the peri-infarct zone. Together, these findings establish a CAR-like NSC strategy for stroke to direct the spatial distribution and tissue engagement of transplanted cells. Molecular targeting of injury-associated cues may improve the precision and regenerative efficacy of cell-based therapies for stroke and related neurological disorders.

neuroscience↗

bioRxiv2026

Disruption of the SYNGAP1 PDZ ligand motif accelerates differentiation of human iPSC-derived GABAergic neurons

SYNGAP1 haploinsufficiency is a leading genetic cause of neurodevelopmental disorders (NDD), including intellectual disability and epileptic encephalopathy. While most studies on SYNGAP1 function have focused on glutamatergic neurons, its role in GABAergic neurons and during early neuronal development is unclear. Using human iPSC-derived GABAergic neurons, we demonstrate that SYNGAP1 haploinsufficiency accelerates neuronal maturation, characterized by increased dendritic length, synaptic density, and maturation of synaptic structures. Disruption of the isoform-specific SYNGAP1 PDZ binding motif reproduces these phenotypes, highlighting the critical role of PDZ-mediated interactions in regulating GABAergic neuronal differentiation. Proteomic and phosphoproteomic analyses reveal significant dysregulation of synaptic proteins, RNA processing, and transcriptional control, with a significant increase in postsynaptic density proteins content. RNA-seq analysis suggest that the acceleration in neuronal differentiation starts few hours after neuronal induction setting a path to a faster neuronal and synapse maturation. These findings establish that SYNGAP1 acts as a key regulator of neuronal differentiation across both excitatory and inhibitory neurons. Our work underscores the importance of the SYNGAP1 PDZ ligand motif for normal neuronal development and suggests translational strategies targeting SYNGAP1 alpha1 isoform levels to mitigate SYNGAP1-related NDD.

neuroscience↗

bioRxiv2026

Temporal synchrony between human odor rhythms and mosquito olfactory preference shapes host attraction

For anthropophilic mosquitoes such as Aedes aegypti, aligning host-seeking with human availability enhances foraging efficiency and reproductive success. Although time of day modulates mosquito activity and olfactory sensitivity, it remains unknown whether human hosts display rhythmic changes in odor cues and whether mosquitoes adjust their sensory responses accordingly. Here, we combine chemical, behavioral, genetic, and transcriptomic approaches to reveal that both mosquitoes and their human hosts in this interaction are temporally synchronized. Gas chromatography-mass spectrometry showed systematic daily shifts in human body odor composition between morning and evening. Correspondingly, mosquitoes prefer host odors that match their own active phase--a time-specific preference abolished in timeless mutants and under constant darkness. Silencing the timeless gene further induced an aversion for the host scent under light-dark conditions. Transcriptomic analysis of mosquito heads and antennae uncovered rhythmic expression of sensory and neuromodulatory genes, driven by both circadian and light-dark cycles and which peaks during mosquitoes active periods, with rhythmic co-expression networks collapsing in timeless knockouts. Together, these results show that mosquito attraction to humans is temporally tuned by the interplay of host odor rhythms and mosquito sensory rhythms, revealing a previously unrecognized form of interspecific temporal synchronization in vector-host interactions.

animal behavior and cognition↗

bioRxiv2025

Hypoxia preconditioned neural xenografts promote repair of brain tissue after stroke

Stroke is a leading cause of long-term disability, yet no effective regenerative therapies exist. While cell-based therapies have shown promise in preclinical animal models, their clinical application remains limited due to poor survival of transplanted cells in the ischemic stroke environment. Hypoxic preconditioning has emerged as a strategy to potentially enhance graft survival, but the cellular mechanisms and translational relevance in human iPSC-derived neural progenitor cells (NPCs) are not fully understood. Here, we tested whether hypoxic preconditioning of NPCs affects their molecular and functional properties including proliferation and survival in vitro and after transplantation into a stroke mouse model. Hypoxic preconditioning enhanced proliferation and glial differentiation in vitro, improved cell survival post-transplantation, and enhanced regeneration-associated tissue responses such as vascular remodeling in the peri-infarct brain. These findings suggest that hypoxic preconditioning is a clinically translatable approach to increase the NPC graft survival in the post-stroke brain.

neuroscience↗

bioRxiv2025

Multiomic profiling reveals pericyte and smooth muscle cell contributions to CADASIL pathology in cell-specific Notch3 mutant mice

Cerebral ischemic small vessel disease (SVD) is the leading cause of vascular dementia and a major contributor to stroke. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of familial SVD. CADASIL is caused by dominant missense mutations in Notch3, a receptor expressed in mural cells, including smooth muscle cells (SMCs) and pericytes. However, the cell-type specific contributions driving the CADASIL pathology remain unknown due to lack of animal models. Here, we generated two conditional knock-in mouse models carrying the CADASIL-causing Notch3R170C mutation selectively in SMC and brain pericytes. Both Notch3R170Cmodels showed perivascular accumulation of the NOTCH3 extracellular domain, yet developed distinct neurovascular changes depending on the affected cell type. Pericyte-specific Notch3R170C mice displayed pronounced region-selective microglial activation and vascular changes, whereas SMC-specific Notch3R170C mice showed localized perivascular gliosis with minimal vascular remodeling. Proteomic profiling of isolated brain vessels revealed largely unique cell-specific responses. Pericytes Notch3R170C expression dysregulated metabolic pathways, whereas SMC Notch3R170C expression induced immune signaling related pathways. Integration with single-cell RNA-seq data revealed that many of the proteomic and phosphoproteomic shifts might also include brain endothelial cells, including metabolic changes in the presence of pericyte Notch3R170C and inflammatory signaling in the presence of SMC-Notch3R170C. Together, these findings define mural cell-specific mechanisms that contribute to the CADASIL-associated vascular pathology.

neuroscience↗

bioRxiv2025

Brain pericytes derived from human pluripotent stem cells retain vascular and phagocytic functions under hypoxia

The integrity and function of the blood-brain barrier (BBB) are largely regulated by pericytes. Pericyte deficiency leads to BBB breakdown and neurological dysfunction in major neurological disorders including stroke and Alzheimers disease (AD). Transplantation of pericytes derived from induced pluripotent stem cells (iPSC-PC) has been shown to restore the BBB and improve functional recovery in mouse models of stroke and pericyte deficiency. However, the molecular profile and functional properties of iPSC-PC under hypoxic conditions, similar to those found in ischemic and neurodegenerative diseases remain largely unexplored. Here, we demonstrate that iPSC-PC under severe hypoxia retain essential functional properties, including key molecular markers, proliferation rates, and the ability to migrate to host brain vessels via function-associated PDGFRB-PDGF-BB signaling. Additionally, we show that iPSC-PC exhibit similar clearance of amyloid beta (A{beta}) neurotoxins from AD mouse brain sections under both normoxic and hypoxic conditions. These findings suggest that iPSC-PC functions are largely resilient to hypoxia, highlighting their potential as a promising cell source for treating ischemic and neurodegenerative disorders.

neuroscience↗

bioRxiv2025

Delayed transplantation of neural stem cells improves initial graft survival following stroke

Neural stem cell therapies hold great promise for improving stroke recovery, but the hostile stroke microenvironment can hinder the initial graft survival. It has long been well documented that the microenvironment evolves over time, making it crucial to identify the optimal transplantation window to maximize therapeutic efficacy. However, it remains uncertain whether acute or delayed local cell transplantations better supports graft viability after stroke. Here, we show that delayed intracerebral transplantation of neural progenitor cells (NPCs) derived from human induced pluripotent cells (iPSCs) at 7 days post stroke significantly enhances graft proliferation and survival, compared to acute transplantation at 1 day post stroke, in a mouse model of large cortical stroke. Using in vivo bioluminescence imaging over a 6-week period post-transplantation, we observe a more than 5-fold increase in bioluminescence signal in mice that received delayed NPC therapy, compared to those that underwent acute NPC transplantation. The increased number of cell grafts in mice receiving delayed NPC transplantation was driven by increased proliferation rates early after transplantation, which subsequently declined to similarly low levels in both groups. Notably, we found that the majority of transplanted NPCs differentiated into neurons after 6 weeks, with no significant differences in the neuron-to-glia ratio between acute and delayed transplantation groups. These findings suggest that delayed NPC transplantation improves early graft survival and proliferation, which could help identify the optimal therapeutic window for maximizing the effectiveness of NPC-based therapies in stroke.

neuroscience↗

bioRxiv2024

Neuronally differentiated endothelial cell subtype regulates organ blood flow and immune balance

Vascular endothelial cells (ECs) perform key pleiotropic functions to maintain body homeostasis via the regulation of organ blood flow, vascular permeability, tissue growth and inflammation, and angiogenesis. Recent transcriptomic studies uncovered many EC subtypes across organs; however their specific functions are incompletely understood. Here we identified and characterized a novel, minority subtype of scattered ECs with a well-defined arteriovenous zonal localization exclusively in small resistance (strain) arterioles, and with the highest density in the brain>retina>kidney. Due to their expression of both endothelial and neuron-like functional and gene transcriptomic signatures, they were termed neuro-endothelial cells (NECs). High resolution single-cell transcriptome analysis of mouse brain and kidney ECs identified neuronal nitric oxide synthase (Nos1) and cytokine-like 1 (Cytl1) as top NEC biomarkers. Intravital multiphoton imaging of optogenetic mouse models with NEC gain/loss-of-function revealed NEC and Nos1-dependent vasodilation/vasoconstriction of intact brain and kidney arterioles and elevation/reduction in blood flow. Silencing NEC Nos1 and Cytl1 gene expression in vivo caused marked segmental arteriolar vasoconstrictions, reductions in vascular density and organ blood flow, increased vascular permeability and immune cell homing. Cytl1 administration triggered vasodilation and increased blood flow acutely, and increased capillary density and clonal EC remodeling chronically. NECs play major vasodilatory, angiogenic and anti-inflammatory functions that may be therapeutically targeted for vascular and inflammatory diseases.

physiology↗

bioRxiv2024

A molecular brain atlas reveals cellular shifts during the repair phase of stroke

Ischemic stroke triggers a cascade of pathological events that affect multiple cell types and often lead to incomplete functional recovery. Despite advances in single-cell technologies, the molecular and cellular responses that contribute to long-term post-stroke impairment remain poorly understood. To gain better insight into the underlying mechanisms, we generated a single-cell transcriptomic atlas from distinct brain regions using a mouse model of permanent focal ischemia at one month post-injury. Our findings reveal cell- and region-specific changes within the stroke-injured and peri-infarct brain tissue. For instance, GABAergic and glutamatergic neurons exhibited upregulated genes in signaling pathways involved in axon guidance and synaptic plasticity, and downregulated pathways associated with aerobic metabolism. Using cell-cell communication analysis, we identified increased strength in predicted interactions within stroke tissue among both neural and non-neural cells via signaling pathways such as those involving collagen, protein tyrosine phosphatase receptor, neuronal growth regulator, laminin, and several cell adhesion molecules. Furthermore, we found a strong correlation between mouse transcriptome responses after stroke and those observed in human nonfatal brain stroke lesions. Common molecular features were linked to inflammatory responses, extracellular matrix organization, and angiogenesis. Our findings provide a detailed resource for advancing our molecular understanding of stroke pathology and for discovering therapeutic targets in the repair phase of stroke recovery.

neuroscience↗

bioRxiv2024

Human iPSC-derived cell grafts promote functional recovery by molecular interaction with stroke-injured brain

Stroke is a leading cause of disability and death due to the brains limited ability to regenerate damaged neural circuits. To date, stroke patients have only few therapeutic options and are often left with considerable disabilities. Induced pluripotent stem cell (iPSC)-based therapies are emerging as a promising therapeutic approach for stroke recovery. In this study, we demonstrate that local transplantation of iPSC-derived neural progenitor cells (NPCs) improves long-term brain tissue repair responses and reduces neurological deficits after cerebral ischemia in mice. Using in vivo bioluminescence imaging and post-mortem histology, we show long-term graft survival over the course of five weeks and preferential graft differentiation into mature neurons without signs of pluripotent residuals. Transplantation of NPCs led to a set of brain tissue repair responses including increased vascular sprouting and repair, improved blood-brain barrier integrity, reduced microglial activation, and increased neurogenesis compared to littermate control animals receiving sham transplantation. Employing deep learning-assisted behavior analysis, we found that NPC-treated mice displayed improved gait performance and complete fine-motor recovery in the horizontal ladder rung walk, five weeks post-injury. To dissect the molecular graft composition and identify graft-host interactions, single nucleus profiling of the cell transplants and host stroke tissue was performed. We identified graft differentiation preferentially towards neurons with GABAergic and glutamatergic phenotypes in similar proportions, with the remaining cells acquiring astrocyte and NPC-like phenotypes. Interaction between graft and host transcriptome indicated that GABAergic cell grafts were primarily involved in graft-host communication through the regeneration-associated neurexin (NRXN), neuregulin (NRG), neural cell adhesion molecule (NCAM) and SLIT signalling pathways. In conclusion, our study reveals that transplanted iPSC-derived NPCs primarily differentiate into GABAergic neurons contributing to long-term recovery and further delineates the regenerative interactions between the graft and the stroke-injured host tissue.

neuroscience↗

bioRxiv2023

Visualization and estimation of stroke infarct volumes in rodents

Stroke volume is a key determinant of infarct severity and an important metric treatments evaluation. However, accurate estimation of stroke volume can be challenging, due to the often confined 2-dimensional nature of available data. Here, we introduce a comprehensive semi-automated toolkit to reliably estimate stroke volumes based on (1) whole brains ex-vivo magnetic resonance imaging (MRI) and (2) brain sections that underwent immunofluorescence staining. We located and quantified infarct areas from MRI three days (acute) and 28 days (chronic) after photothrombotic stroke induction in whole mouse brains. MRI Results were compared with measures obtained from immunofluorescent histologic sections of the same brains. Using our toolkit, we found that infarct volume determined by post-mortem MRI was highly correlated with a deviation of only 6.6% (acute) and 4.9% (chronic) to the measurements as determined in the histological brain sections indicating that both methods are capable of accurately assessing brain tissue damage.

neuroscience↗

bioRxiv2023

Molecular signature and functional properties of human pluripotent stem cell-derived brain pericytes

Brain pericytes maintain the blood-brain barrier (BBB), secrete neurotrophic factors and clear toxic proteins. Their loss in neurological disorders leads to BBB breakdown, neuronal dysfunction, and cognitive decline. Therefore, cell therapy to replace lost pericytes holds potential to restore impaired cerebrovascular and brain functions. However, the molecular composition and function of human iPSC-derived brain pericytes (iPSC-PC) remains poorly characterized. Here, we show by a quantitative analysis of 8,344 proteins and 20,572 phosphopeptides that iPSC-PC share 96% of total proteins and 98% of protein phosphorylation sites with primary human brain pericytes. This includes cell adhesion and tight junction proteins, transcription factors, and different protein kinase families of the human kinome. In pericyte-deficient mice, iPSC-PC home to host brain capillaries to form hybrid human-mouse microvessels with ligand-receptor associations. They repair BBB leaks and protect against neuron loss, which we show requires PDGRFB and pleiotrophin. They also clear Alzheimers amyloid-{beta} and tau neurotoxins in an ex vivo brain slice assay via lipoprotein receptor. Thus, iPSC-PC may have potential as a replacement therapy for pericyte-deficient neurological disorders.

neuroscience↗