Bone marrow dynamics
Adult haematopoietic stem cells (HSC) maintain all peripheral blood and immune system lineages during steady-state and in response to injuries. Their function depends on a tight balance between quiescence, self-renewal and differentiation, regulated by both cell intrinsic and extrinsic mechanisms. About three decades ago it was postulated that the stem cell microenvironment (or niche) contributes to maintaining their quiescence and regulates their number. Leukaemia develops from defects in such balance and overtakes normal haematopoiesis.While the interaction between HSC and the bone marrow microenvironment, or niche, has been proven key for correct haematopoiesis, little is known about the interrelationship between normal HSC, leukaemia cells and the bone marrow microenvironment.
In vivo image of a fluorescently labelled HSC (white) observed in the calvarium (top of the skull) bone marrow of an irradiated, anesthetised, Col2.3GFP recipient mouse one hour after transplantation.
Three components of the bone marrow microenvironment are visualised. The osteoblasts;(bone making cells lining the endosteal surface) express high levels of GFP and are in green. Bone collagen (blue) is detected by two-photon microscopy second harmonic generation. The vasculature (red) is visualised through intravenous injection of non-targeted, circulating quantum dots®. Haematopoietic stem and progenitor cells are labelled with lipophilic membrane dyes prior transplantation. For this image, confocal microscopy was used to detect GFP, quantum dots and the injected cells; two-photon microscopy was used to detect collagen. Scale bar: 50 micrometers.
Intravital confocal/two-photon microscopy allows direct observation of transplanted, fluorescently labelled haematopotietic stem and progenitor cells in the bone marrow contained within the mouse calvarium (top of the skull). Cells can be observed upon their initial arrival in the niche (homing) and through the first divisions (early engraftment). The most primitive HSC selectively localise proximal to osteoblasts (bone-making cells), whereas their progeny are more distal. Analysis of homing and early engraftment patterns of mutant HSCs known to dominate or fail competition with normal HSCs for bone marrow engraftment has provided further evidence that HSCs and HSC progeny localisation near osteoblasts correlates with positive transplantation outcome.
The laboratory focuses on understanding the mechanisms regulating HSC function and position within the bone marrow cavity during steady state and in response to perturbations, such as inflammation and leukaemia development. The development of new and improved intravital microscopy approaches to answer these questions is a fundamental part of our activity.
Bone marrow dynamics group sharepoint(lab members only)
Funding and awards
- European Research Council
- Bloodwise (formerly LLR)
- Cancer Research UK
- Kay Kendall Leukaemia Fund
- Human Frontiers Science Program
- Biotechnology and Biological Sciences Research Council