Balanced Wnt/Dickkopf1 signaling by mesenchymal vascular progenitor cells in the microvascular niche maintains distal lung structure and function

Abstract

The well described Wnt inhibitor Dickkopf-1 (DKK1) plays a role in angiogenesis as well as regulation of growth factor signaling cascades in pulmonary remodeling associated with chronic lung diseases including emphysema and fibrosis. However, the specific mechanisms by which DKK1 influences mesenchymal vascular progenitor (MVPC), endothelial and smooth muscle cells within the microvascular niche have not been elucidated. In this study, we show that knock down of DKK1 in Abcg2pos lung mouse adult tissue resident MVPC alters lung stiffness, parenchymal collagen deposition, microvessel muscularization and density as well as loss of tissue structure in response to hypoxia exposure. To complement the in vivo mouse modeling, we also identified cell or disease specific responses to DKK1, in primary lung COPD MVPC, COPD MVEC and SMC, supporting a paradoxical disease specific response of cells to well-characterized factors. Cell responses to DKK1 were dose dependent and correlated with varying expression of the DKK1 receptor, CKAP4. These data demonstrate that DKK1 expression is necessary to maintain the microvascular niche while its effects are context specific. They also highlight DKK1 as a regulatory candidate to understand the role of Wnt and DKK1 signaling between cells of the microvascular niche during tissue homeostasis and during the development of chronic lung diseases.