Investigating the recovery of blood stem cells from infection

The ability of haematopoietic stem cells (HSC) to expand and differentiate is key to normal homeostasis and the systemic immune response. HSCs promote a rapid immune response by generating innate and adaptive immune cells that are recruited to the site of infection. After the infection has been overcome HSC numbers decline to pre-infection levels, however what controls this reduction in numbers is not known. Our laboratory has shown that the non-haematopoietic cells (fibroblasts and adipocytes) support HSC maintenance in the bone marrow (BM) microenvironment. Others have shown that BM macrophages also support HSC expansion. However, the primary function of macrophages is phagocytosis (to engulf dead cells, debris or microbes). Recently, a pathway called cGAS-STING, which is activated by DNA has been shown to be important in clearing dead cells. Here we hypothesise that cGAS-STING pathway controls the reduction of HSC and progenitor cells in the BM after infection and that deficiencies in cGAS-STING allow for a dysfunctional HSC phenotype. Therefore, we aim to study the role of macrophage cGAS-STING pathway on regulating the HSC pool in the BM microenvironment in response to infection and whether defective cGAS-STING leads to a dysfunctional immune response. The PhD student will be trained in vivo techniques including animal handling, isolation of primary cells and techniques to assess functional characteristics of cells including FACS analysis, qPCR to analyse nucleic acids and western blot, ELISA and immunohistochemistry for protein analysis. This will give them a number of valuable transferrable skills which will help their scientific career progression. The project will be carried out at the Rushworth Lab based at the Norwich Medical School, UEA, which combines research laboratories with medical training facilities. This work will be in close collaboration with the Beraza Lab at Quadram Institute, Norwich Research Park.

References

Regulation of intestinal senescence during cholestatic liver disease modulates barrier function and liver disease progression. Moreno-Gonzalez, M., Hampton, K., Ruiz, P., Beasy, G., Nagies, F. S. P., Parker, A., Lazenby, J., Bone, C., Alava-Arteaga, A., Patel, M., Hellmich, C., Luri-Martin, P., Silan, E., Philo, M., Baker, D., Rushbrook, S. M., Hildebrand, F., Rushworth, S. A. & Beraza, N., 29 Jun 2024.

p16INK4A-dependent senescence in the bone marrow niche drives age-related metabolic changes of hematopoietic progenitors. Hellmich, C., Wojtowicz, E., Moore, J. A., Mistry, J. J., Jibril, A., Johnson, B. B., Smith, J. G. W., Beraza, N., Bowles, K. M. & Rushworth, S. A., 24 Jan 2023, In: Blood Advances. 7, 2, p. 256-268 13 p.

Plasma cell derived mtDAMPs activate macrophage STING pathway which promotes myeloma progression. Jibril, A., Hellmich, C., Wojtowicz, E. E., Hampton, K., Maynard, R., De Silva, R., Fowler-Shorten, D. J., Mistry, J. J., Moore, J. A., Bowles, K. M. & Rushworth, S. A., 22 Jun 2023, In: Blood. 141, 25, p. 3065–3077 13 p.

LC3-associated phagocytosis in bone marrow macrophages suppresses acute myeloid leukemia progression through STING activation. Moore, J. A., Mistry, J. J., Hellmich, C., Horton, R. H., Wojtowicz, E. E., Jibril, A., Jefferson, M., Wileman, T., Beraza, N., Bowles, K. M. & Rushworth, S. A., 1 Mar 2022, In: Journal of Clinical Investigation. 132, 5, e153157.