Professor of Transfusion Medicine
Research themes:Stem Cell
Description of research
Adult stem cells reside in specialised niches that allow them to self-renew, proliferate, differentiate, and migrate according to the organism’s requirements. These niches were first discovered and are best understood in the blood system. Using the mouse bone marrow as a model, our group studies multisystem regulatory mechanisms by which the stem cell niche fulfils these complex functions and how the deregulation of these mechanisms contributes to disease. This will potentially offer novel therapeutic approaches.
Blood cells are produced in the bone marrow, which contains two distinct adult stem cell types: blood (‘haematopoietic’) stem cells (HSCs), that generate all blood and immune cells, and mesenchymal stem cells (bone marrow stem cells BMSCs), thought to form the skeleton. Our work has found a connection between the bone marrow stem-cell niche to remote signals from hormones and the brain, which can control BMSCs and HSCs through nerves that penetrate the bones associated with blood vessels. Using a multidisciplinary approach going from development to disease, we aim to understand how different types of nerves, blood vessels and BMSCs associated with them can control HSC function in health and disease. This could help find ways to obtain more stem cells, improve HSC cell transplantation procedures and treat incurable myeloproliferative disorders.
How niches develop and remodel in disease
The ancestry and the functional relationships among non-haematopoietic cells has remained largely unclear, in contrast to what is known about their haematopoietic neighbours in the bone marrow. We have shown that nestin+ BMSCs innervated by sympathetic nerve fibres (Figure 1) regulate normal HSCs, revealing a close interaction between both marrow stem cell types. This is also one of the first examples of organismal control of a peripheral stem cell niche through a master regulator of vertebrates − the autonomic nervous system. This neural-BMSC network might build upon shared ancestry of its cellular components, since our recent data shows that the neural crest (the source of peripheral neurons and associated Schwann cells) also contributes during development to BMSCs with a specialised HSC niche function. Dissecting how cell fate and HSC supporting properties are determined in these cells might facilitate regenerative approaches. Also, understanding these properties might facilitate finding ways to expand HSCs ex vivo. Moreover, this developmental plan might be reactivated (reprogrammed) in certain haematological diseases, and its disentangling might offer new therapeutic strategies. We are dissecting how different neurovascular beds control HSC function and their relevance in blood diseases.
Migration of blood stem cells
HSCs continuously migrate between the bone marrow and the bloodstream. This normal traffic can be intensified, allowing for the mobilisation and non-invasive harvest of HSCs for life-saving transplantation procedures. HSC transplantation is routinely performed in patients with blood cancer or inherited metabolic/immune disorders. The proper engraftment of HSCs in the bone marrow after their infusion is also critical for the transplantation’s success. Unfortunately, a number of patients are poor mobilisers and/or exhibit insufficient engraftment after transplantation.
Our recent work has determined that the number of HSCs in the blood is not constant or random, but follows instead rhythmic (circadian) oscillations governed by the molecular clock. There are two to three times more HSCs circulating in the blood during the resting period, both in mice and humans. These differences are maintained even after enforced HSC mobilisation induced by the cytokine granuylocyte colony-stimulating factor (G-CSF), commonly used in clinics. We took advantage of these oscillations to study the mechanisms regulating HSC traffic. Oscillations in HSCs mirror fluctuations in the expression of CXCL12 in the bone marrow. This chemokine is the only one known to be capable of directing HSC migration. Sympathetic nerve fibres transmit signals from the brain to the bone marrow, and control the expression of CXCL12. HSCs and leukocytes are preferentially released in the bloodstream during the resting phase and preferentially home back to the bone marrow during the activity phase. We are now investigating new pathways that control HSC migration, with the aim of improving the efficacy of HSC transplantation procedures.
Targeting the HSC niche to control disease – a novel approach
In specific blood disorders known as myeloproliferative neoplasms (MPNs), a defective gene causes blood stem cells to multiply thereby making too many. As the blood cells build up, the disease worsens, sometimes developing into cancer. Relating this fact directly to the “niche”, our team discovered that the excess mutant cells directly damage nearby nerves and MSCs, which prevent them from acting as they should in a healthy bone marrow, where they normally help to control the number and retention of blood stem cells. In this state, and left unchecked, the increase of mutant blood stem cells brings with it the likelihood of the blood disorders (MPNs). However, the disease can be blocked in mice by providing drugs which mimic the effects of the nerves (Figure 2), an approach currently being tested in a phase-II clinical study (https://clinicaltrials.gov/ct2/show/NCT02311569).
Hormonal regulation of bone marrow stem cells
It is likely that a combined therapy targeting both stem and niche cells will in the future be the way leukaemic stem cells can be eradicated. We are investigating new ways to target leukaemic stem cells based on susceptibility factors. One factor might be gender. For some time it has been known that men are more susceptible to leukaemias than women. We have taken this observation a step forward and found that sex hormones might explain gender differences in blood cancer susceptibility and might offer complementary ways to treat these disorders. This is because the female sex hormones oestrogens can regulate the survival, growth and maintenance of normal and mutated HSCs. We found that drugs mimicking the effects of these sex hormones can block the development of myeloproliferative neoplasms in mice, an approach that will be soon tested in humans. A phase-II clinical study will also help us understand the correlation of the disease course and in turn its response to treatment with genetic and epigenetic studies which will be mainly focused on oestrogen receptor signalling.
The importance of the stem cell niche
Overall, our research is focused on having a better understanding of how bone marrow stem cell niches work as this will potentially reveal better therapeutic targets in performing successful HSC transplants and treating currently incurable myeloproliferative diseases.
Livia Lisi Vega, Elodie Grockowiak, Claire Fielding, Rebecca France, Eman Khatib-Massalha, Prof. Simon Mendez-Ferrer, Zijian Fang
Keywords: Haematopoietic stem cell niche, bone marrow stem/progenitor cells, multisystem physiology
Clinical conditions: Bone marrow transplantation, myeloproliferative neoplasms, myeloid malignancies
Methodologies: Mouse models, clinical trials