Lesley Forrester
Director of Postgraduate Studies

Address
- Street
-
Centre for Regenerative Medicine
Institute for Regeneration and Repair
The University of Edinburgh
Edinburgh BioQuarter
5 Little France Drive - City
- Edinburgh
- Post code
- EH16 4UU
Background
- Professor of Stem Cell Differentiation, MRC Centre for Regenerative Medicine (2012-present)
- Reader, Centre for Inflammation Research (2007-2012
- LRF Senior Lecturer, John Hughes Bennett Laboratory, University of Edinburgh (1998-2007)
- MRC Senior Fellowship, Centre for Genome Research, University of Edinburgh (1993-1998)
- EMBO Postdoctoral Research Fellow, Samuel Lunenfeld Research Institute, Toronto, Canada (1989-1993)
- ICRF Postdoctoral Research Fellow, University of Edinburgh (1986-89)
- PhD: University of Edinburgh (1986)
Responsibilities & affiliations
CRM Director of Postgraduate Studies
Deanery of Clinical Sciences Depute Director of Postgraduate Studies
College of Medicine and Veterinary Medicine Academic Misconduct Officer
Undergraduate teaching
3rd year:Clinical Immunology and Haematology
4th year: Regenerative Medicine; Reproductive Biology
Postgraduate teaching
Depute Director MRes Regenerative Medicine and Tissue Repair
CRM Director Postgraduate Studies
Current PhD students supervised
Alisha May
Telma Ventura
Past PhD students supervised
Gurman Pall
Alistair Watt
Anna Krassowska
Tim Chevassut
Anestis Tsakiridis
Richard Axton
Sabrina Gordon-Keylock
Katrin Buerger
Lindsay Fraser
Madina Kara
Caoxin Huang
Rui Ma
Maria Kydonaki
Sharmin Haidera
Cheng-Tao Yang
Martha Lopez Yrigoyen
Research summary
Haematopoietic cell differentiation
Diseases of the blood system such as leukaemia and anaemia are often treated using cell therapies such as bone marrow transplantation and blood transfusion. However, these procedures are reliant on a limited donor supply and are complicated by transmissible infections. The long-term goal of our research is to replace these procedures with haematopoietic stem cells and red blood cells that have been produced in the laboratory from pluripotent stem cells. We are studying the molecular processes involved in the production of blood cells from pluripotent stem cells so we can optimise the production of cells with the appropriate function.
Aims and areas of interest
Haematopoietic progenitor cells and mature blood cells, including macrophages, granulocytes, mast cells and erythrocytes can be generated in vitro from human pluripotent stem cells (hPSCs). However, it has proven challenging to manufacture fully functional cells that are comparable to the cells that are generated in the body. For example, it has not been possible to produce fully functional haematopoietic stem cells (HSCs) that are capable of robust reconstitution of the haematopoietic system and the erythrocytes that are produced in vitro from hPSCs are immature and they fail to enucleate efficiently.
1. Functional HSCs from human PSCs.
To understand why it has proven so difficult to generate fully functional reconstituting HSCs from PSCs, we have taken a single cell sequencing approach to define the transcriptome of the haematopoietic progenitor cells that can be generated in vitro. By comparing these to HSCs that arise in vivo we aim to uncover the molecular pathways that are missing in PSC-derived progenitors. That knowledge will be used to refine differentiation culture conditions and/or to genetically programme cells by the activation of endogenous transcription factors using CRISPR/CAS9 approaches.
2. Maturation of erythroid cells.
Erythroid cells mature within erythroid island (EI) niche that consists of a central macrophage surrounded by developing erythroid cells. To uncover the molecular processes involved in erythroid maturation, we have developed an in vitro model for the EI niche using genetically programmed iPSC-derived macrophages. We are using this model to identify novel pathways associated with RBC maturation that could be applied to the manufacture of RBCs in vitro and to identify novel therapies for anaemia.
3. Macrophages from human PSCs
We have developed an efficient protocol to generate monocytes and mature macrophages from human PSCs pluripotent stem and have established a number of collaborations to study the role of macrophages in disease including liver fibrosis, arthritis and cancer.
Current project grants
2020-2023. MRC (MR/T013923/1). Identification and characterisation of the molecular components associated with the human erythroid island niche in normal and abnormal erythropoiesis. (£780K)
2018-2021. BBSRC (BB/S002219/1). An inducible CRISPR/dCAS9 strategy for directed differentiation of pluripotent stem cells. (ca.£700K).
-
The Erythroblastic Island Niche: Modelling in Health, Stress and Disease.
In:
Experimental Hematology
DOI: https://doi.org/10.1016/j.exphem.2020.09.185
Research output: Contribution to Journal › Review article (E-pub ahead of print) -
Single cell analyses and machine learning define hematopoietic progenitor and HSC-like cells derived from human PSCs.
In:
Blood
Research output: Contribution to Journal › Article (Published) -
Alternatively activated macrophages promotes necrosis resolution following acute liver injury
In:
Journal of Hepatology
DOI: https://doi.org/10.1016/j.jhep.2020.02.031
Research output: Contribution to Journal › Article (E-pub ahead of print) -
Robustness of dead Cas9 activators in human pluripotent and mesenchymal stem cells
In:
Molecular therapy. Nucleic acids
DOI: https://doi.org/10.1016/j.omtn.2020.02.009
Research output: Contribution to Journal › Article (Published) -
Human tumor-associated macrophage and monocyte transcriptional landscapes reveal cancer-specific reprogramming, biomarkers and therapeutic targets
In:
Cancer cell
DOI: https://doi.org/10.1016/j.ccell.2019.02.009
Research output: Contribution to Journal › Article (E-pub ahead of print) -
Genetic programming of macrophages generates the first in vitro model for the human erythroid island niche
In:
Nature Communications
DOI: https://doi.org/10.1038/s41467-019-08705-0
Research output: Contribution to Journal › Article (Published) -
Rapid mast cell generation from Gata2 reporter pluripotent stem cells
In:
Stem Cell Reports
DOI: https://doi.org/10.1016/j.stemcr.2018.08.007
Research output: Contribution to Journal › Article (Published) -
A human iPSC line capable of differentiating into functional macrophages expressing ZsGreen: a tool for the study and in vivo tracking of therapeutic cells
(9 pages)
In:
Philosophical Transactions of the Royal Society B: Biological Sciences, vol. 373
DOI: https://doi.org/10.1098/rstb.2017.0219
Research output: Contribution to Journal › Article (Published) -
Insulin fine-tunes self-renewal pathways governing naïve pluripotency and extra-embryonic endoderm
In:
Nature Cell Biology
DOI: https://doi.org/10.1038/ncb3617
Research output: Contribution to Journal › Article (E-pub ahead of print) -
FANTOM5 CAGE profiles of human and mouse samples
In:
Scientific Data, vol. 4
DOI: https://doi.org/10.1038/sdata.2017.112
Research output: Contribution to Journal › Article (Published) -
An all-in-one UniSam vector system for efficient gene activation
In:
Scientific Reports
DOI: https://doi.org/10.1038/s41598-017-06468-6
Research output: Contribution to Journal › Article (E-pub ahead of print) -
Injection of embryonic stem cell derived macrophages ameliorates fibrosis in a murine model of liver injury
In:
npj Regenerative Medicine
DOI: https://doi.org/10.1038/s41536-017-0017-0
Research output: Contribution to Journal › Article (Published) -
SplitAx: A novel method to assess the function of engineered nucleases
In:
PLoS ONE, vol. 12, pp. e0171698
DOI: https://doi.org/10.1371/journal.pone.0171698
Research output: Contribution to Journal › Article (Published) -
Activation of KLF1 Enhances the Differentiation and Maturation of Red Blood Cells from Human Pluripotent Stem Cells
In:
Stem Cells
DOI: https://doi.org/10.1002/stem.2562
Research output: Contribution to Journal › Article (E-pub ahead of print) -
Enforced Expression of HOXB4 in Human Embryonic Stem Cells Enhances the Production of Hematopoietic Progenitors but Has No Effect on the Maturation of Red Blood Cells
In:
Stem cells translational medicine, vol. 5, pp. 981-990
DOI: https://doi.org/10.5966/sctm.2015-0324
Research output: Contribution to Journal › Article (Published) -
Concise review: programming human pluripotent stem cells into blood
In:
British journal of haematology
DOI: https://doi.org/10.1111/bjh.14010
Research output: Contribution to Journal › Literature review (E-pub ahead of print) -
The European Hematology Association Roadmap for European Hematology Research. A Consensus Document
In:
Haematologica
DOI: https://doi.org/10.3324/haematol.2015.136739
Research output: Contribution to Journal › Article (Published) -
Conditional-ready mouse embryonic stem cell derived macrophages enable the study of essential genes in macrophage function
(11 pages)
In:
Scientific Reports, vol. 5
DOI: https://doi.org/10.1038/srep08908
Research output: Contribution to Journal › Article (Published) -
Gene regulation. Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells
(5 pages)
In:
Science, vol. 347, pp. 1010-4
DOI: https://doi.org/10.1126/science.1259418
Research output: Contribution to Journal › Article (Published) -
A role for mospd1 in mesenchymal stem cell proliferation and differentiation
In:
Stem Cells
DOI: https://doi.org/10.1002/stem.2102
Research output: Contribution to Journal › Article (Published)
- Jo Mountford, Scottish National Blood Transfusion Service
- Jan Frayne, University of Bristol
- Jim Beiker, ICAHN School of Medicine, New York
- Pablo Menendez, School of Medicine, University of Barcelona
- Gavin Wright, Sanger Institute.
- Stuart Forbes, CRM
- Jeff Pollard, Centre for Reproductive Health
- Mariola Kurowska-Stolarska, University of Glasgow