Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina , Charleston, South Carolina.
Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina , Charleston, South Carolina.
Am J Physiol Lung Cell Mol Physiol. 2018 Dec 1;315(6):L991-L1002. doi: 10.1152/ajplung.00289.2018. Epub 2018 Oct 18.
Pericytes are key regulators of the microvasculature through their close interactions with the endothelium. However, pericytes play additional roles in tissue homeostasis and repair, in part by transitioning into myofibroblasts. Accumulation of myofibroblasts is a hallmark of fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). To understand the contribution and role of pericytes in human lung fibrosis, we isolated these cells from non-IPF control and IPF lung tissues based on expression of platelet-derived growth factor receptor-β (PDGFR-β), a common marker of pericytes. When cultured in a specialized growth medium, PDGFR-β+ cells retain the morphology and marker profile typical of pericytes. We found that IPF pericytes migrated more rapidly and invaded a basement membrane matrix more readily than control pericytes. Exposure of cells to transforming growth factor-β, a major fibrosis-inducing cytokine, increased expression of α-smooth muscle actin and extracellular matrix genes in both control and IPF pericytes. Given that pericytes are uniquely positioned in vivo to respond to danger signals of both systemic and tissue origin, we stimulated human lung pericytes with agonists having pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). Both control and IPF lung pericytes increased expression of proinflammatory chemokines in response to specific PAMPs and DAMPs released from necrotic cells. Our results suggest that control and IPF lung pericytes are poised to react to tissue damage, as well as microbial and fibrotic stimuli. However, IPF pericytes are primed for migration and matrix invasion, features that may contribute to the function of these cells in lung fibrosis.
周细胞通过与内皮细胞的紧密相互作用，成为微血管的关键调节因子。然而，周细胞在组织稳态和修复中发挥额外的作用，部分是通过向肌成纤维细胞转化。肌成纤维细胞的积累是特发性肺纤维化 (IPF) 等纤维化疾病的标志。为了了解周细胞在人类肺纤维化中的贡献和作用，我们根据血小板衍生生长因子受体-β (PDGFR-β) 的表达，从非 IPF 对照和 IPF 肺组织中分离这些细胞，PDGFR-β 是周细胞的常见标志物。当在专门的生长培养基中培养时，PDGFR-β+细胞保留了周细胞典型的形态和标志物特征。我们发现，与对照周细胞相比，IPF 周细胞迁移速度更快，更容易侵入基底膜基质。细胞暴露于转化生长因子-β (TGF-β) ，一种主要的纤维化诱导细胞因子，增加了对照和 IPF 周细胞中α-平滑肌肌动蛋白和细胞外基质基因的表达。鉴于周细胞在体内独特的位置，能够对来自全身和组织来源的危险信号做出反应，我们用具有病原体相关分子模式 (PAMP) 或损伤相关分子模式 (DAMP) 的激动剂刺激人肺周细胞。对照和 IPF 肺周细胞都对来自坏死细胞的特定 PAMP 和 DAMPs 做出反应，增加了促炎趋化因子的表达。我们的研究结果表明，对照和 IPF 肺周细胞能够对组织损伤以及微生物和纤维化刺激做出反应。然而，IPF 周细胞已经为迁移和基质侵袭做好了准备，这些特征可能有助于这些细胞在肺纤维化中的功能。
