113 Dysregulated cross talk between alveolar epithelial cells and stromal cells in IPF reduces epithelial regenerative capacity INTRODUCTION Idiopathic Pulmonary Fibrosis (IPF) is a progressive lung disease characterized by aberrant repair responses in the alveoli, leading to fibrosis and rapid lung function decline. A high mortality rate, while having no cure available, illustrates the urgent need to understand IPF pathogenesis to identify new therapeutic strategies [1]. The origin of the disease is still unknown, but ongoing alveolar epithelial micro-injury and aberrant interactions within the stromal micro-environment are thought to induce the abnormal alveolar regeneration and tissue repair [2]. The crosstalk between epithelial cells and their stromal niche composed of supportive cells and extracellular matrix (ECM) is critical for alveolar repair [3]. The stromal compartment includes fibroblasts, mesenchymal stromal cells, macrophages and endothelial cells, as well as ECM [4]. Emerging data suggests that stromal alterations in IPF lead to inadequate alveolar epithelial regeneration [5]. In this study we hypothesized that the crosstalk between alveolar epithelial cells and other cell types present in the fibrotic micro-environment of the lung is disrupted, resulting in reduced regenerative capacity of alveolar epithelial progenitors derived from IPF patients. We studied epithelial regenerative potential using an organoid model where alveolar epithelial progenitors were seeded into a 3-dimensional (3D) hydrogel (Matrigel) with stromal cells to recapitulate critical aspects of alveolar regeneration [6], including self-organization into 3D structures, proliferation and differentiation. MATERIALS AND METHODS Subjects Parenchymal lung tissue was derived from 10 non-IPF donors undergoing tumour resection surgery and 4 IPF donors undergoing lung transplantation surgery (characteristics are shown in Table 1). Tissue derived from the non-IPF donors was taken from anatomically normal tissue as assessed by experienced pathologists, as far away from the tumour region as possible. This protocol was consistent with the Research Code of the University Medical Center Groningen (https://www.umcg.nl/ documents/770534/2183586/umcg-research-code-2018-en.pdf/9680a460-3feb-543d7d58-bc9d4f7277de?t=1614951313016) and national ethical and professional guidelines (https://www.coreon.org/gedragscode-gezondheidsonderzoek; Code of conduct - in Dutch) 5
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