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Neural Crest Cell-Derived Pericytes Act As Pro-Angiogenic Cells in Human

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Neural Crest Cell-Derived Pericytes Act As Pro-Angiogenic Cells in Human Girolamo et al. Fluids Barriers CNS (2021) 18:14 https://doi.org/10.1186/s12987-021-00242-7 Fluids and Barriers of the CNS REVIEW Open Access Neural crest cell-derived pericytes act as pro-angiogenic cells in human neocortex development and gliomas Francesco Girolamo1*† , Ignazio de Trizio1,2†, Mariella Errede1†, Giovanna Longo3, Antonio d’Amati1,4 and Daniela Virgintino1 Abstract Central nervous system diseases involving the parenchymal microvessels are frequently associated with a ‘microvas- culopathy’, which includes diferent levels of neurovascular unit (NVU) dysfunction, including blood–brain barrier alterations. To contribute to the understanding of NVU responses to pathological noxae, we have focused on one of its cellular components, the microvascular pericytes, highlighting unique features of brain pericytes with the aid of the analyses carried out during vascularization of human developing neocortex and in human gliomas. Thanks to their position, centred within the endothelial/glial partition of the vessel basal lamina and therefore inserted between endothelial cells and the perivascular and vessel-associated components (astrocytes, oligodendrocyte precursor cells (OPCs)/NG2-glia, microglia, macrophages, nerve terminals), pericytes fulfl a central role within the microvessel NVU. Indeed, at this critical site, pericytes have a number of direct and extracellular matrix molecule- and soluble factor- mediated functions, displaying marked phenotypical and functional heterogeneity and carrying out multitasking services. This pericytes heterogeneity is primarily linked to their position in specifc tissue and organ microenviron- ments and, most importantly, to their ontogeny. During ontogenesis, pericyte subtypes belong to two main embry- onic germ layers, mesoderm and (neuro)ectoderm, and are therefore expected to be found in organs ontogenetically diferent, nonetheless, pericytes of diferent origin may converge and colonize neighbouring areas of the same organ/ apparatus. Here, we provide a brief overview of the unusual roles played by forebrain pericytes in the processes of angiogenesis and barriergenesis by virtue of their origin from midbrain neural crest stem cells. A better knowledge of the ontogenetic subpopulations may support the understanding of specifc interactions and mechanisms involved in pericyte function/dysfunction, including normal and pathological angiogenesis, thereby ofering an alternative perspective on cell subtype-specifc therapeutic approaches. Keywords: Human brain development, Prosencephalon, Microvessels, Pericytes, Neural crest cells, Tunnelling nanotubes, Angiogenesis, Blood–brain barrier, Human gliomas Background Te Rouget cells, frstly described by Charles-Marie Benjamin Rouget in the late 19th century [1], were later *Correspondence: [email protected] †Francesco Girolamo, Ignazio de Trizio and Mariella Errede contributed denoted as pericytes (PCs) [2]. Tey are described as vas- equally to this work cular cells that, at the level of the microvessel segments 1 Department of Basic Medical Sciences, Neuroscience and Sensory (precapillary arterioles, capillary, and postcapillary ven- Organs, Human Anatomy and Histology Unit, University of Bari School of Medicine, Bari, Italy ules) of the vascular tree, wrap around the endothelial Full list of author information is available at the end of the article cells (ECs), being retained within the vessel basal lamina, © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Girolamo et al. Fluids Barriers CNS (2021) 18:14 Page 2 of 26 that is known to be formed by two layers, pertaining to provided, together with subsequent 3D reconstructions ECs and astrocytes, respectively. Herein, the term ‘basal by TEM serial sections [5, 6], a complete rendering of lamina’ is used instead of ‘basement membrane’, since the 3D morphology and relationships of PCs (Figs. 1, brain microvessels only show a ‘basal lamina’ without the 2). PCs show a prominent nuclear region bulging out on ‘lamina reticularis’ made up by fbrillar collagens, type the abluminal vessel side, two longitudinally oriented I, III, and V. After the pioneering descriptions of brain primary processes sending out transversely arranged PCs’ morphology in primates, including humans, gained secondary processes and additional fat, fnger-like, pro- by electron transmission microscopy (TEM) [3, 4], the trusions that interdigitate to fll the remaining gaps. As emergence of scanning electron microscopy (SEM) has a consequence of their location within the neurovascular Fig. 1 Pericyte morphology and relationships within the NVU. a, b Scanning electron microscope images of 14-day-old chick embryo microvessels, showing in a primary (red arrow) and secondary (red arrowheads) pericyte processes and in b their highly indented and interdigitated fnger-like processes (red arrows) [from [5] with permission]. c Dorsal wall of the telencephalic vesicles (forebrain, future neocortex) of an 18-week-old human fetus, GFAP+ (glial fbrillary acidic protein) radial glia fbers and a pericyte coverage NG2 2164C3 +, the latter shows fnger-like processes (arrows); note the very fne perivascular processes of OPCs (arrowheads). d A schematic representation showing NVU components: ECs, PCs, perivascular astrocytes, vessel-associated microglial cells, OPCs/NG2-glia, macrophages, nerve fber terminal [from [13] with permission]. PCs, embedded in the vessel basal lamina (here not shown) are the cells closest to the endothelium and display a variety of extensive contacts on their abluminal surface, in particular the relation with astrocytes and OPCs/NG2-glia [10]. e Astrocyte-pericyte relations are shown by glutamine synthetase (GS), confned within the astrocyte body (arrow) and in perivascular endfeet (arrowheads), most of which are in contact with CD248 + PCs rather than, directly, with ECs. Scale bars a, b 1 µm; c 20 µm; e 10 µm Girolamo et al. Fluids Barriers CNS (2021) 18:14 Page 3 of 26 Fig. 2 Pericyte morphology and vessel basal lamina relationships. a Morphology of an activated, PDGFR-β+ pericyte in contact with the collagen type IV+ basal lamina of a neocortex microvessel from a 22-week-old human fetus; note the abluminal bumpy surface of the PC (arrow), a detail well-depicted by the scanning electron microscopy 3D image (b; 14-day-old chick embryo) [from [5] with permission]. c, d The NG2 isoform, specifcally recognized by antibody 2161F9, is able to outlines the fner cell details, thus describing the real extension of the pericyte coverage (c, inset) and its relation with the collagen VI-enriched basal lamina (d); note a pericyte conduit and its collagen VI sleeve (d, inset). e, f NG2 2161F9 immunostaining shows few large gaps in the pericyte coverage (better shown in e, inset); on the same feld (f), a TNT/MT-like intervascular bridge is revealed by collagen VI staining; the inset shows two PCs close to the site of TNT/MT origin (arrowheads). a, c–f, Human telencephalon 22 wg. Scale bars a 7.5 µm; b–f 10 µm Girolamo et al. Fluids Barriers CNS (2021) 18:14 Page 4 of 26 unit (NVU) of the central nervous system (CNS), PCs heterogeneity [11]. Genome-wide association and develop their two-sided activity: direct communica- RNA-seq studies have revealed morphological and tion with ECs through peg socket connections and het- functional astrocytes and microglia subtypes associated erotypic gap junctions, interactions through extracellular to both normal and pathological conditions [27–29]. matrix molecules and soluble factors, autocrine and par- Transcriptional profling has highlighted the presence acrine signaling pathways, including those involved in of diferent glial sub-populations [30–32], includ- the astrocyte-pericyte crosstalk [7, 8] and in interactions ing neurotoxic, type A1, and neuroprotective, type with all the other vessel-associated NVU components A2, astrocytes associated to astrogliosis [33]. In addi- (Fig. 1) [9–13]. Te NVU is essential in CNS homeosta- tion, high-resolution transcriptomic analyses, together sis, neurovascular coupling, regulation of blood fow, with the emergence of novel single-cell techniques as well as diferentiation and functional activities of the and single-cell RNA sequencing, now propel studies of blood-brain barrier (BBB) [14, 15]. In this context, PCs microglia heterogeneity, unveiling a variety of spatially accomplish direct roles in leading microvessel develop- and developmentally distinct microglia subtypes (for a ment, maturation, and remodeling, fnally stabilizing
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