Tenascin-C inactivation impacts lung structure and function beyond lung development

Abstract

Johannes c. Schittny 4 & tiziana p. cremona 4 tenascin-c (tnc) is an extracellular matrix protein expressed at high levels during lung organogenesis. Later, tnc is only transiently de novo expressed to orchestrate tissue repair in pathological situations. We previously showed that TNC inactivation affects lung development and thus evaluated here the implications on lung function in newborn/adult mice. Respiratory function parameters were measured in anesthetized and mechanically ventilated wild-type (WT) and TNC-deficient mice at 5 (P5) and 90 (P90) days of age under basal conditions, as well as following high tidal volume (HTV) ventilation. At P5, TNC-deficient mice showed an increased static compliance (Cst) and inspiratory capacity (IC) relative to WT at baseline and throughout HTV. At P90, however, Cst and IC were only elevated at baseline. Control non-ventilated newborn and adult TNC-deficient mice showed similar lung morphology, but less alpha smooth muscle actin (α-SMA) around small airways. SMA + cells were decreased by 50% in adult TNCdeficient lungs and collagen layer thickened around small airways. Increased surfactant protein C (SPc) and altered tGfβ and TLR4 signaling pathways were also detected. Thus, TNC inactivation-related defects during organogenesis led to persisting functional impairment in adulthood. this might be of interest in the context of pulmonary diseases with thickened airway smooth muscle layer or ventilation heterogeneity, like asthma and COPD.

Single cell transcriptomic analysis of murine lung development on hyperoxia-induced damage

“…6a ). Tnc contributes to normal alveolarization and development of lung SMCs 42 and protects from hyperoxia-induced lung injury 43 .…”

The Role of the ECM in Lung Cancer Dormancy and Outgrowth

“…It is highly expressed in lung development during branching morphogenesis and alveolarization. However, in adult lungs it is only transiently expressed in response to injury ( 76 ). Loss of tenascin-C during lung development alters TGFβ signaling, reduces fibroblast to myofibroblast transformation and increases collagen deposition in small airways ( 76 ).…”

“…However, in adult lungs it is only transiently expressed in response to injury ( 76 ). Loss of tenascin-C during lung development alters TGFβ signaling, reduces fibroblast to myofibroblast transformation and increases collagen deposition in small airways ( 76 ). Conversely, in response to injury, Tenascin-C stimulates TGFβ responsiveness to promote collagen deposition and fibrosis ( 77 ).…”

Fgf10/Fgfr2b Signaling Orchestrates the Symphony of Molecular, Cellular, and Physical Processes Required for Harmonious Airway Branching Morphogenesis

“…TNC also serves as a binding partner to many ligands and morphogens diffusing through the ECM (De Laporte et al, 2013 ). It is unsurprising, therefore, that TNC has consistently been shown to be critical for proper lung branching morphogenesis (Roth-Kleiner et al, 2004 ; Gebb et al, 2005 ; Spurlin et al, 2019 ; Gremlich et al, 2020 ).…”