Mobilising epithelial stem cells for human lung regeneration

Lead Research Organisation: University College London
Department Name: Medicine

Abstract

Chronic lung disease is responsible for 6 million inpatient bed days a year in the UK. Chronic obstructive pulmonary disease (COPD; including emphysema) and idiopathic pulmonary fibrosis (IPF) are increasingly recognised as diseases of epithelial damage and failed epithelial regeneration, with no treatments that reverse lung function decline. Epithelial cells and tissue line the outer surfaces of organs and blood vessels throughout the body. Unfortunately, a limited amount is known about adult stem cell populations that maintain adult human lung and in particular, strategies to support or enhance epithelial regeneration do not exist.

During my prior research, I worked with Dr Emma Rawlins at Cambridge University on human lung developmental biology. Together, we developed a novel cell culture system which allowed the expansion of lung stem cells for the first time. Over the coming years, I hope to establish myself as a clinical academic group leader and the opportunity to work within the UKRMP network under Profs. Janes and Watt is an ideal opportunity to turn my basic research towards translational end points for my patients. A Fellowship at UCL Respiratory would allow me the opportunity to develop my independent work with access to adult human clinical specimens and a multitude of murine models available between the two main centres.

Aim1: I intend to develop methods to expand adult stem cells from the human lung. I will systematically evaluate the importance of individual factors within the culture medium for the expansion of adult lung stem cells. This work will be greatly facilitated by collaboration with CSCRM as the Kings Stem Cell Hotel has partnership arrangements with several companies that provide high-content imaging platforms which is ideally suited for tracking stem cell self-renewal and differentiation. These experiments will define specific factors and pathways that orchestrate epithelial stem cell self-renewal and differentiation during homeostasis.

Aim 2: Using the factors identified as controlling lung stem cell behaviour, I will examine their role in living organisms such as mice.

Aim 3: Finally, I will focus on whether manipulation of basal stem cells can be protective against injury. To test this hypothesis, I will use tracheal injury models as these are most relevant to human airway regeneration. These findings will be of broad relevance given that the pathogenesis of many chronic lung diseases, including COPD, idiopathic pulmonary fibrosis and interstitial lung disease are thought to involve repetitive epithelial injury resulting in a loss of epithelial stem cells.

Technical Summary

Chronic lung disease is responsible for 6 million inpatient bed days a year in the UK. Chronic obstructive pulmonary disease (COPD; including emphysema) and idiopathic pulmonary fibrosis (IPF) are increasingly recognised as diseases of epithelial damage and failed epithelial regeneration, with no treatments that reverse lung function decline. Unfortunately, a limited amount is known about adult stem cell populations that maintain adult human lung and in particular, strategies to support or enhance epithelial regeneration do not yet exist.

During prior research, with Dr Emma Rawlins (Cambridge University) on human lung developmental biology, I developed a novel cell culture system which allowed the expansion of lung stem cells for the first time. I hope to establish myself as a clinical academic group leader and develop my independent work with access to adult human clinical specimens and a multitude of murine models available between the two main centres.

Aim1: I intend to develop methods to expand adult stem cells from the human lung. I will systematically evaluate the importance of individual factors within the culture medium for the expansion of adult lung stem cells. This work will be greatly facilitated by collaboration with CSCRM as the Kings Stem Cell Hotel. These experiments will define specific factors and pathways that orchestrate epithelial stem cell self-renewal and differentiation during homeostasis.

Aim 2: Using the factors identified as determinants of lung stem cell behaviour, I will examine their role during lung homeostasis in living organisms such as mice.

Aim 3: Finally, I will focus on whether manipulation of basal stem cells can be protective against injury. To test this hypothesis, I will use tracheal injury models (naphthalene and polidocanol) as these are most relevant to human airway regeneration.

Publications

10 25 50
 
Description Postgraduate course in Respiratory Medicine at UCL Respiratory
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
URL https://www.ucl.ac.uk/medical-sciences/respiratory-clinical-science-msc
 
Description Consumables for PhD rotation project by Jessica Allen-Hyttinen as part of the UCL-Birkbeck MRC Doctoral Training Programme
Amount £1,666 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 02/2019 
End 05/2019
 
Description Consumables for PhD rotation project by Kaylee Worlock as part of the UCL-Birkbeck MRC Doctoral Training Programme
Amount £1,666 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2018 
End 02/2019
 
Description Jikei University School of Medicine - Salary for Dr Masahiro Yoshida
Amount £61,677 (GBP)
Organisation The Jikei University School of Medicine 
Sector Academic/University
Country Japan
Start 04/2019 
End 04/2021
 
Description Towards human lung regeneration: study of cell interactions and epithelial maturation in human lung development
Amount £60,000 (GBP)
Funding ID M899 
Organisation Rosetrees Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2019 
End 09/2021
 
Description scRNAseq of paediatric normal lungs as part of the Human Cell Atlas (jointly award to Kerstin Meyer at the Sanger and me at UCL)
Amount $250,000 (USD)
Organisation Chan Zuckerberg Initiative 
Sector Private
Country United States
Start 06/2020 
End 06/2023
 
Description Dutch Lung Foundation (Longfonds) as part of BREATH consortium 
Organisation Longfonds
Country Netherlands 
Sector Charity/Non Profit 
PI Contribution Invited to contribute by Hans Clevers and Carla Kim Attended and presented initial meeting at the Academy of Arts and Science in Amsterdam in February 2019
Collaborator Contribution Ideas for collaborations
Impact Nil yet
Start Year 2019
 
Description Human lung vascular development - collaboration with Christiana Ruhrberg and shared PhD student Tsvetana Stoilova 
Organisation University College London
Department Institute of Ophthalmology UCL
Country United Kingdom 
Sector Academic/University 
PI Contribution Secondary PhD supervisor for Tsvetana Stoilova Ideas, tissue and support for research plans
Collaborator Contribution s.a.
Impact Co-supervising of PhD student
Start Year 2018
 
Description Professor Paolo de Coppi at Great Ormond Street Hospital/Institute of Child Health 
Organisation University College London
Department Institute of Child Health
Country United Kingdom 
Sector Academic/University 
PI Contribution research idea and development consumables PhD student - me as primary supervisor and Paolo de Coppi as subsidiary
Collaborator Contribution research idea and development
Impact Joint PhD student
Start Year 2019
 
Description UK Regenerative Medicine Platform 
Organisation UK Regenerative Medicine Platform
Country United Kingdom 
Sector Academic/University 
PI Contribution I am part of UKRMP2, the Engineered Cell Environment Hub. We have monthly Webex meetings including twice yearly face-to-face meetings. It is very interactive and collaborative and we support each other's research.
Collaborator Contribution Presentations on research progress
Impact Close collaboration with Fiona Watt and Niwa Ali at the Kings College London, Centre for Stem Cells & Regenerative Medicine Close collaboration with Ling-Pei Ho from Oxford University Potential collaboration with Shukry Habib at the Kings College London, Centre for Stem Cells & Regenerative Medicine
Start Year 2018
 
Description scRNAseq collaboration with Kerstin Meyer and Sarah Teichmann at Sanger Institute, Cambridge 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution initiation of collaboration experimental design, tissue research question functional data
Collaborator Contribution scRNAseq pipeline
Impact In progress. Successful joint application to Chan Zuckerberg Initiative for 250,000 USD grant
Start Year 2019
 
Description Invited seminar Stanford University, Institute for Stem Cell Biology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Researchers and students attended this talk and engaged with it.
Year(s) Of Engagement Activity 2019
 
Description Invited seminar at Cincinnati Children's Hospital Medical Center (Center for Stem Cell and Organoid Medicine), USA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Lots of discussion and further ideas, including collaborations and new research ideas after the talk
Year(s) Of Engagement Activity 2020
 
Description Invited seminar at Kings College Stem Cell Institute (Stem cells @ lunch) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Talk on human lung development delivered to other researchers and students, very well received and lots of discussion initiated.
Year(s) Of Engagement Activity 2019
 
Description Lecture on human lung development for East of England Respiratory Registrars training day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Lecture on human lung development for East of England Respiratory Registrars training day at Royal Papworth Hospital, Cambridge
Year(s) Of Engagement Activity 2019
 
Description Lecture on the "Development of the respiratory system" for MSc students in prenatal genetics and foetal medicine 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Lecture on "The development of the respiratory system" at University College London, MSc in Prenatal genetics and foetal medicine, Module: organogenesis and foetal development (February 2019)
Year(s) Of Engagement Activity 2019
 
Description Lecture on the "Development of the respiratory system" for MSc students in prenatal genetics and foetal medicine 2020 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact 20 postgraduate students on course learning about lung development and its relevant to lung regeneration, sparked questions and discussion afterwards
Year(s) Of Engagement Activity 2020