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  • Mid-Term Report Summary - HSCNICHEIVM (In vivo imaging of haematopoietic stem cells in their natural niches to uncover cellular and molecular dynamics regulating self-renewal)

HSCnicheIVM Report Summary

Project ID: 337066
Funded under: FP7-IDEAS-ERC
Country: United Kingdom

Mid-Term Report Summary - HSCNICHEIVM (In vivo imaging of haematopoietic stem cells in their natural niches to uncover cellular and molecular dynamics regulating self-renewal)

Haematopoietic stem cells (HSCs) are responsible for the production of billions of new red blood cells, immune cells and platelets every day throughout our life. They do this correctly because they reside in specific areas, called niches, inside the bone marrow. Understanding the exact cellular and molecular components of these niches, and how they change under stress (for example if infection or leukaemia develops) is critical to enable us to develop better HSC-based therapies. The HSCniceIVM project uses cutting edge microscopy techniques to identify where HSCs reside in the bone marrow. We have further developed our methodological approach by generating an automated image analysis algorithm that systematically segments the highly variable and heterogeneous 3D intravital microscopy images (Khorshed et al., Stem Cell reports 2015) and by obtaining bone marrow-wide, single cell resolution images, monitoring events that develop over the course of hours or days (Hawkins et al., Nature in press). Moreover, we have implemented quantitative analysis of microscopy and flow cytometry data to generate mathematical models of haematopoiesis (Vainieri et al., Opn Biology 2016).

With these approaches, we have achieved a number of discoveries:

-that infection-activated HSCs engage larger niches rich in osteoblastic cells (Rashidi et al., Blood 2014; Khorshed et al., Stem Cell Reports 2015);

-that Plasmodium berghei infection affects the haematopoietic cascade at multiple levels, including stem and early progenitor cells differentiation, and partial de-differentiation of committed progenitors (Vainieri et al., 2016);

-that T acute lymphoblastic leukaemia cells are continuously motile and entertain short and promiscuous interactions with any kind of neighbouring cell/bone marrow microenvironment. This is the case from early infiltration of the bone marrow, to overt development of chemoresistance (Hawkins et al., Nature in press);

-that at late stages of leukaemia the endosteal microenvironment is severely remodelled through loss of osteoblastic cells, a change that is likely to critically impair healthy residual haematopoiesis (Hawkins et al., Nature in press).

These discoveries are shedding light on the biology of haematopoietic stem cells, especially on their response to infection-mediated stress, and on how they are likely lost during leukaemia development. In particular our leukaemia studies suggest that novel anti-leukaemia therapeutic interventions should target the ability of leukaemia to thrive in unselected microenvironments and support endosteal niches that are normally associated with healthy haematopoiesis.

We are currently further developing our experimental approaches to further address the question how haematopoietic stem cell function is preserved/lost during diseases such as severe infection and leukaemia.

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United Kingdom
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