Delineating late foetal human lung development and maturation
Lead Research Organisation:
University College London
Department Name: Medicine
Abstract
Our understanding of how the lung develops is very poor. Addressing this is really important because we can work out how to help premature babies and how to regenerate lungs to help those with severe lung disease. End-stage lung disease of any cause is a major global health problem. On the other hand, the death rate and problems arising from premature birth are mostly caused by the fact that the lung is too immature or underdeveloped to function as opposed to in healthy term babies. This is despite the use of some treatments such as steroids which do not overcome the long-term effects of premature birth on lung function as an adult.
I have already made important discoveries to understand lung development. This was made using human embryonic and foetal lungs up to 20 weeks post-conception - notably I have developed a 3D culture system which can be used to study human lung development in a dish. My work also includes how immune cells interact with the developing lung using various, cutting edge molecular methods that can look at each cell individually. The period of development after 20 weeks to birth is virtually unexplored and is referred to as the "gap" in the scientific world. In close collaboration with obstetricians and other doctors at UCL, I have designed a way of receiving fresh healthy tissue from any organ from this crucial period of development during the final part of pregnancy.
My aims will be 1) to study how the lining of the lung matures, 2) to study how the immune system matures within the lung and also elsewhere in our body, 3) to study how blood vessels mature and how they interact with the lung lining to make a functioning gas exchange unit, allowing oxygen to be transported into the blood compartment and carbon dioxide to be transferred into the air compartment, and finally 4) to set up a late foetal tissue resource for the other research groups working on the maturation of other organs.
My overall objective is to study late stage foetal human lung development and maturation, which has the potential for wide-reaching impact on various fields, most notably to improve survival in premature babies and to find ways to reverse the effects of severe lung disease.
I have already made important discoveries to understand lung development. This was made using human embryonic and foetal lungs up to 20 weeks post-conception - notably I have developed a 3D culture system which can be used to study human lung development in a dish. My work also includes how immune cells interact with the developing lung using various, cutting edge molecular methods that can look at each cell individually. The period of development after 20 weeks to birth is virtually unexplored and is referred to as the "gap" in the scientific world. In close collaboration with obstetricians and other doctors at UCL, I have designed a way of receiving fresh healthy tissue from any organ from this crucial period of development during the final part of pregnancy.
My aims will be 1) to study how the lining of the lung matures, 2) to study how the immune system matures within the lung and also elsewhere in our body, 3) to study how blood vessels mature and how they interact with the lung lining to make a functioning gas exchange unit, allowing oxygen to be transported into the blood compartment and carbon dioxide to be transferred into the air compartment, and finally 4) to set up a late foetal tissue resource for the other research groups working on the maturation of other organs.
My overall objective is to study late stage foetal human lung development and maturation, which has the potential for wide-reaching impact on various fields, most notably to improve survival in premature babies and to find ways to reverse the effects of severe lung disease.
Technical Summary
End-stage lung disease is a major global health problem and understanding normal human lung development is an essential part of regenerative medicine. At the same time, the mortality and morbidity associated with prematurity is mostly caused by lung immaturity, despite the use of antenatal corticosteroids, which do not overcome the longterm effects of prematurity on lung function. I have made various important discoveries using human embryonic and foetal lungs up to 20 weeks post-conception - notably I have developed a genetically-modifiable organoid culture system which can be used to study human lung development in vitro. My work also includes developmental immunobiology in the lung using scRNAseq and novel approaches such as CITE-seq. The period of development after 20 weeks to birth is virtually unexplored and is referred to as the "gap". In close collaboration with obstetricians and histopathologists at UCL, I have designed a tractable way of receiving fresh healthy tissue from any organ from this crucial period of in utero development.
My aims are 1) to study late foetal epithelial maturation in the lung by scRNAseq, spatial transcriptomics and organoids in order to identify novel regulators in alveolar cell fate specification, 2) to study late foetal maturation of the immune system and whether the immune system in turn affects lung epithelial differentiation, 3) to study lung vascular maturation and the mechanism of endothelial-epithelial interactions to make a functioning gas exchange unit at the air-blood interface, and finally 4) to set up a late foetal tissue resource for the Human Cell Atlas, to facilitate functional work on other organs.
My overall objective is to delineate late foetal human lung development and maturation, which has the potential for wide-reaching impact on the whole field of lung developmental biology, lung regeneration and neonatal medicine.
My aims are 1) to study late foetal epithelial maturation in the lung by scRNAseq, spatial transcriptomics and organoids in order to identify novel regulators in alveolar cell fate specification, 2) to study late foetal maturation of the immune system and whether the immune system in turn affects lung epithelial differentiation, 3) to study lung vascular maturation and the mechanism of endothelial-epithelial interactions to make a functioning gas exchange unit at the air-blood interface, and finally 4) to set up a late foetal tissue resource for the Human Cell Atlas, to facilitate functional work on other organs.
My overall objective is to delineate late foetal human lung development and maturation, which has the potential for wide-reaching impact on the whole field of lung developmental biology, lung regeneration and neonatal medicine.
Publications
Guo SA
(2023)
Obesity Is Associated with Attenuated Tissue Immunity in COVID-19.
in American journal of respiratory and critical care medicine
Kumasaka N
(2023)
Mapping interindividual dynamics of innate immune response at single-cell resolution.
in Nature genetics
Madissoon E
(2023)
A spatially resolved atlas of the human lung characterizes a gland-associated immune niche.
in Nature genetics
Sikkema L
(2022)
An integrated cell atlas of the human lung in health and disease
Sikkema L
(2023)
An integrated cell atlas of the lung in health and disease
in Nature Medicine
Urciuolo A
(2023)
Hydrogel-in-hydrogel live bioprinting for guidance and control of organoids and organotypic cultures.
in Nature communications
Description | Dissecting the role of mechanical lung compression in Congenital Diaphragmatic Hernia on a single cell level |
Amount | £243,891 (GBP) |
Funding ID | V5021 |
Organisation | Great Ormond Street Hospital Children's Charity (GOSHCC) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2022 |
End | 07/2025 |
Description | High-throughput drug screening for identification of novel therapeutic targets for lung regeneration |
Amount | £12,600 (GBP) |
Funding ID | PhD2022 100046 |
Organisation | Rosetrees Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 10/2022 |
End | 04/2023 |
Description | Study of human late fetal lung tissue and 3D in vitro organoids to replace and reduce animals in lung developmental research |
Amount | £120,000 (GBP) |
Funding ID | NC/X001644/1 |
Organisation | National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) |
Sector | Public |
Country | United Kingdom |
Start | 01/2023 |
End | 12/2026 |
Description | "Lung development in health and disease" (invited seminar by Cambridge University Respiratory Research Seminars) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | Invited seminar |
Year(s) Of Engagement Activity | 2022 |
Description | "Lung development in health and disease" (invited seminar speaker at Edinburgh University) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | invited seminar - Centre for Regenerative Medicine, Edinburgh University |
Year(s) Of Engagement Activity | 2022 |
Description | Invited speaker at British Thoracic Society Winter Meeting: "Can we fix it? Possibilities for lung regeneration" |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | International Respiratory conference talk - invited speaker |
Year(s) Of Engagement Activity | 2022 |
Description | Nature webinar with panel discussion "Local and systemic responses to SARS-CoV-2 infection in children and adults" |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | webinar organised by Nature, sponsored by 10x, presentation with panel discussion |
Year(s) Of Engagement Activity | 2022 |
Description | UCL Grand Round: "Mechanisms of why children are generally protected from severe COVID-19" |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | invited Grand Round talk |
Year(s) Of Engagement Activity | 2022 |