Understanding Mechanisms Driving Lung Disease Caused by Environmental Particulate Matter
Lead Research Organisation:
University of Nottingham
Department Name: School of Medicine
Abstract
Collectively, respiratory diseases are the leading cause of death worldwide. As a consequence respiratory research has increased by 500% and animal models have supported approximately 20% of this research. More than 900,000 mice have been used in the last decade alone to help understand human respiratory health, however, the physiological and anatomic differences between the human and mouse lungs have made it difficult to translate research findings into human therapies. Inhalation research focuses on the effect of inhaled chemicals, particles, bacteria, viruses, drug delivery systems and pollution in both healthy lung and diseased lungs. The most widely used human specific models of the human lung are cell-based models that focus on lung epithelial cells, the cells that make up the surface of the lungs. While these models are useful to model the response of epithelium to inhaled substances, the whole lung response is extremely important and encompasses complex cell-to-cell interactions and signalling, immune cells and extracellular matrix modifications that currently only mouse models can fully replicate, hence their over-use.
We will address this gap in model platforms by creating a multi-cell type, immune competent model of human lung alveoli that is animal-free, capable of stretching and applicable to many areas of respiratory research. To achieve this we will use stem cell derived type II alveoli epithelial cells with macrophages, fibroblasts and endothelial cells in a synthetic hydrogel developed by our industrial partner Manchester BIOGEL. We will demonstrate application of the model to understand how atmospheric particulate matter, the most significant environmental pollutant in the world, affects lung health. The objectives below will provide an opportunity for a "next-generation" model of the human lung alveoli, capable of modelling epithelial response, fibrosis as well as that of the immune system and could provide important mechanistic, diagnostic and therapeutic information across many areas of respiratory research.
1): Combine hIPSC derived lung cell types into synthetic animal-free hydrogels.
We will bring together our stem cell derived type II alveoli epithelial cells, with macrophages, fibroblasts and endothelial cells in a synthetic hydrogel to generate a 3D multi-cell-type, immune competent organoid model of the human lung alveoli. We will characterise structure of the organoid in different hydrogel formulations that mimic fibrosis both with and without stretch forces. We will then compare and validate individual cell behaviour to human precision cut lung slices cultured under equivalent conditions.
2) Understand the impact of particulate matter on lung alveoli tissue
To further demonstrate application of the model we will expose the alveoli organoids to environmental particulate matter in different hydrogel and stretch characteristics identified in Obj 1. We will then characterise the response of each cell type and compare and validate the response using human precision cut lung slices as in Obj 1.
3) Educate and train new users in development and manipulation of hIPSC derived alveoli organoids.
We will host a conference focussed on current animal free models of human health and disease to educate current and future research leaders in use and development of animal-free models of human health. We will also host a 1-week training course for researchers that would like to adopt and use our model for their own research purposes.
Together these objective will create a "next generation" model of human alveoli tissue applicable that could reduce and replace animal models across many different respiratory diseases. Importantly, there will be training opportunities provided to other researchers that will allow them to adopt and modify the model to their own experimental needs, further enhancing the possibility that the platform will have a positive impact in reducing animal use in research.
We will address this gap in model platforms by creating a multi-cell type, immune competent model of human lung alveoli that is animal-free, capable of stretching and applicable to many areas of respiratory research. To achieve this we will use stem cell derived type II alveoli epithelial cells with macrophages, fibroblasts and endothelial cells in a synthetic hydrogel developed by our industrial partner Manchester BIOGEL. We will demonstrate application of the model to understand how atmospheric particulate matter, the most significant environmental pollutant in the world, affects lung health. The objectives below will provide an opportunity for a "next-generation" model of the human lung alveoli, capable of modelling epithelial response, fibrosis as well as that of the immune system and could provide important mechanistic, diagnostic and therapeutic information across many areas of respiratory research.
1): Combine hIPSC derived lung cell types into synthetic animal-free hydrogels.
We will bring together our stem cell derived type II alveoli epithelial cells, with macrophages, fibroblasts and endothelial cells in a synthetic hydrogel to generate a 3D multi-cell-type, immune competent organoid model of the human lung alveoli. We will characterise structure of the organoid in different hydrogel formulations that mimic fibrosis both with and without stretch forces. We will then compare and validate individual cell behaviour to human precision cut lung slices cultured under equivalent conditions.
2) Understand the impact of particulate matter on lung alveoli tissue
To further demonstrate application of the model we will expose the alveoli organoids to environmental particulate matter in different hydrogel and stretch characteristics identified in Obj 1. We will then characterise the response of each cell type and compare and validate the response using human precision cut lung slices as in Obj 1.
3) Educate and train new users in development and manipulation of hIPSC derived alveoli organoids.
We will host a conference focussed on current animal free models of human health and disease to educate current and future research leaders in use and development of animal-free models of human health. We will also host a 1-week training course for researchers that would like to adopt and use our model for their own research purposes.
Together these objective will create a "next generation" model of human alveoli tissue applicable that could reduce and replace animal models across many different respiratory diseases. Importantly, there will be training opportunities provided to other researchers that will allow them to adopt and modify the model to their own experimental needs, further enhancing the possibility that the platform will have a positive impact in reducing animal use in research.
Technical Summary
The mouse is the primary model in respiratory research as it provides whole organ data on disease mechanisms. Human specific models focus only on epithelial cells leaving significant gaps in our understanding of disease mechanisms. What is desperately needed is a human specific, multi-cell-type, immune competent model of the lungs.
We will address this need by creating a human specific, multi-cell type, immune competent model of human lung alveoli that is animal-free, capable of stretching and applicable to many areas of respiratory research. We will apply the model to understand how atmospheric particulate matter affects lung health. The objectives below will provide an opportunity for a human specific, multi-cell-type and immune competent model of the human lung alveoli that could provide important mechanistic, diagnostic and therapeutic information across many areas of respiratory research.
1): Combine hIPSC derived lung cell types into synthetic animal-free hydrogels.
We will bring together stem cell derived type II alveoli epithelial cells, with macrophages, fibroblasts and endothelial cells in a synthetic hydrogel to generate a 3D human alveoli organoids and compare these to human precision cut lung slices.
2) Understand the impact of particulate matter on lung alveoli tissue.
We will expose the alveoli organoids to environmental particulate matter and characterise the response of each cell type and validate against the response of precision cut lung slices.
3) Educate and train new users in development and manipulation of hIPSC derived alveoli organoids.
We will host a conference focussed on animal free models of human health and disease as well as a 1-week training course for researchers that would like to adopt and use our model.
Together these objectives will create a new human specific model of human alveoli tissue applicable to a broad number a respiratory research areas, that could reduce and replace >90,000 mice in the next decade.
We will address this need by creating a human specific, multi-cell type, immune competent model of human lung alveoli that is animal-free, capable of stretching and applicable to many areas of respiratory research. We will apply the model to understand how atmospheric particulate matter affects lung health. The objectives below will provide an opportunity for a human specific, multi-cell-type and immune competent model of the human lung alveoli that could provide important mechanistic, diagnostic and therapeutic information across many areas of respiratory research.
1): Combine hIPSC derived lung cell types into synthetic animal-free hydrogels.
We will bring together stem cell derived type II alveoli epithelial cells, with macrophages, fibroblasts and endothelial cells in a synthetic hydrogel to generate a 3D human alveoli organoids and compare these to human precision cut lung slices.
2) Understand the impact of particulate matter on lung alveoli tissue.
We will expose the alveoli organoids to environmental particulate matter and characterise the response of each cell type and validate against the response of precision cut lung slices.
3) Educate and train new users in development and manipulation of hIPSC derived alveoli organoids.
We will host a conference focussed on animal free models of human health and disease as well as a 1-week training course for researchers that would like to adopt and use our model.
Together these objectives will create a new human specific model of human alveoli tissue applicable to a broad number a respiratory research areas, that could reduce and replace >90,000 mice in the next decade.