Profiling the mouse brain endothelial transcriptome in health and disease models reveals a core blood–brain barrier dysfunction module

Munji, Roeben N.; Soung, Allison; Weiner, Geoffrey; Sohet, Fabien; Semple, Bridgette D.; Trivedi, Alpa; Gimlin, Kayleen; Kotoda, Masakazu; Korai, Masaaki; Aydin, Sidar; Batugal, Austin; Cabangcala, Anne Christelle; Schupp, Patrick G.; Oldham, Michael C.; Hashimoto, Tomoki; Noble-Haeusslein, Linda J.; Daneman, Richard

doi:10.1038/s41593-019-0497-x

Cited by 247 publications

(357 citation statements)

References 48 publications

Supporting

Mentioning

341

Contrasting

Order By: Relevance

“…Given that gene expression programs and gene synergy determine the cellular function to respond to external signals and to carry out complex cellular activities, high-throughput sequencing technologies are now in place to discover gene expression programs and explore the biological mechanism that they govern. Existing genomic profiling studies for cerebrovascular cells use the marker-based method to isolate a single type of vasculature cells for further sequencing (Munji et al, 2019). However, distinct cell types in BBB have their own unique functions and perform highly coordinated actions to keep the central nervous system (CNS) homeostasis (Zhao et al, 2015); therefore, it is important to accurately distinguish different vascular components in the brain to explore the potential function in BBB disruption.…”

Section: Discussionmentioning

confidence: 99%

Secondary single-cell transcriptomic analysis reveals common molecular signatures of cerebrovascular injury between traumatic brain injury and aging

Guo

Zhang

Gómez‐Pinilla

et al. 2020

Preprint

View full text Add to dashboard Cite

AbstractCerebrovascular injury is a common pathological feature of a spectrum of neurological disorders including traumatic brain injury (TBI), stroke, Alzheimer’s disease (AD), as well as aging. Vascular manifestations among these conditions are similar indeed, including the breakdown of the blood-brain barrier (BBB). However, whether there is a common molecular mechanism underlying the vascular changes among these conditions remains elusive. Here, we report secondary transcriptomic analysis on cerebrovascular cells based single-cell RNA-seq datasets of mouse models of mild TBI and aging, with a focus on endothelial cells and pericytes. We identify several molecular signatures commonly found between mTBI and aging vasculature, including Adamts1, Rpl23a, Tmem252, Car4, Serpine2, and Ndnf in endothelial cells, and Rps29 and Sepp1 in pericytes. These markers may represent the shared endophenotype of microvascular injury and be considered as cerebrovascular injury responsive genes. Additionally, pathway analysis on differentially expressed genes demonstrated alterations in common pathways between mTBI and aging, including vascular development and extracellular matrix pathways in endothelial cells. Hence, our analysis suggests that cerebrovascular injury triggered by different neurological conditions may share common molecular signatures, which may only be detected at the single-cell transcriptome level.

show abstract

Section: Discussionmentioning

confidence: 99%

Secondary single-cell transcriptomic analysis reveals common molecular signatures of cerebrovascular injury between traumatic brain injury and aging

Guo

Zhang

Gómez‐Pinilla

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Thus, it is important to understand how each of the individual cell types in the NVU responds to potentially harmful stimuli, such as drugs or toxins. While extensive brain cell-specific proteome mapping has been carried out recently in mice [1][2][3] these data do not directly translate to the human NVU as proteomic analysis of whole isolated vessels from human and mouse cortices demonstrated large…”

Section: Introductionmentioning

confidence: 99%

Proteomic and Metabolomic Characterization of Human Neurovascular Unit Cells in Response to Methamphetamine

et al. 2020

View full text Add to dashboard Cite

The functional state of the neurovascular unit (NVU), composed of the blood–brain barrier and the perivasculature that forms a dynamic interface between the blood and the central nervous system (CNS), plays a central role in the control of brain homeostasis and is strongly affected by CNS drugs. Human primary brain microvascular endothelium, astrocyte, pericyte, and neural cell cultures are often used to study NVU barrier functions as well as drug transport and efficacy; however, the proteomic and metabolomic responses of these different cell types are not well characterized. Culturing each cell type separately, using deep coverage proteomic analysis and characterization of the secreted metabolome, as well as measurements of mitochondrial activity, the responses of these cells under baseline conditions and when exposed to the NVU‐impairing stimulant methamphetamine (Meth) are analyzed. These studies define the previously unknown metabolic and proteomic profiles of human brain pericytes and lead to improved characterization of the phenotype of each of the NVU cell types as well as cell‐specific metabolic and proteomic responses to Meth.

show abstract

“…Subsequently, mTBI can elicit a complex sequence of cellular cascades, and lead to genomic responses and transcriptional changes in vascular cells [52], including vascular endothelial growth factor A (VEGFA) [53], and compensatory changes in the extracellular matrix proteins and expansion of the basal lamina [24,44], which not only alter the basement membrane structure and perivascular space but also affect brain infiltration of peripheral leukocytes. Recent evidence from RNA sequencing of brain endothelial cells in different animal models has demonstrated that similar vascular gene expression profiles exist among multiple neurodegenerative diseases including TBI [54], suggesting perhaps that the molecular signature of vascular impairment might be common. Nevertheless, future studies exploring vascular associated transcriptomic changes at single-cell level in both mouse models and human patients are necessary for defining the exact microvascular molecular signature in mTBI, and beyond.…”

Section: Discussionmentioning

confidence: 99%

Microvascular Injury in Mild Traumatic Brain Injury Accelerates Alzheimer-like Pathogenesis in Mice

Zeng

Pluimer

et al. 2020

Preprint

View full text Add to dashboard Cite

Introduction: Traumatic brain injury (TBI) is considered as the most robust environmental risk factor for Alzheimer's disease (AD). Besides direct neuronal injury and neuroinflammation, vascular impairment is also a hallmark event of the pathological cascade after TBI. However, the vascular connection between TBI and subsequent AD pathogenesis remains underexplored. Methods:We established a closed-head mild TBI (mTBI) model in mice with controlled cortical impact, and examined the time courses of microvascular injury, blood-brain barrier (BBB) dysfunction, gliosis and motor function impairment in wild type C57BL/6 mice. We also determined the brain clearance of βamyloid, as well as amyloid pathology and cognitive functions after mTBI in the 5xFAD mouse model of AD.Results: mTBI induced microvascular injury with BBB breakdown, pericyte loss and cerebral blood flow reduction in mice, which preceded gliosis. mTBI also impaired brain amyloid clearance via the vascular pathways. More importantly, mTBI accelerated amyloid pathology and cognitive impairment in the 5xFAD mice.Discussion: Our data demonstrated that microvascular injury plays a key role in the pathogenesis of AD after mTBI. Therefore, restoring vascular functions might be beneficial for patients with mTBI, and potentially reduce the risk of developing AD. Ethics approval and consent to participateThe animal experiments were approved by the Institutional Animal Care and Use Committee at the University of Southern California per NIH guidelines. BackgroundAlzheimer's disease (AD) is an age-related progressive neurodegenerative condition, manifesting amyloid plaque and neurofibrillary tangle formation, neurovascular and neuroimmune dysfunctions, and cognitive impairment [1,2]. While advanced aging increases the likelihood of AD, genetic inheritance and environmental risk factors also contribute significantly [3]. For example, Traumatic brain injury (TBI) is considered as the most robust environmental risk factor for AD [4]. TBI is a leading cause of death and disability, particularly in young adults, resulting in a great impact on productivity and dependence on health care in later life [5,6]. Both clinical and preclinical studies have demonstrated that TBI triggers multiple neurodegenerative cascades, including axonal and dendritic damage, excitatory toxicity, neuroinflammation and cell death [7,8], as well as cerebrovascular impairment such as edema, circulatory insufficiency, and blood-brain barrier (BBB) breakdown [9,10], exhibiting a high similarity with AD [6,11]. TBI is highly prevalent during military service and contact sports, and doubles the risk of developing AD and dementia [12,13]. More importantly, it also exacerbates certain pathological events that are specific to AD, including the brain's overproduction and accumulation of β-amyloid (Aβ), and neurofibrillary tangles consisting of hyperphosphorylated Tau [14]. Yet the underlying mechanisms remain elusive.Histological and neuroimaging assessments have demonstrated that microvascular injury with...

show abstract

Profiling the mouse brain endothelial transcriptome in health and disease models reveals a core blood–brain barrier dysfunction module

Cited by 247 publications

References 48 publications

Secondary single-cell transcriptomic analysis reveals common molecular signatures of cerebrovascular injury between traumatic brain injury and aging

Secondary single-cell transcriptomic analysis reveals common molecular signatures of cerebrovascular injury between traumatic brain injury and aging

Proteomic and Metabolomic Characterization of Human Neurovascular Unit Cells in Response to Methamphetamine

Microvascular Injury in Mild Traumatic Brain Injury Accelerates Alzheimer-like Pathogenesis in Mice

Contact Info

Product

Resources

About