McGowan Stephen E, McCoy Diann M
Department of Veterans Affairs Research Service and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa
Department of Veterans Affairs Research Service and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa.
Am J Physiol Lung Cell Mol Physiol. 2017 Dec 1;313(6):L1174-L1187. doi: 10.1152/ajplung.00185.2017. Epub 2017 Aug 3.
Platelet-derived growth factor (PDGF)-A, which only signals through PDGF-receptor-α (PDGFR-α), is required for secondary alveolar septal formation. Although PDGFR-α distinguishes mesenchymal progenitor cells during the saccular stage, PDGFR-α-expressing alveolar cells persist through adulthood. PDGF-A sustains proliferation, limits apoptosis, and maintains α-smooth muscle actin (α-SMA)-containing alveolar cells, which congregate at the alveolar entry ring at postnatal day (P)12. PDGFR-α-expressing, α-SMA-containing alveolar cells redistribute in the elongating septum, suggesting that they migrate to the alveolar entry rings, where mechanical tension is higher. We hypothesized that PDGFR-α and Ras-related C3 botulinum toxin substrate 1(Rac1) are required for mechanosensitive myofibroblast migration. Spreading of PDGFR-α-deficient lung fibroblasts was insensitive to increased rigidity, and their migration was not reduced by Rac1-guanine exchange factor (GEF)-inhibition. PDGFR-α-expressing fibroblasts migrated toward stiffer regions within two-dimensional substrates by increasing migrational persistence (durotaxis). Using a Förster resonance energy transfer (FRET) biosensor for Rac1-GTP, we observed that PDGFR-α was required for fibroblast Rac1 responsiveness to stiffness within a three-dimensional collagen substrate, which by itself increased Rac1-FRET. Rho-GTPase stabilized, whereas Rac1-GTPase increased the turnover of focal adhesions. Under conditions that increased Rac1-GTP, PDGFR-α signaled through both phosphoinositide-3-kinase (PIK) or Src to engage the Rac1 GEF dedicator of cytokinesis-1 (Dock180) and p21-activated-kinase interacting exchange factor-β (βPIX). In cooperation with collagen fibers, these signaling pathways may guide fibroblasts toward the more rigid alveolar entry ring during secondary septation. Because emphysema and interstitial fibrosis disrupt the parenchymal mechanical continuum, understanding how mechanical factors regulate fibroblast migration could elicit strategies for alveolar repair and regeneration.
血小板衍生生长因子A（PDGF - A）仅通过血小板衍生生长因子受体α（PDGFR - α）发出信号，是次级肺泡间隔形成所必需的。尽管PDGFR - α在囊状期可区分间充质祖细胞，但表达PDGFR - α的肺泡细胞会持续存在至成年期。PDGF - A可维持增殖、限制细胞凋亡，并维持含α平滑肌肌动蛋白（α - SMA）的肺泡细胞，这些细胞在出生后第12天聚集在肺泡入口环处。表达PDGFR - α、含α - SMA的肺泡细胞在延长的间隔中重新分布，这表明它们迁移到了机械张力较高的肺泡入口环处。我们假设PDGFR - α和Ras相关的C3肉毒杆菌毒素底物1（Rac1）是机械敏感型肌成纤维细胞迁移所必需的。缺乏PDGFR - α的肺成纤维细胞的铺展对硬度增加不敏感，并且其迁移不会因Rac1 - 鸟嘌呤交换因子（GEF）抑制而减少。表达PDGFR - α的成纤维细胞通过增加迁移持续性（趋硬性）向二维基质内更硬的区域迁移。使用用于Rac1 - GTP的荧光共振能量转移（FRET）生物传感器，我们观察到在三维胶原基质中，成纤维细胞Rac1对硬度的反应需要PDGFR - α，而三维胶原基质本身会增加Rac1 - FRET。Rho - GTP酶稳定，而Rac1 - GTP酶增加粘着斑的周转。在增加Rac1 - GTP的条件下，PDGFR - α通过磷酸肌醇 - 3 - 激酶（PIK）或Src发出信号，以激活细胞分裂的Rac1 GEF胞质分裂素 - 1（Dock180）和p21活化激酶相互作用交换因子 - β（βPIX）。与胶原纤维协同作用，这些信号通路可能在次级间隔形成期间引导成纤维细胞朝向更硬的肺泡入口环迁移。由于肺气肿和间质性纤维化会破坏实质的机械连续性，了解机械因素如何调节成纤维细胞迁移可能会引出肺泡修复和再生的策略。
