Project Reference: ICS27-SCI-EL1

Project title: Modelling and Reversing Age-Associated Immune Dysfunction Using Human Blood Stem Cells

Project outline

Extending the healthspan is a major challenge of ageing societies. This requires a better understanding of how tissue regeneration and immunity change over life. Blood stem cells, or hematopoietic stem cells (HSCs), are crucial because they sustain production of all blood cells, including immune cells, and exert systemic effects. Our laboratory has recently demonstrated that as we age, i) blood production becomes oligoclonal, with a few stem cells taking over blood production carrying specific mutations (Nature, 2022), ii) some of these mutations intrinsically drive the production of innate immune cells with altered function (BioRxiv, 2025), iii) perturbation of innate immune cell production occurs in the absence of mutations in healthy elderly individuals (unpublished). 

This project will build on this foundation to identify the epigenetic mechanisms by which aged HSCs give rise to immune cells that are intrinsically dysfunctional and how to potentially intervene to restore their function. This will be achieved via 3 objectives.

Objective 1: in collaboration with the industrial partner, the student will optimise innovative HSC differentiation protocols to study innate immune function during ageing. 

Objective 2: the student will then use these protocols to produce immune cells from HSCs isolated from young and elderly healthy donors. Both HSC and the immune cells produced will be benchmarked at the transcriptional, epigenetic and functional level to their counterparts freshly isolated from humans. 

Objective 3: CRISPR and small molecule screens and/or target validation will be performed to identify genes, pathways and molecules restoring immune cell function to a youthful condition.

Overall, this project will deliver i) novel HSC ageing models, enabling manipulation of cells in and out of ageing; ii) new insights into how age-driven epigenetic changes in stem cells alter immune function and potential ways to improve immunity in the elderly.

Principal Supervisor

Professor Elisa Laurenti

Email address: el422@cam.ac.uk

Department / Partner Institute: Cambridge Stem Cell Institute 

Website: https://www.stemcells.cam.ac.uk/people/pi/laurenti

Industrial Partner

Stem Cell Technologies

BBSRC strategic theme

Understanding the rules of life