Development of an in vitro human lung organoid system to study alveolar type 2 stem cell maintenance and dysfunction during disease
type: CreativeWork
description: The human adult distal lung parenchyma is maintained by alveolar type 2 (hAT2) cells that have the ability to self-renew and differentiate into alveolar type 1 (hAT1) cells, a critical cell type involved in gas-exchange. Cellular damage within the alveoli can lead to severe lung dysfunction, and major alveolar defects are characteristic of a number of incurable lung diseases, including Idiopathic pulmonary fibrosis (IPF). The appearance of aberrant cell types within disease-associated honeycomb regions of the distal lung are a hallmark of human IPF. However, the role of hAT2 cells in IPF development has not been fully explored, partially due to current in vitro human alveolar models failing to maintain hAT2 identity, limiting their study. Therefore, development of alternative platforms are essential for elucidation of hAT2 maintenance during alveolar homeostasis and their potential dysfunction during disease. Utilising primary adult hAT2 cells isolated from human distal lung samples, I successfully developed and characterised a novel in vitro 3D organoid platform that allowed for long-term hAT2 maintenance in chemically-defined conditions. Cultured hAT2-derived organoids underwent clonal expansion, were functionally mature and exhibited maintenance of differentiation capacity. High Wnt signalling and FGF7 presence were found to be essential for primary hAT2 self-renewal, while reduction of Wnt signalling led to hAT1 differentiation. To understand hAT2 dysregulation during disease, hypoxia was used to mimic an aspect of the IPF lung environment. Culture of healthy hAT2 cells in hypoxic conditions resulted in aberrant differentiation of hAT2 cells to SOX2-expressing airway-like cells. These cells exhibited higher proliferative capacity than normal hAT2 cells, with inhibition of Notch signalling resulting in a reduction in both the number of proliferative cells and SOX2+ organoids, indicating that hypoxia-induced induction of SOX2 in hAT2 cells may function through Not…
abstract: The human adult distal lung parenchyma is maintained by alveolar type 2 (hAT2) cells that have the ability to self-renew and differentiate into alveolar type 1 (hAT1) cells, a critical cell type involved in gas-exchange. Cellular damage within the alveoli can lead to severe lung dysfunction, and major alveolar defects are characteristic of a number of incurable lung diseases, including Idiopathic pulmonary fibrosis (IPF). The appearance of aberrant cell types within disease-associated honeycomb regions of the distal lung are a hallmark of human IPF. However, the role of hAT2 cells in IPF development has not been fully explored, partially due to current in vitro human alveolar models failing to maintain hAT2 identity, limiting their study. Therefore, development of alternative platforms are essential for elucidation of hAT2 maintenance during alveolar homeostasis and their potential dysfunction during disease. Utilising primary adult hAT2 cells isolated from human distal lung samples, I successfully developed and characterised a novel in vitro 3D organoid platform that allowed for long-term hAT2 maintenance in chemically-defined conditions. Cultured hAT2-derived organoids underwent clonal expansion, were functionally mature and exhibited maintenance of differentiation capacity. High Wnt signalling and FGF7 presence were found to be essential for primary hAT2 self-renewal, while reduction of Wnt signalling led to hAT1 differentiation. To understand hAT2 dysregulation during disease, hypoxia was used to mimic an aspect of the IPF lung environment. Culture of healthy hAT2 cells in hypoxic conditions resulted in aberrant differentiation of hAT2 cells to SOX2-expressing airway-like cells. These cells exhibited higher proliferative capacity than normal hAT2 cells, with inhibition of Notch signalling resulting in a reduction in both the number of proliferative cells and SOX2+ organoids, indicating that hypoxia-induced induction of SOX2 in hAT2 cells may function through Not…
author: Evans, Kelly
language: eng
keywords: Organoids, Human lung, Human stem cells, Alveolar stem cells, Human lung disease, Idiopathic pulmonary fibrosis
license: http://purl.org/NET/rdflicense/allrightsreserved
date published: 2021-11-01
date modified: 2026-07-22T22:23:59Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.85289