Haematology and Angiology

Transverse histological section of a mouse embryo stained with an antibody anti-PW1 (green), anti-Pax3 )(red). Nuclei are stained in blue with DAPI. Image courtesy of G. Cossu.

Haematology and angiology

The use of bone marrow transplants is one the longest standing clinical techniques in Regenerative Medicine; it has been refined to the point where only haematopoietic stem cells can be transplanted when needed.  This greater understanding of how blood and blood vessels are generated holds great potential, which includes not only the growth of blood vessels, but also the generation of whole blood  in vitro. 

Academic

Dr Georges Lacaud

Cancer Research UK Manchester Institute
The University of Manchester
georges.lacaud@cruk.manchester.ac.uk
Dr Lacaud’s University Profile

Haematopoesis and Direct Reprogramming to Haematopoetic Progenitors

Bone marrow transplantations are well-established cellular therapies for the treatment of a variety of malignant or genetic disorders of blood cells. The success of these transplantations relies on a rare population of haematopoietic stem cells (HSCs), which can reconstitute the entire blood and immune system cells. However, a major restriction to the wider application of these curative treatments is the difficulty, or even the possibility, to find a healthy source of donor tissue that is immunologically compatible. The scarcity in matched donors could potentially be overcome in the future by the provision of unlimited and renewable sources of HSCs from pluripotent stem cells such as embryonic stem cells (ESCs) or patient derived induced pluripotent stem cells (iPSCs). Similarly, differentiation of pluripotent stem cells (PSCs) could represent a sustainable source of red blood cells and platelets for transfusions. The fulfilment of these promises relies on a better understanding of the molecular and cellular mechanisms underlying the development of the haematopoietic system and the establishment of improved protocols of differentiation of pluripotent stem cells toward the blood lineage. Along this line, the Lacaud and Kouskoff laboratories identified the transcription factor RUNX1 and the transcriptional repressor GFI1 and GFI1B as major player in the generation of the first blood cells. Direct lineage reprogramming provides an alternative tool to ES and iPS cells for regenerative medicine. Recent reports have shown that somatic cells, under appropriate culture conditions, could be directly reprogrammed to cardiac, hepatic or neuronal phenotype by lineage specific transcription factors. Work from the Lacaud and Kouskoff laboratories demonstrate that embryonic fibroblasts, as well as adult fibroblasts, can be directly reprogrammed to blood cells by over expression of haematopoietic transcription factors. Reprogrammed cells can be differentiated to erythroid, myeloid and to some extent lymphoid lineages under specific culture conditions. Their results also suggest that fibroblasts upon TFs inductions are reprogrammed to haematopoietic cells via a progenitor state called haemogenic endothelial, but not pluripotent stage. Importantly, as in the case of reprogramming to dedifferentiated stage, loss of p53 function facilitates reprograming to blood. Taken together this data provide an impetus to further evaluate direct reprogramming as an alternate approach to generate blood cell populations for autologous cell replacement therapies.

Dr Valerie Kouskoff

Cancer Research UK Manchester Institute
The University of Manchester
valerie.kouskoff@cruk.manchester.ac.uk
Dr Kouskoff’s University Profile

Stem Cell Haematopoiesis

Understanding the cellular and molecular mechanisms that lead to the formation of the haematopoietic lineage is of considerable interest as this should provide new insights into the mechanism of diseases that affect haematopoietic subpopulations in adult. To study haematopoietic development, Dr Kouskoff uses in vitro differentiation of embryonic stem (ES) cells as a model system. The ability to generate differentiated cell populations from ES cells in culture offers a powerful alternative approach to the mouse embryo for studying lineage induction and specification, as this model provides easy access to large numbers of early developmental cells. Her studies focus on the formation of the first known haematopoietic precursor, the haemangioblast which give rise to both haematopoietic and endothelial lineages. Her aim is to identify the cascades of gene expression that regulate either initial haemangioblast formation or its subsequent decisions to differentiate. The Kouskoff/Lacaud groups wish to use these basic findings to investigate the possibility of generating blood cell populations for autologous cell replacement therapies.

Dr Brian Bigger

Reader
Faculty of Biology, Medicine and Health
brian.bigger@manchester.ac.uk
Dr Bigger’s University Profile

Haematopoetic Stem Cell/Gene Therapy for Neurological Diseases

Neurodegenerative metabolic diseases mainly affect children and often lack effective treatments. Dr Bigger’s Stem Cell Neurotherapies laboratory works on understanding the pathology and delivering stem cell and gene therapy treatments, via the haematopoetic system, for mucopolysaccharide diseases (a type of lysosomal storage disorder affecting the brain). The lab uses a multidisciplinary approach including development of a novel substrate reduction drug for Sanfilippo disease, currently in phase III trial, haematopoietic stem cell gene therapy for Sanfilippo disease A and B, as well as Hunter disease, and a gene therapy approach for MPSIIIC. In order to develop effective treatments, a complete understanding of the underlying pathology in mouse models and their comparison to patients is critical, and assists with the development of suitable biomarkers and clinical outcome measures for subsequent trials.

Dr Ian Crocker

Senior Lecturer in Maternal and Fetal Health
Faculty of Biology, Medicine and Health
ian.crocker@manchester.ac.uk
Dr Crocker’s University Profile

Placental Immunology and Vascular Biology

Dr Ian Crocker’s research has been dedicated to many aspects of human pregnancy; it’s physiology and complications. His current studies identify previously unrecognised roles for fetal endothelial progenitor cells in the placenta and maternal uterus, immune tolerance in pregnancy and autoimmunity, and drug therapies for combating fetal growth restriction and stillbirth. He collaborates with all lead clinicians in the high risk antenatal clinics of St Mary’s Hospital, Manchester.

Academic-Clinical

Dr Ed Johnston

Consultant Obstetrician/Senior Lecturer in Obstetrics and Fetal Medicine
Faculty of Biology, Medicine and Health
Central Manchester Foundation Trust
Edward.Johnstone@manchester.ac.uk
Dr Johnston’s University Profile

Placental Development

Dr Johnston is an academic Obstetrician with a special interest in Fetal Growth Restriction (FGR). Dr Johnston leads multiple projects examining both placental development of the treatment of this condition using basic science, ultrasound and MRI techniques. Additionally he manages the fetal growth restriction service at St. Mary’s.

Clinical

Professor Robert Wynn

Consultant Paediatric Haematologist & Director of Paediatric Bone Marow Transplant Programme
Central Manchester Foundation Trust
Robert.Wynn-2@manchester.ac.uk
Profressor Wynn’s NHS Profile

Cell/Gene Therapy for MPS

Mr Wynn’s Regenerative Medicine interests lie in the treatment of mucopolysaccharidosis (MPS) via gene therapy, bone marrow and bone marrow stem cell transplant. He works closely with Dr’s Brian Bigger and Simon Jones.