Neurosci. Bull. June, 2019, 35(3):551–560 www.neurosci.cn https://doi.org/10.1007/s12264-018-0296-5 www.springer.com/12264 REVIEW Pericyte Plasticity in the Brain 1 2 2 Gabryella S. P. Santos • Luiz A. V. Magno • Marco A. Romano-Silva • 3 1,3 Akiva Mintz • Alexander Birbrair Received: 19 February 2018 / Accepted: 6 August 2018 / Published online: 26 October 2018 Ó Shanghai Institutes for Biological Sciences, CAS and Springer Nature Singapore Pte Ltd. 2018 Abstract Cerebral pericytes are perivascular cells that origins from the Greek ‘‘kytos’’ (cell), properly illustrating stabilize blood vessels. Little is known about the plasticity a cell encircling a blood vessel [3]. Until the end of the of pericytes in the adult brain in vivo. Recently, using state- 20th century, pericytes were identified still based mainly on of-the-art technologies, including two-photon microscopy their anatomical location and morphology. Pericytes have in combination with sophisticated Cre/loxP in vivo tracing long processes surrounding blood vessel walls and are techniques, a novel role of pericytes was revealed in widely dispersed in all tissues [4]. They encircle endothe- vascular remodeling in the adult brain. Strikingly, after lial cells, and communicate with them along the length of pericyte ablation, neighboring pericytes expand their the blood vessels by paracrine signaling and physical processes and prevent vascular dilatation. This new contact [5]. In the brain, the ratio of endothelial cells to knowledge provides insights into pericyte plasticity in the pericytes is *3:1 [6, 7], implying an immense importance adult brain. of cerebral pericytes. Formerly, the accurate distinction of pericytes from Keywords Pericytes Á Brain Á Blood vessel Á Plasticity other perivascular cells was impossible, as light and electron microscopy were the only technologies able to visualize these cells, limiting the information acquired. Introduction This resulted in the illusory notion that pericytes are merely inert supporting cells, limited exclusively to the physio- In the 19th century, a French scientist, Charles-Marie logical function of vascular stability. Already in the 21th Benjamin Rouget, reported the presence of a population of century, the combination of fluorescent and confocal contractile cells in small blood vessels, referred to as microscopy with genetic tools, such as fate lineage tracing, Rouget cells [1]. Later, in the 20th century, a German enabled the discovery of novel and unexpected roles for scientist, Karl Wilhelm Zimmermann, renamed these cells pericytes in health and disease [8]. Recently, quickly ‘‘pericytes’’ due to their distinct anatomical position around expanding insights into the pathophysiological functions of the vasculature [2]. The word pericyte comes from ‘‘peri’’ pericytes have attracted the attention of many researchers. meaning ‘‘around’’ and ‘‘cyte’’ from Latin, which has Pericytes participate in blood vessel development, maturation, and permeability, as well as contributing to their normal architecture [9, 10]. They regulate blood flow & Alexander Birbrair [11, 12], and affect coagulation [13]. Pericytes also [email protected] collaborate with astrocytes, neurons, and endothelial cells, 1 Departamento de Patologia, Universidade Federal de Minas forming the neurovascular unit [12, 14, 15], to regulate Gerais, Belo Horizonte, MG 31270-901, Brazil maintenance of the functional integrity of the blood brain 2 Department of Mental Health, Federal University of Minas barrier [16–21]. This may occur via pericyte-derived Gerais, Belo Horizonte, MG 30130-100, Brazil molecules, such as platelet-derived growth factor subunit 3 Department of Radiology, Columbia University Medical B (PDGFB)/PDGF receptor-beta (PDGFRb) signaling, Center, New York, NY 10032, USA which is indispensable for the formation and maturation 123 552 Neurosci. Bull. June, 2019, 35(3):551–560 of this barrier [22]. In addition, pericytes perform several Perspectives and Future Directions immune functions [23], regulate lymphocyte activation in the retina [24, 25], attract innate leukocytes to exit through Pericyte Heterogeneity in the Brain sprouting blood vessels in the skin [26], and contribute to the clearance of toxic cellular byproducts, having direct Pericytes are heterogeneous regarding their distribution, phagocytic activity in the brain [27]. Interestingly, follow- phenotype, marker expression, origin, and function [42]. In ing white matter demyelination, pericytes promote the the past century, pericytes were distinguished into three differentiation of oligodendrocyte progenitors involved in types based on their mural location and morphology: pre- central nervous system regeneration via a2-chain of capillary, mid-capillary, and post-capillary [2, 43]. Berthi- laminin [28]. Pericytes may also behave as stem cells in aume and colleagues exclusively studied pericytes sur- several tissues [29], generating other cell populations, as rounding mid-capillary regions [41]. Thus, it remains well as regulating the behavior of other stem cells, as unknown whether pre-capillary and post-capillary pericytes hematopoietic stem cells in their niches [30–34]. Note that present different behavior. This should be taken into pericytes from distinct peripheral tissues may have various consideration in future work; discovering specific markers properties, and may differ from those in brain. Increasing for pre-capillary and post-capillary pericytes will help to evidence also shows that brain pericytes alter their traits address this question. Separately analyzing the behavior of following stimuli and develop stemness, demonstrating pericytes from different locations in the blood vessels may their plasticity [35–39]. reveal their functional heterogeneity. Pericyte heterogene- Pericytes exhibit structural plasticity during embryonic ity is also based on their molecular marker expression cerebral development, participating in vascular remodeling profiles. Capillary pericytes express desmin but are com- [40]. Understanding pericyte behavior in the adult brain is monly negative for a smooth muscle actin (aSMA), while a central question in neuroscience, as these cells may play venular pericytes express both desmin and aSMA proteins central roles in the pathogenesis of neurodegenerative [44]. Moreover, Kir6.1 is highly expressed in a subset of disorders. Nevertheless, whether pericytes participate in brain pericytes, but is undetectable in others [45]. In vascular remodeling in the adult brain remains unknown. addition, arteriolar pericytes that do not express the leptin Now, in a recent article in Cell Reports, Berthiaume and receptor (LEPR) have been described to be distinct from colleagues investigated the behavior of pericytes in the sinusoidal pericytes in the bone marrow that express LEPR adult mouse brain [41]. The authors revealed pericyte [31, 46]. Also, both nerve/glial antigen 2-positive (NG2?) plasticity in the adult brain by using elegant state-of-the-art and -negative (NG2-) pericytes have been described in the techniques, including two-photon microscopy in combina- skin [26]. Furthermore, pericytes positive and negative for tion with sophisticated Cre/loxP in vivo tracing technolo- glutamate aspartate transporter and the cytoskeletal protein gies. Berthiaume and colleagues imaged, at high-resolution Nestin have been described in the spinal cord [47, 48]. over several weeks, cerebral pericytes in NG2-CreER/ Cerebral pericytes also differ in their embryonic origins TdTomato, Myh11-CreER/TdTomato, and PDGFRb-Cre/ [42]. While pericytes in coleomic organs are mesoderm- YFP mice. These experiments unveiled that pericytes derived [7], most cephalic pericytes are of neuroectodermal comprise a quasi-continuous, non-overlapping network origin [49], and recent studies have shown that a subpop- along the entire length of blood vessels. Interestingly, the ulation of pericytes in the embryonic brain may derive pericyte prolongations were not stable in length, extending from hematopoietic progenitors [42, 50]. All these descrip- or retracting during the period of analysis. Then, the tive characteristics in which pericytes differ are also authors explored the effect of pericyte death on its important regarding their functions, as pericytes in distinct neighboring pericytes. After pericyte ablation, using tar- locations [30], with different marker expression profiles geted two-photon irradiation, Berthiaume and colleagues [51], and from varying origins [42] differ in their functions. showed that adjacent pericytes extend their processes into For instance, after brain injury, while one subset partici- the uncovered area, covering the exposed blood vessel pates in scar tissue formation [52], another is capable of [41]. Strikingly, neighboring pericytes are able to reverse generating new blood vessels [53]. Thus, subsets of the vascular dilatation that occurs after pericyte depletion pericytes can contribute to distinct pathological conditions [41] (Fig. 1). Thus, this longitudinal imaging study in varying ways. Importantly, similar analysis as done by demonstrated pericyte plasticity in the adult brain. Berthiaume et al. (2018), should be performed on cerebral Here, we consider these findings, and evaluate recent pericytes from other blood vessels and in distinct brain advances in our knowledge of pericyte biology in the brain. regions, as their behavior may differ. 123 G. S. P. Santos et al.: Pericytes are Plastic in the Brain 553 Fig. 1 Cerebral pericyte plasticity in response to neighbor