2024 Theses Doctoral
Nucleolar stress and IL-1 signaling in hematopoietic stem cell aging
The aging of the hematopoietic system is driven in part by defects occurring in hematopoietic stem cells (HSC). Given that HSCs provide the organism with blood and immune cells lifelong, understanding the mechanisms underlying HSC aging is vital to develop interventions that address the deterioration of the hematopoietic system at its root. Past work has indicated roles for both intrinsic and extrinsic processes in driving HSC decline during aging. Still, their roles are not fully understood, especially the relationship between different drivers, and the mechanisms by which HSCs maintain functionality in the face of age-related insults.
To better understand cell-intrinsic regulation of HSC aging, we investigated nucleolar DNA damage marks stemming from replication stress in old HSCs, and connected it with nucleolar stress induction which impairs protein translation and cell cycling. Although nucleolar stress dampens old HSC activity, we reveal the cytoprotective effect of the p53-mediated nucleolar stress response to be essential for preserving the residual potential of old HSCs.
Additionally, though inflammation from the niche contributes to HSC aging, the exact role of microenvironmental alterations often remains unclear. Here, we uncover an important role for IL-1 derived from endosteal stromal cells in driving both HSC and niche cell aging, and demonstrate inhibition of IL-1 signaling as a tractable strategy that counters niche deterioration to improve HSC function. These findings unveil new mechanisms of HSC aging, raise the possibility that nucleolar stress signaling could be harnessed to improve the output of old HSCs in clinical settings, and demonstrate the therapeutic viability of IL-1 blockade in improving old HSC function.
Subjects
Files
- Mitchell_columbia_0054D_18606.pdf application/pdf 12 MB Download File
More About This Work
- Academic Units
- Cellular, Molecular and Biomedical Studies
- Thesis Advisors
- Passegue, Emmanuelle
- Degree
- Ph.D., Columbia University
- Published Here
- July 3, 2024