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Balanced Wnt/Dickkopf1 signaling by mesenchymal vascular progenitor cells in the microvascular niche maintains distal lung structure and function
American Journal of Physiology-Cell Physiology ( IF 5.0 ) Pub Date : 2020-10-21 , DOI: 10.1152/ajpcell.00277.2020
Megan E Summers 1 , Bradley W Richmond 2, 3 , Jonathan A Kropski 2, 3 , Sarah A Majka 1 , Julie A Bastarache 2, 3 , Antonis K Hatzopoulos 2, 3 , Jeffery Bylund 2, 3 , Moumita Ghosh 1 , Irina Petrache 1 , Robert F Foronjy 4 , Patrick Geraghty 4 , Susan M Majka 1, 5, 6
Affiliation  

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.

中文翻译:


微血管生态位中间充质血管祖细胞平衡的 Wnt/Dickkopf1 信号传导维持远端肺结构和功能



充分描述的 Wnt 抑制剂 Dickkopf-1 (DKK1) 在血管生成以及与慢性肺病(包括肺气肿和纤维化)相关的肺重塑中生长因子信号级联的调节中发挥作用。然而,DKK1影响微血管微生境内的间充质血管祖细胞(MVPC)、内皮细胞和平滑肌细胞的具体机制尚未阐明。在这项研究中,我们发现敲除 Abcg2 pos小鼠肺成体组织 MVPC 中的 DKK1 会改变肺硬度、实质胶原蛋白沉积、微血管肌肉化和密度以及响应缺氧暴露的组织结构损失。为了补充体内小鼠模型,我们还在原发性肺 COPD MVPC、COPD MVEC 和 SMC 中鉴定了对 DKK1 的细胞或疾病特异性反应,支持细胞对充分表征的因素的矛盾疾病特异性反应。细胞对 DKK1 的反应呈剂量依赖性,并与 DKK1 受体 CKAP4 的不同表达相关。这些数据表明 DKK1 表达对于维持微血管生态位是必要的,而其作用是特定于环境的。他们还强调 DKK1 作为一种调控候选者,以了解组织稳态和慢性肺部疾病发展过程中微血管生态位细胞之间 Wnt 和 DKK1 信号传导的作用。
更新日期:2020-10-27
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