Pericytes: The lung-forgotten cell type

Abstract

Pericytes are a heterogeneous population of mesenchymal cells located on the abluminal surface of microvessels, where they provide structural and biochemical support. Pericytes have been implicated in numerous lung diseases including pulmonary arterial hypertension (PAH) and allergic asthma due to their ability to differentiate into scar-forming myofibroblasts, leading to collagen deposition and matrix remodelling and thus driving tissue fibrosis. Pericyte-extracellular matrix interactions as well as other biochemical cues play crucial roles in these processes. In this review, we give an overview of lung pericytes, the key pro-fibrotic mediators they interact with, and detail recent advances in preclinical studies on how pericytes are disrupted and contribute to lung diseases including PAH, allergic asthma, and chronic obstructive pulmonary disease (COPD). Several recent studies using mouse models of PAH have demonstrated that pericytes contribute to these pathological events; efforts are currently underway to mitigate pericyte dysfunction in PAH by targeting the TGF-β, CXCR7, and CXCR4 signalling pathways. In allergic asthma, the dissociation of pericytes from the endothelium of blood vessels and their migration towards inflamed areas of the airway contribute to the characteristic airway remodelling observed in allergic asthma. Although several factors have been suggested to influence this migration such as TGF-β, IL-4, IL-13, and periostin, recent evidence points to the CXCL12/CXCR4 pathway as a potential therapeutic target. Pericytes might also play an essential role in lung dysfunction in response to ageing, as they are responsive to environmental risk factors such as cigarette smoke and air pollutants, which are the main drivers of COPD. However, there is currently no direct evidence delineating the contribution of pericytes to COPD pathology. Although there is a lack of human clinical data, the recent available evidence derived from in vitro and animal-based models shows that pericytes play important roles in the initiation and maintenance of chronic lung diseases and are amenable to pharmacological interventions. Therefore, further studies in this field are required to elucidate if targeting pericytes can treat lung diseases.

Role of Sensory Nerves in Pulmonary Fibrosis

“…Despite their location on the vessel exterior, they are capable of associating with ECs and influencing their function [ 139 ]. Pericytes have been implicated in numerous lung diseases including PF, PH, and asthma, due to their ability to differentiate into myofibroblasts that enhance collagen deposition and drive matrix remodeling [ 140 ]. Depending on the disease context, pericytes can lead to scar formation in either the subepithelium or the pulmonary arteries [ 141 , 142 ].…”

“…Despite clear evidence of the contribution of pericytes to pulmonary vascular disease, identifying their specific contributions remains an ongoing endeavor. Within the lung, pericytes share many common markers with fibroblasts such as CD73, CD90, CD44, PDGFRα, and CD105 in addition to sharing a similar morphology [ 138 , 140 ]. Pericytes from PH patients additionally have a high degree of transcriptional similarity to SMCs [ 143 , 144 ].…”

“…The disruption of pericyte recruitment can attenuate pulmonary arterial muscularization, reduce disease severity, and restore hemodynamic parameters in the lung [ 153 ]. In addition, increased pericyte recruitment to vessels caused by a loss of prolyl hydroxylase domain protein 2 in ECs leads to perivascular fibrosis, right ventricular hypertrophy, and PH independent from any other stimuli [ 140 ]. Hypertrophic airway smooth muscles can limit apoptosis in neighboring myofibroblasts [ 154 ], and such effects may further the vascular remodeling observed in pulmonary vessels.…”

“…Pericytes are important regulators of angiogenesis [ 144 , 155 ] and may contribute to the differential response between the proangiogenic response in the nonfibrotic region of the lungs and vessel rarefaction in the fibrotic region of the lungs. Pericytes express VEGF receptors, which can stabilize vascular integrity and promote endothelial tube formation in the brain [ 140 , 156 ]. In contrast, findings from Yuan et al illustrate that pericyte dysfunction following CH contributes to the loss of microvessels in the lung [ 144 ].…”

“…Pericytes are also capable of regulating arterial diameter. They express the contractile proteins SM22 and α-smooth muscle actin [ 137 , 140 ]. Perivascular pericytes can increase contractile forces produced by SMCs [ 140 ].…”