MicroRNA-Based Regulation of Embryonic Endothelial Cell Heterogeneity at Single-Cell Resolution
2022; Lippincott Williams & Wilkins; Volume: 42; Issue: 3 Linguagem: Inglês
10.1161/atvbaha.122.317400
ISSN1524-4636
AutoresThomas Wälchli, Fiona Farnhammer, Jason E. Fish,
Tópico(s)Extracellular vesicles in disease
ResumoHomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 42, No. 3MicroRNA-Based Regulation of Embryonic Endothelial Cell Heterogeneity at Single-Cell Resolution Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessResearch ArticlePDF/EPUBMicroRNA-Based Regulation of Embryonic Endothelial Cell Heterogeneity at Single-Cell Resolution Thomas Wälchli, Fiona Farnhammer and Jason E. Fish Thomas WälchliThomas Wälchli Correspondence to: Thomas Wälchli, MD, PhD, FMH, Toronto Western Hospital, University Health Network, 60 Leonard Ave, Toronto, Ontario, M5T 2S8, Canada, Email E-mail Address: [email protected], E-mail Address: [email protected], E-mail Address: [email protected], E-mail Address: [email protected] https://orcid.org/0000-0002-8961-6551 Group Brain Vasculature and Perivascular Niche, Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Ontario, Canada (T.W., F.F.). Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University Health Network, University of Toronto, Ontario, Canada (T.W., F.F.). Group of CNS Angiogenesis and Neurovascular Link, Neuroscience Center Zurich, and Division of Neurosurgery, University and University Hospital Zurich, and Swiss Federal Institute of Technology (ETH) Zurich, Switzerland (T.W., F.F.). Division of Neurosurgery, University Hospital Zurich, Switzerland (T.W., F.F.). , Fiona FarnhammerFiona Farnhammer https://orcid.org/0000-0003-4149-8215 Group Brain Vasculature and Perivascular Niche, Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Ontario, Canada (T.W., F.F.). Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University Health Network, University of Toronto, Ontario, Canada (T.W., F.F.). Group of CNS Angiogenesis and Neurovascular Link, Neuroscience Center Zurich, and Division of Neurosurgery, University and University Hospital Zurich, and Swiss Federal Institute of Technology (ETH) Zurich, Switzerland (T.W., F.F.). Division of Neurosurgery, University Hospital Zurich, Switzerland (T.W., F.F.). Department of Physiology, Faculty of Medicine (F.F.), University of Toronto, Ontario, Canada. and Jason E. FishJason E. Fish Jason Fish, PhD, Toronto General Hospital Research Institute, University Health Network, 101 College St, 3-308 Princess Margaret Cancer Research Tower, Toronto, Ontario M5G 1L7, Canada, Email E-mail Address: [email protected] https://orcid.org/0000-0003-0640-7277 Department of Laboratory Medicine and Pathobiology, Faculty of Medicine (J.E.F.), University of Toronto, Ontario, Canada. Toronto General Hospital Research Institute (J.E.F.), University Health Network, Ontario, Canada. Peter Munk Cardiac Centre (J.E.F.), University Health Network, Ontario, Canada. Originally published23 Feb 2022https://doi.org/10.1161/ATVBAHA.122.317400Arteriosclerosis, Thrombosis, and Vascular Biology. 2022;42:343–347is related toSingle-Cell Transcriptome Analysis Reveals Embryonic Endothelial Heterogeneity at Spatiotemporal Level and Multifunctions of MicroRNA-126 in MiceCellular heterogeneity is an indispensable feature of functional vascular networks, and the phenotype and function of endothelial cells (ECs)—specialized cells lining the inner wall of all blood and lymphatic vessels—is fine-tuned to the diverse needs of organ systems.1,2 Whereas all ECs share a mesodermal origin and a common set of pan-EC functions, their cellular, molecular, and functional properties differ considerably depending on the vessel type along the arteriovenous tree (ie, large vessels versus capillaries) and the organ in which they reside.1 This remarkable EC heterogeneity and organ specificity is established as vessels are formed during development and is further modulated and reinforced as they mature through adulthood and is subsequently altered in pathological settings.1,3 The mechanisms that establish and maintain EC heterogeneity remain incompletely understood. In this issue of ATVB, Guo et al4 demonstrate that microRNA (miRNA) can contribute to EC heterogeneity and organ-specific EC functions during vascular development.See accompanying article on page 326Along the arteriovenous axis, the endothelium of arteries and veins forms a continuous EC monolayer, whereas capillary ECs are either continuous, fenestrated, or discontinuous depending on the specific barrier functions and the degree of endothelial permeability in different organs.1 Accordingly, fenestrated endothelium is prevalent in tissues involved in filtration and secretion, including kidney glomeruli, intestinal mucosa, and exocrine and endocrine glands, and a discontinuous endothelium is characteristic of sinusoidal vascular beds in the liver and bone marrow, allowing for passage of small particles from the blood.1,5 On the contrary, a continuous endothelium in the brain is connected by specialized tight junctions and adherens junctions and is further stabilized by perivascular cells and astrocytes to form the blood-brain barrier,2,6,7 which protects the brain parenchyma from immune cells, toxic molecules, and pathogens. Interestingly, EC heterogeneity and EC barrier properties also regulate perivascular cells in the neurovascular unit and stem cell niches.1 For instance, in the bone marrow, permeable sinusoidal vessels promote differentiation and activation of hematopoietic stem cells and less permeable arteries maintain hematopoietic stem cells in a quiescent state,1,2,8 whereas brain tumor ECs are critical for maintenance of undifferentiated states of brain tumor stem cells and their survival.9 Thus, EC heterogeneity and organ specificity underly the specialized functions of ECs, enabling them to fulfill organ- or tissue-specific tasks and needs, and are essential for normal organ development and function, adult homeostasis, as well as for interactions with perivascular cells in development and disease.Mechanistically, endothelial heterogeneity and specialization are thought to be regulated by cell-intrinsic developmental pathways and transcriptional programs on the one hand and by microenvironment signals such as extracellular growth factors, metabolic stimuli, mechanical forces, and cell-matrix as well as cell-cell interactions on the other.1 However, while morphological and functional differences of ECs are increasingly being appreciated, the molecular basis of endothelial heterogeneity and organ specialization remains largely obscure.10 New approaches that investigate gene expression and regulation at the single-cell level including single-cell RNA sequencing (scRNA-seq)11–17 are revolutionizing our understanding of EC heterogeneity and the molecular processes involved. Recently, single-cell transcriptome atlases of cell types of the human body,13 the human heart,14 and the human lung15 as well as murine atlases of ECs and perivascular cells across all organs11 and the adult mouse brain vasculature18 have been established and have shed light on inter- and intratissue EC and perivascular cell heterogeneity. We have recently contributed with a comprehensive single-cell landscape of the cellular composition and heterogeneity of the human brain vasculature during development, adulthood, and in disease, and the power of single-cell analyses unveiled key signaling pathways in brain ECs active during development that were silenced in the adult healthy brain ECs and subsequently reactivated in brain tumor and brain vascular malformation ECs.3 Another recent study determined the epigenetic and transcriptional mechanisms driving functional EC heterogeneity in 6 different organs during mouse development and adulthood and revealed key gene regulatory networks and transcriptional regulators controlling organ-specific endothelial specialization and the maturation and maintenance of the cerebrovasculature.10 Yet, much remains to be discovered about the complex regulatory networks that control EC phenotype.Despite important roles for miRNAs in the regulation of global gene expression and EC phenotypes,19,20 their contribution to establishing and maintaining EC heterogeneity at the single-cell level has not been investigated. Guo et al4 assess EC heterogeneity by performing scRNA-seq of ECs from the entire mouse embryo at an embryonic stage (E14.5) and characterize the impact of deletion of the endothelial-restricted miRNA, miR-126, on EC gene regulatory pathways and cellular phenotypes (Figure). This novel approach reveals new functions for miR-126 and demonstrates that a miRNA can control EC heterogeneity.Download figureDownload PowerPointFigure. Single-cell RNA sequencing reveals organ-specific functions of miR-126 in endothelial cells (ECs).A, Schematic workflow for the sequencing of ECs from whole miR-126 endothelial-specific KO (knockout; Tie2-Cre; miR-126fl/fl) and wild-type control (miR-126fl/fl) embryos. B, scRNA-seq and cell clustering revealed organ-specific changes in miR-126 target genes and cellular pathways in ECs from miR-126 endothelial-specific KOs. Compared with control embryos, miR-126 KO embryos showed liver fibrosis, vascular calcification in brain and lung, as well as widespread EC hypoxia, apoptosis, and reduced glucose tolerance. CD indicates cluster of differentiation; and E14.5, embryonic day 14.5.miRNAs repress target genes by binding to the 3′ untranslated region of mRNAs and antagonizing their stability or translation,21 and they can act as buffers to confer robustness to biological systems.22,23 By fine-tuning gene regulation and ultimately controlling the activation of signaling pathways, miRNAs can alter EC phenotype.24 miRNA-126 was among the first EC miRNAs to be characterized and was shown to promote angiogenic signaling to control vessel development and integrity.25–28 Additional functions include the control of EC progenitor cell development and function,29 repair and inflammation of the aorta,30 and leukemic stem cell expansion.31Guo et al4 clustered single-cell transcriptomes from >12 000 wild-type ECs at E14.5 to identify 11 primary clusters of ECs, including organ-specific microvascular ECs (brain, liver, lung, heart/muscle, endocardium, kidney, and intestine), large vessel ECs (arteries, veins, and lymphatics), as well as ECs undergoing endothelial-to-mesenchymal transition. Comparison to existing adult EC scRNA-seq data sets11,32 revealed similar clustering of cellular transcriptomes, with a distinct elevation of cell proliferation in embryonic stages. Analysis of a larger number of cells or investigation of differential gene expression patterns would be expected to uncover additional pathways involved in vascular maturation, for example, the induction of WNT (wingless/int-1)/β-catenin signaling and establishment of the blood-brain barrier.33 Indeed, recent studies have begun to dissect these maturation pathways10 and have revealed a return to embryonic immaturity in disease.3Notably, performing scRNA-seq on >5000 ECs isolated from embryos (E14.5) of EC-specific miR-126 knockout mice revealed altered clustering primarily in the hepatic, pulmonary, and endothelial-to-mesenchymal transition cell clusters. Upregulated genes in miR-126 knockout ECs were primarily related to the hypoxic response, as well as apoptosis. Interestingly, previous studies in cultured ECs revealed that hypoxia and apoptosis were among the most dysregulated pathways when miR-126-5p expression was disrupted, and this was attributed, in part, to a noncanonical nuclear role for miR-126-5p in the Mex3a-dependent suppression of caspase activation.34 Among induced genes in EC-specific miR-126 knockout embryos was the hypoxic transcription factor HIF1A (hypoxia-inducible factor 1A), which has been shown to be a direct target of miR-126.35 While sprouting angiogenesis and lymphangiogenesis were reduced in miR-126 knockout embryos, the authors observed an increase in intussusceptive angiogenesis—a process that has previously been linked to hypoxic environments.36 It remains unclear whether the upregulation of hypoxia response genes was due to genuine oxygen deprivation in tissue—because of reduced vascularization—or was instead the result of upregulation of HIF1A following loss of miR-126–mediated repression.Detailed analysis of EC clusters in the liver revealed dysregulation of glucose metabolism genes in miR-126 knockout ECs, including induction of the glucose transporter GLUT1 (glucose transporter 1), which is known to be a transcriptional target of HIF1A.37,38 The defects in glucose metabolism continued to be present in adult mice, as demonstrated by increased HIF1A and GLUT1 expression in hepatic ECs and reduced glucose and pyruvate tolerance. These metabolic defects could be reversed by delivering miR-126-3p to the vasculature, suggesting that miR-126 is required for maintenance of glucose homeostasis. miR-126 was previously found to be downregulated in ECs exposed to hyperglycemic conditions,39 and levels of miR-126 were downregulated in the blood and EC-derived microparticles in type 2 diabetics, which was accompanied by deficient vascular repair.40,41 The finding that miR-126 can directly regulate glucose metabolism suggests that this miRNA may be functionally implicated in antagonizing hyperglycemia.Guo et al4 additionally implicate miR-126 in the regulation of fibrosis and vascular calcification. Fibrosis was increased in the vessels of the liver, which may be related to tissue hypoxia. Excessive endothelial-to-mesenchymal transition and expression of extracellular matrix genes was present in multiple miR-126 knockout tissues, accompanied by increased calcification in the brain and lung. This may be due to endothelial-to-cartilage transition, but this needs to be formally demonstrated.It was notable that pan-endothelial deletion of miR-126 resulted in changes in the clustering of only a subset of ECs. One possible reason could be the nonuniform expression of miR-126 in distinct vascular beds.4 This has not been systematically explored, but it is known that miR-126 expression can be impacted by blood flow patterns.27,30,42 Another contributor to differential effects may be variations in expression of target genes across tissues. Indeed, Guo et al report discrepancies in the induction of known and predicted target genes of miR-126 in the liver endothelium compared with other organs. The upregulated genes were distinct in the three affected cell clusters, which may be related to the expression level of the transcripts in these tissues. The availability of target genes is an important determinant of a miRNA's function in a given cell type, and target prediction algorithms are beginning to take this into account.43 It is also important to note that since miRNAs potently regulate the translational output of mRNAs, scRNA-seq may not capture the full extent of the EC heterogeneity regulated by miR-126 loss. Finally, the limited number of cells in some clusters may have posed a limitation to identifying further effects of miR-126 on EC heterogeneity.Taken together, using a novel approach, Guo et al identify new roles for miR-126 during vascular development and reveal the contribution of this miRNA to EC heterogeneity in various embryonic organs. This expands our understanding of miR-126 biology and organ-specific functions and may have important ramifications for its role in disease.Article InformationSources of FundingT. Wälchli was supported by the OPO Foundation, the Swiss Cancer Research Foundation (KFS-3880-02-2016-R and KFS-4758-02-2019-R), the Stiftung zur Krebsbekämpfung, the Kurt und Senta Herrmann Foundation, the Forschungskredit of the University of Zurich, the Zurich Cancer League, the Theodor und Ida Herzog Egli Foundation, the Novartis Foundation for Medical-Biological Research, and the HOPE Foundation. J.E. Fish is supported by a Canada Research Chair from the Canadian Institutes of Health Research (CIHR), and his laboratory received infrastructure funding from the Canada Foundation for Innovation, the John R. Evans Leaders Fund, and the Ontario Research Fund. Research in the laboratory of J.E. Fish is supported by the CIHR (PJT148487, PJT173489, and PJT175301) and Medicine by Design, which received funding from the Canada First Research Excellence Fund.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 346.Correspondence to: Thomas Wälchli, MD, PhD, FMH, Toronto Western Hospital, University Health Network, 60 Leonard Ave, Toronto, Ontario, M5T 2S8, Canada, Email [email protected]uzh.ch, thomas.[email protected]ca, thomas.[email protected]ch, thomas.[email protected]utoronto.caJason Fish, PhD, Toronto General Hospital Research Institute, University Health Network, 101 College St, 3-308 Princess Margaret Cancer Research Tower, Toronto, Ontario M5G 1L7, Canada, Email jason.[email protected]caReferences1. Potente M, Mäkinen T. 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Arteriosclerosis, Thrombosis, and Vascular Biology. 2022;42:326-342 March 2022Vol 42, Issue 3Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.122.317400PMID: 35196110 Originally publishedFebruary 23, 2022 Keywordsendothelial cellsEditorialsembryonic developmentphenotypesingle-cell analysismicroRNAsPDF download Advertisement
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