A 2026 Crick PhD project with Dominique Bonnet.
Project background and description
This project title and description will be used to advertise your position, so please ensure that you use appropriate language and provide appropriate information to inform the applicants’ project selection. It may also be used to inform the allocation of studentships (as required).
Human bone marrow tissue is a complex interactive highly vascularized structural system with distinctive niches that provide support to the HSPCs[1]. There is ample published data suggesting the existence of anatomical gradients across the bone marrow tissue, with each niche having distinctive role, and the biophysical gradations linking these niches. Mimicking the bone marrow niche as a coordinated entity of action requires understanding the HSPC fate decisions in response to multiplexed cellular components, biophysical, and biomolecular signals. Efforts to understand these signals has been mainly impeded by the lack of reliable ex vivo models that can emulate the human bone marrow structure. The aim of the project is to create an innovative bioengineered fully humanised 3D in vitro model of the bone marrow microenvironment that will enable us study both normal and malignant haematopoiesis. We have recently developed a 3D humanised ossicles in vivo[2, 3] system, that has allowed us to reliably study the crosstalk between the human bone marrow niche components and haematopoietic stem cells, as well as evaluate the alterations that are induced during leukemic development. Although, this in vivo humanized ossicle model allows us to perform long term experiments (>6 weeks), however there are some limitations for example serial sampling of the cells (or secretory factors), feasibility of performing short-term experiments, large scale drug testing and the need to use mice, that are known to be associated with high costs.
We have recently generated in vivo data (unpublished) using confocal microscopy that has allowed us to map the structural architecture of the bone and the associated vasculature which is known to be crucial in HSPC maintenance and proliferation. Combining this microscopy data with various mathematical modelling tools has enabled to create a detailed map of the bone marrow vasculature system and this available data can be used to print structures using a 3D bioprinter. We will also use various available bio-inks to mimic (and advanced biodegradable hydrogels) and recapitulate the mechanical properties of the BM. Our in vitro model will be based entirely on 3D bioprinting the structure to mimic BM niche architecture.
Our proposed in vitro model will allow us to study the secretory factors (such as cytokines) and niche component(s) that could be responsible for maintaining normal stem cells, induce their differentiation as well as monitor the elements that mediate the HSPCs mobilization out of the niche(s). This system will also enable us to understand the mechanisms of leukemogenesis and test the drugs.
Candidate background
I am particularly interested in receiving applications from candidates with a degree in (stem) cell biology, and molecular biology. An individual being familiar with flow cytometry analysis and/or bioengineering will be a plus.
References
* Morrison, S.J. and Scadden, D.T. (2014) The bone marrow niche for haematopoietic stem cells. Nature 505: 327-334. PubMed abstract
* Abarrategi, A., Foster, K., Hamilton, A., Mian, S.A., Passaro, D., Gribben, J.,.. Bonnet, D. (2017) Versatile humanized niche model enables study of normal and malignant human hematopoiesis. Journal of Clinical Investigation 127: 543-548. PubMed abstract
* Mian, S.A., Abarrategi, A., Kong, K.L., Rouault-Pierre, K., Wood, H., Oedekoven, C.A.,.. Bonnet, D. (2021) Ectopic humanized mesenchymal niche in mice enables robust engraftment of myelodysplastic stem cells. Blood Cancer Discovery 2: 135-145. PubMed abstract
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