Abstract
Pulmonary fibrosis is a severely disabling disease often leading to death. CCN2 (Cellular Communication Network factor 2, also known as CTGF) is a known mediator of fibrosis and clinical trials studying anti-CCN2 efficacy in pulmonary fibrosis are currently underway. Fork head box D1 (FoxD1) transcription factor is transiently expressed in several mesenchymal cell types, including those of fetal lungs. Differentiation of FoxD1-progenitor derived pericytes into myofibroblasts involves CCN2 expression and contributes importantly to maladaptive tissue remodeling in e.g. kidney and lung fibrosis models. To generate a model for studying the contribution of CCN2 expression in FoxD1-progenitor derived cells to development of fibrotic tissue remodeling, we set out to establish a FoxD1Cre - CCN2flox/flox mouse colony. However, all double-transgenic mice died soon after birth due to asphyxia. Histopathological examination revealed a reduction in alveolar space and lung weight, and subtle axial (thoracic and cervical) skeletal deformities. Together with the previously reported association of a FoxD1 containing locus with human adolescent idiopathic scoliosis, our data suggest that the development of fatal pulmonary hypoplasia caused by selective deletion of CCN2 from FoxD1-progenitor derived mesenchymal cells was secondary to aberrant axial skeletogenesis.
Highlights
IntroductionPulmonary fibrosis is a very severe and life-threatening disease characterized by interstitial fibrosis in the lung parenchyma leading to reduced lung and diffusion capacity, with consequent respiratory failure and often death
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Pulmonary fibrosis is a very severe and life-threatening disease characterized by interstitial fibrosis in the lung parenchyma leading to reduced lung and diffusion capacity, with consequent respiratory failure and often death
We show that loss of Communication Network factor 2 (CCN2) from Fork head box D1 (FoxD1)-lineage cells leads to aberrant lung morphology with post-natal asphyxiation, and axial skeletal deformities
Summary
Pulmonary fibrosis is a very severe and life-threatening disease characterized by interstitial fibrosis in the lung parenchyma leading to reduced lung and diffusion capacity, with consequent respiratory failure and often death. Fibrosis is the final common pathway of maladaptive tissue remodeling and loss of organ function. Cellular Communication Network factor 2 (CCN2; known as Connective Tissue Growth Factor, CTGF) is an important mediator of fibrosis in virtually all organs, including the kidneys and the lungs (Pan et al 2001; Wang et al 2019). Myofibroblasts are the main effector cells during tissue fibrosis. Transformation of mesenchyme derived lung pericytes contributes importantly to the increase in myofibroblast numbers during pulmonary and kidney fibrosis a process known to be CCN2 dependent (Shiwen et al 2009; Hung et al 2013)
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