Pericyte Contractility Reset via Selective PDGFR-β Agonism

Kidney fibrosis is the hallmark of chronic kidney disease progression; however, at present no antifibrotic therapies exist1-3. The origin, functional heterogeneity and regulation of scar-forming cells that occur during human kidney fibrosis remain poorly understood1,2,4. Here, using single-cell RNA sequencing, we profiled the transcriptomes of cells from the proximal and non-proximal tubules of healthy and fibrotic human kidneys to map the entire human kidney. This analysis enabled us to map all matrix-producing cells at high resolution, and to identify distinct subpopulations of pericytes and fibroblasts as the main cellular sources of scar-forming myofibroblasts during human kidney fibrosis. We used genetic fate-tracing, time-course single-cell RNA sequencing and ATAC-seq (assay for transposase-accessible chromatin using sequencing) experiments in mice, and spatial transcriptomics in human kidney fibrosis, to shed light on the cellular origins and differentiation of human kidney myof

Kidney fibrosis is a hallmark of chronic kidney disease (CKD) and a potential therapeutic target. However, clinical interventions and therapies targeting kidney fibrosis remain conceptual and practical challenges due to the complex origin, functional heterogeneity, and regulation of scar-forming cells. Here, we define fibroblasts, pericytes, and myofibroblasts as the major extracellular matrix (ECM)-producing cells in the kidney, highlighting their primary contribution to kidney fibrosis. We then identify platelet-derived growth factor receptor β (PDGFRβ) as a potential targeting surface antigen for anti-fibrotic chimeric antigen receptor (CAR)-T against CKD. In multiple mouse CKD models, both adoptive transfer and CD5-lipid nanoparticle (LNP)-mediated in vivo generation of PDGFRβ CAR-T cells significantly ameliorate fibrosis-associated pathologies, including kidney, myocardial interstitial, and perivascular fibrosis without notable toxicity, evoking an integrated therapeutic strategy

Vascular contributions to dementia and Alzheimer's disease are increasingly recognized1-6. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human cognitive dysfunction7, including the early clinical stages of Alzheimer's disease5,8-10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease11-14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15-19, which maintain BBB integrity20-22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured

Vascular contributions to cognitive impairment are increasingly recognized1-5 as shown by neuropathological6,7, neuroimaging4,8-11, and cerebrospinal fluid biomarker4,12 studies. Moreover, small vessel disease of the brain has been estimated to contribute to approximately 50% of all dementias worldwide, including those caused by Alzheimer's disease (AD)3,4,13. Vascular changes in AD have been typically attributed to the vasoactive and/or vasculotoxic effects of amyloid-β (Aβ)3,11,14, and more recently tau15. Animal studies suggest that Aβ and tau lead to blood vessel abnormalities and blood-brain barrier (BBB) breakdown14-16. Although neurovascular dysfunction3,11 and BBB breakdown develop early in AD1,4,5,8-10,12,13, how they relate to changes in the AD classical biomarkers Aβ and tau, which also develop before dementia17, remains unknown. To address this question, we studied brain capillary damage using a novel cerebrospinal fluid biomarker of BBB-associated capillary mural cell peri

BACKGROUND: Endothelial cells (ECs) and pericytes (PCs) are crucial components of the vascular system, with ECs lining the inner layer of blood vessels and PCs surrounding capillaries to regulate blood flow and angiogenesis. Intercellular communication between ECs and PCs is vital for the formation, stability, and function of blood vessels. Various signaling pathways, such as the vascular endothelial growth factor/vascular endothelial growth factor receptor pathway and the platelet-derived growth factor-B/platelet-derived growth factor receptor-β pathway, play roles in communication between ECs and PCs. Dysfunctional communication between these cells is associated with various diseases, including vascular diseases, central nervous system disorders, and certain types of cancers. AIM OF REVIEW: This review aimed to explore the diverse roles of ECs and PCs in the formation and reshaping of blood vessels. This review focused on the essential signaling pathways that facilitate communication

CNS injury often severs axons. Scar tissue that forms locally at the lesion site is thought to block axonal regeneration, resulting in permanent functional deficits. We report that inhibiting the generation of progeny by a subclass of pericytes led to decreased fibrosis and extracellular matrix deposition after spinal cord injury in mice. Regeneration of raphespinal and corticospinal tract axons was enhanced and sensorimotor function recovery improved following spinal cord injury in animals with attenuated pericyte-derived scarring. Using optogenetic stimulation, we demonstrate that regenerated corticospinal tract axons integrated into the local spinal cord circuitry below the lesion site. The number of regenerated axons correlated with improved sensorimotor function recovery. In conclusion, attenuation of pericyte-derived fibrosis represents a promising therapeutic approach to facilitate recovery following CNS injury.

Fibrotic scar tissue limits central nervous system regeneration in adult mammals. The extent of fibrotic tissue generation and distribution of stromal cells across different lesions in the brain and spinal cord has not been systematically investigated in mice and humans. Furthermore, it is unknown whether scar-forming stromal cells have the same origin throughout the central nervous system and in different types of lesions. In the current study, we compared fibrotic scarring in human pathological tissue and corresponding mouse models of penetrating and non-penetrating spinal cord injury, traumatic brain injury, ischemic stroke, multiple sclerosis and glioblastoma. We show that the extent and distribution of stromal cells are specific to the type of lesion and, in most cases, similar between mice and humans. Employing in vivo lineage tracing, we report that in all mouse models that develop fibrotic tissue, the primary source of scar-forming fibroblasts is a discrete subset of perivascul

Pericytes, specialized mural cells of capillaries, fulfill crucial physiological functions including promoting endothelial barrier function and regulating angiogenesis. Pericyte loss or dysfunction represents a central pathological feature in diabetic retinopathy (DR) and is increasingly recognized in neurodegenerative diseases as well as in poor stroke outcomes, underscoring an urgent need for therapies that restore pericyte function or promote their regeneration. Here, we utilized a Frizzled4 (FZD4) and Low-Density Lipoprotein Receptor-Related Protein 5 (LRP5) agonist antibody (F4L5.13) to investigate the functional consequences of mimicking β-catenin-dependent signaling in CNS endothelial cells (ECs), which is physiologically induced by Norrin or WNT7A/B. In platelet-derived growth factor subunit B (Pdgfb) EC-specific knockout (ECKO) mice, a model of severe developmental pericyte deficiency with secondary blood-retina barrier (BRB) defects and hemorrhages, F4L5.13 significantly prom

Determining platelet-derived growth factor receptor β (PDGFRβ) expression in biological specimens is pivotal for cancer diagnosis, drug development, and therapeutic monitoring. After tyrosine kinase inhibitor (TKI) therapy, altered PDGFRβ expression may correlate with treatment resistance mechanisms. Real-time, accurate detection of PDGFRβ levels pre- and post-TKI treatment holds substantial clinical value, as it enables therapeutic efficacy evaluation, resistance prediction, and timely regimen adjustment. However, the current repertoire of real-time technologies for precise PDGFRβ monitoring remains highly limited. Herein, we present a novel nanoprobe (Cy3-Gint4.T@BPNSs) for PDGFRβ detection based on a fluorescence quenching-recovery mechanism. Cy3-Gint4.T is a cyanine 3 (Cy3)-labeled aptamer with high specificity and strong selective binding affinity for PDGFRβ. Black phosphorus nanosheets (BPNSs) adsorb Cy3-Gint4.T via van der Waals forces to quench its fluorescence. Upon targeting

Brain pericytes are mediators of neuroinflammation, as evidenced in vitro, in animal models and humans. We and others have identified the platelet-derived growth factor (PDGF)-BB -PDGF receptor beta (PDGFRB) pathway as a key modulator of inflammatory cues in human brain pericytes. We investigate the receptor for interkeukin-33 (IL-33), interkeukin-1 receptor-like 1 (IL1RL1; also known as ST2) as a highly upregulated transcript in response to PDGF-BB stimulation in pericyte cultures. We show that pericytes express transcripts for both the membrane bound form of the receptor (ST2L) and the soluble form (sST2) that acts as a decoy and blocks IL-33 signalling. Human brain pericytes secrete sST2 in response to PDGF-BB, but also to transforming growth factor alpha (TGF) alpha and interleukin-4 (IL-4), although they are unresponsive to IL-33 treatment. We also examine pericyte expression of both IL1RL1 transcripts using RNAscope in two different in vivo models of neuroinflammation, experiment

BACKGROUND: The retina, part of the central nervous system, reflects brain pathology. In Alzheimer's disease (AD), it shows changes like amyloid beta (Aβ) accumulation and vascular alterations. Pericytes modulate the glymphatic system, crucial for Aβ clearance, but their role in the ocular glymphatic system is unclear. This study explores pericytes' impact on the glymphatic system and AD-related retinal pathology. METHODS: APP/PS1 mice, a model of progressive Aβ deposition, were crossed with Pdgfr-β+/- mice, which exhibit pericyte dysfunction due to haploinsufficiency of platelet-derived growth factor receptor β (Pdgfr-β), generating four littermate genotypes: wild type, Pdgfr-β+/-, APP/PS1 and APP/PS1:Pdgfr-β+/-. Retinal pericytes were assessed by PDGFR-β and NG 2 labelling, vascular complexity by OCTA and CD31 immunostaining and glymphatic-related regulation by laminin-211 and perivascular aquaporin-4 (AQP-4) expression. Retinal Aβ and p-Tau pathology was evaluated by immunofluoresce

Neurovascular unit (NVU) inflammation via activation of glial cells and neuronal damage plays a critical role in neurodegenerative diseases. Though the exact mechanism of disease pathogenesis is not understood, certain biomarkers provide valuable insight into the disease pathogenesis, severity, progression and therapeutic efficacy. These markers can be used to assess pathophysiological status of brain cells including neurons, astrocytes, microglia, oligodendrocytes, specialized microvascular endothelial cells, pericytes, NVU, and blood-brain barrier (BBB) disruption. Damage or derangements in tight junction (TJ), adherens junction (AdJ), and gap junction (GJ) components of the BBB lead to increased permeability and neuroinflammation in various brain disorders including neurodegenerative disorders. Thus, neuroinflammatory markers can be evaluated in blood, cerebrospinal fluid (CSF), or brain tissues to determine neurological disease severity, progression, and therapeutic responsiveness.

Primary familial brain calcification (PFBC), also known as Fahr's disease, is a rare inherited disorder characterized by bilateral calcification in the basal ganglia according to neuroimaging. Other brain regions, such as the thalamus, cerebellum, and subcortical white matter, can also be affected. Among the diverse clinical phenotypes, the most common manifestations are movement disorders, cognitive deficits, and psychiatric disturbances. Although patients with PFBC always exhibit brain calcification, nearly one-third of cases remain clinically asymptomatic. Due to advances in the genetics of PFBC, the diagnostic criteria of PFBC may need to be modified. Hitherto, seven genes have been associated with PFBC, including four dominant inherited genes (SLC20A2, PDGFRB, PDGFB, and XPR1) and three recessive inherited genes (MYORG, JAM2, and CMPK2). Nevertheless, around 50% of patients with PFBC do not have pathogenic variants in these genes, and further PFBC-associated genes are waiting to b

BACKGROUND: Torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor which raises high-density lipoprotein (HDL) cholesterol and reduces low-density lipoprotein (LDL) cholesterol level, has been documented to increase mortality and cardiac events associated with adverse effects. However, it is still unclear the underlying mechanisms of the off-target effects of torcetrapib. RESULTS: In the present study, we developed a systems biology approach by combining a human reassembled signaling network with the publicly available microarray gene expression data to provide unique insights into the off-target adverse effects for torcetrapib. Cytoscape with three plugins including BisoGenet, NetworkAnalyzer and ClusterONE was utilized to establish a context-specific drug-gene interaction network. The DAVID functional annotation tool was applied for gene ontology (GO) analysis, while pathway enrichment analysis was clustered by ToppFun. Furthermore, potential off-targets of torcetrapib we

The low-density lipoprotein receptor (LDLR) gene family includes LDLR, very LDLR, and LDL receptor-related proteins (LRPs) such as LRP1, LRP1b (aka LRP-DIT), LRP2 (aka megalin), LRP4, and LRP5/6, and LRP8 (aka ApoER2). LDLR family members constitute a class of closely related multifunctional, transmembrane receptors, with diverse functions, from embryonic development to cancer, lipid metabolism, and cardiovascular homeostasis. While LDLR family members have been studied extensively in the systemic circulation in the context of atherosclerosis, their roles in pulmonary arterial hypertension (PAH) are understudied and largely unknown. Endothelial dysfunction, tissue infiltration of monocytes, and proliferation of pulmonary artery smooth muscle cells are hallmarks of PAH, leading to vascular remodeling, obliteration, increased pulmonary vascular resistance, heart failure, and death. LDLR family members are entangled with the aforementioned detrimental processes by controlling many pathway

Pericytes are perivascular cells along capillaries that are critical for the development of a functional vascular bed in the central nervous system and other organs. Pericyte functions in the adult brain are less well understood. Pericytes have been suggested to mediate functional hyperemia at the capillary level, regulate the blood-brain barrier and to give rise to scar tissue after spinal cord injury. Furthermore, pericyte loss has been suggested to precede cognitive decline in mouse models of Alzheimer's disease. Despite this observation, there is no convincing causality between pericyte loss and the pathogenesis of Alzheimer's disease. However, recent loss-of-function mutations in PDGFB and PDGFRB genes have implicated pericytes as the principle cell type affected in primary familiar brain calcification (PFBC), a neuropsychiatric disorder with dominant inheritance. Here we review the role of the PDGFB/PDGFRB signaling pathway in pericyte development and briefly discuss homeostatic

Pericytes (PCs) are multifunctional mural cells embedded in the basement membrane of microvessels and play essential roles in the development and maintenance of the central nervous system. This review provides a comprehensive synthesis of the current knowledge on PC biology, tracing their trajectory from embryonic origins to specialized functions in the adult brain. During early brain development, PCs are recruited via platelet-derived growth factor B (PDGF-BB)/platelet-derived growth factor receptor beta (PDGFRβ) signaling and contribute to the formation of the blood-brain barrier (BBB), cortical architecture, and vascular stability. Their developmental plasticity is shaped by multiple embryonic origins and dynamic interactions with endothelial and neural precursor cells. In the adult central nervous system, PCs are central to maintaining BBB integrity, regulating cerebral blood flow, and modulating neurovascular coupling. They also participate in immune responses, metabolic waste cle

Primary familial brain calcification (PFBC) is a dominantly or recessively inherited neurodegenerative disease characterized by bilateral basal ganglia calcifications. Patients affected by PFBC present with diverse motor and nonmotor symptoms. Mutations in seven genes (SLC20A2, XPR1, PDGFB, PDGFRB, MYORG, NAA60, and JAM2) are associated with PFBC. PFBC genes encode proteins that comprise inorganic phosphate transporters, growth factor and its receptor, a cell adhesion molecule, and enzymes. It remains to be determined whether these proteins interact within a single disrupted pathway or whether mutations affect distinct pathways in the same cell type. Although vessel calcification is a diagnostic criterion of PFBC, its causal role in neurodegeneration needs to be established. This review provides an overview of PFBC genes, including animal models that have yielded insights into the underlying pathophysiologic mechanisms, such as the role of specific cell types in the progression of vasc