Pericytes in Microvessels: From “Mural” Function to Brain and Retina Regeneration

Abstract

Pericytes are branched cells located in the wall of capillary blood vessels that are found throughout the body, embedded within the microvascular basement membrane and wrapping endothelial cells, with which they establish a strong physical contact. Pericytes regulate angiogenesis, vessel stabilization, and contribute to the formation of both the blood-brain and blood-retina barriers by Angiopoietin-1/Tie-2, platelet derived growth factor (PDGF) and transforming growth factor (TGF) signaling pathways, regulating pericyte-endothelial cell communication. Human pericytes that have been cultured for a long period give rise to multilineage progenitor cells and exhibit mesenchymal stem cell (MSC) features. We focused our attention on the roles of pericytes in brain and ocular diseases. In particular, pericyte involvement in brain ischemia, brain tumors, diabetic retinopathy, and uveal melanoma is described. Several molecules, such as adenosine and nitric oxide, are responsible for pericyte shrinkage during ischemia-reperfusion. Anti-inflammatory molecules, such as IL-10, TGFβ, and MHC-II, which are increased in glioblastoma-activated pericytes, are responsible for tumor growth. As regards the eye, pericytes play a role not only in ocular vessel stabilization, but also as a stem cell niche that contributes to regenerative processes in diabetic retinopathy. Moreover, pericytes participate in melanoma cell extravasation and the genetic ablation of the PDGF receptor reduces the number of pericytes and aberrant tumor microvessel formation with important implications for therapy efficacy. Thanks to their MSC features, pericytes could be considered excellent candidates to promote nervous tissue repair and for regenerative medicine.

Pericytes in Vascular Development

“…In a model of hyperoxia, disrupted pericyte-endothelial cell associations contributed to retinal vessel regression and abnormal microvascular remodeling [50]. Pericyte detachment or absence has also been associated with the rarefaction of kidney capillaries [115] and with the malformation of retinal vasculature akin to defects observed in diabetic retinopathy [70] and in tumors [116]. This role for direct pericyte-endothelial contact in vessel stability may involve intercellular communication mechanisms such as those mediated by Cx43-based gap junctions [117], but the specific molecular cues regulating these interactions are still being established.…”

How Long Are Reperfusion Therapies Beneficial for Patients after Stroke Onset? Lessons from Lethal Ischemia Following Early Reperfusion in a Mouse Model of Stroke

“…Compared with permanent ischemia, reperfusion during stage II decreases the size of the ischemic area at post-stroke day 7 [ 25 ]. Although the precise mechanism underlying these effects is not fully understood, reperfusion during this stage dramatically promotes proliferation of brain pericytes, which are known to have an important role in wound healing following injuries like ischemic stroke [ 49 , 50 , 51 , 52 ], within ischemic areas at post-stroke day 7. It remains unclear how pericytes are increased after reperfusion; however, cell niches around pericytes such as surviving endothelial cells may contribute to the production of pericytes within ischemic areas.…”

“…In support of this hypothesis, compared with permanent ischemia, we found that early reperfusion following ischemia increased the number of anti-inflammatory CD206 + M2 macrophage/microglia within ischemic areas proportionally to pericyte number at post-stroke day 7 [ 25 ]. Similar to pericytes [ 49 , 50 , 51 , 52 ], M2 macrophage/microglia are also associated with tissue repair [ 55 , 56 , 57 ]. Therefore, an increase of M2 macrophage/microglia by early reperfusion may promote brain repair following ischemic stroke.…”

“…Further, accumulating evidence shows that pericytes have similar traits to those of mesenchymal stem cells (MSCs) [ 51 , 88 , 89 ]. Akin to iSCs, MSCs also have multipotent stem cell activity.…”

Uveal Melanoma Cells Elicit Retinal Pericyte Phenotypical and Biochemical Changes in an in Vitro Model of Coculture

“…Dynamic and bidirectional crosstalk between TME and cancer cells plays a key role in the processes of tumor growth and invasiveness, destabilizing tissue homeostasis by modifying pH, promoting angiogenesis, and secreting several molecules including metabolites, cytokines, and chemokines [ 4 , 5 , 6 , 7 ]. Pericytes are mainly described as “mural” cells, specialized in vascular homeostasis, and they participate in angiogenesis by regulating the remodeling and stabilization of the blood–brain and blood–retina barriers [ 8 ]. Cell plasticity of pericytes is also described since they can differentiate into different cell types including phagocytes, chondrocytes, adipocytes, myocytes, and osteoblasts and can contribute to naturally occurring regenerative processes [ 8 , 9 ].…”