Platelet-derived Growth Factor-α and Neuropilin-1 Mediate Lung Fibroblast Response to Rigid Collagen Fibers
| Autor: | Alexei V. Tivanski, Lien Zhu, Diann M. McCoy, Thiranjeewa I. Lansakara, Stephen E. McGowan |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Pulmonary and Respiratory Medicine Platelet-derived growth factor Clinical Biochemistry Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Alveolar duct Neuropilin 1 medicine Animals Mechanotransduction Myofibroblasts Fibroblast Lung Molecular Biology Platelet-Derived Growth Factor Focal Adhesions Chemistry Cell Biology Fibroblasts respiratory system Actins Neuropilin-1 Extracellular Matrix Cell biology Pulmonary Alveoli 030104 developmental biology medicine.anatomical_structure 030228 respiratory system Female Collagen Saccule Myofibroblast Signal Transduction |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 62:454-465 |
| ISSN: | 1535-4989 1044-1549 |
| DOI: | 10.1165/rcmb.2019-0173oc |
| Popis: | During pulmonary secondary alveolar septation, the rudimentary distal saccule subdivides by extending tissue sheets into the saccular air space, creating alveoli, which open into the alveolar duct. The sheets originate from saccular mesenchymal cells, which contain α-SMA (αSMA [ACTA2]) and abut elastic fibers (myofibroblasts [MF]), characteristics that are shared by cells that subsequently occupy the secondary septal tips. During elongation, collagen fibers are positioned to provide a scaffold for translocating septal mesenchymal cells. We hypothesized that collagen fibers direct the migration, orientation, and location of MFs during septal elongation. To address this hypothesis, we examined how electrospun collagen fibers direct the migration of fibroblasts bearing targeted deletions of PDGFRα (platelet-derived growth factor receptor-α) or Nrp1 (neuropilin-1), after their isolation from lungs that exhibit reduced secondary septation. We observed that deletion of either gene reduced Rac1 activation and the speed of migration of lung fibroblasts (LF) along electrospun fibers. The deletions did not reduce the proportion of LF that displayed collagen-binding integrins and increased the proportion of LF bearing activated β1-integrin. LF bearing the PDGFRα deletion failed to localize focal adhesions over electrospun fibers, suggesting that they may not appropriately sense and respond to regionally increased stiffness near the fibers. In lungs of mice bearing the PDGFRα deletion, collagen fibers are delocalized from ACTA2-containing MF, and their orientation deviated from the plane of the alveolar walls. Diminished PDGFRα or Nrp1 reduces LF localization to stiffer regions of fibrillar collagen substrates, suggesting that signaling through these receptors enables responsiveness to regional differences in extracellular matrix rigidity. |
| Databáze: | OpenAIRE |
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