Date of Award

8-2025

Document Type

Thesis

Degree Name

Master of Science in Biology

Department

Biology

First Reader/Committee Chair

Bournias, Nicole

Abstract

Hematopoietic stem and progenitor cells (HSPCs) quiescence is vital for the success of bone marrow transplantation, as it preserves long term self- renewal and prevents premature exhaustion (Takubo et al., 2013; Wilson et al., 2008). However, bone marrow transplant (BMT) failure remains a clinical challenge, often due to lack of long-term engraftment and insufficient stress reliance. Both of these characteristics are tightly linked to disrupted stem cell quiescence and metabolic imbalance (Anso et al., 2017; Vannini et al., 2016). One key player is S-phase kinase protein (SKP2), an E3 ubiquitin ligase that targets cell cycle inhibitors, like p27, for proteosome degradation (Carrano et al., 1999). SKP2 is overexpressed in HSCs in response to hematopoietic stress and SKP2 deletion increases HSC pool size and enhances quiescence, making it a viable therapeutic target for improving hematopoietic stem cell transplantation outcomes (Rodriquez et al., 2011).

Given SKP2’s regulatory role in the cell cycle and key metabolic pathways through target proteins such as AKT and LKB1 (Gao et al., 2009; Lin et al., 2009), and its interplay between metabolism and aging by cell cycle exhaustion in HSCs (Ito et al., 2012; Mohrin et al., 2015), we hypothesized SKP2 inhibition may allow HSPCs to have a metabolically resilient and quiescent state. Using both genetic (SKP2 knockout) and pharmacological (DT204) inhibition, we found that inhibition of SKP2 increased ATP production and spare respiratory capacity, indicating a metabolically “primed” state, even in quiescence. MitoTracker imaging showed reduced mitochondrial membrane

potential when SKP2 was inhibited, a phenotype that is associated with stem cell quiescence and long-term potency.

Together, these findings support a model where SKP2 inhibition promotes HSPC stress resilience, preserves quiescence, and enhanced metabolic readiness. These traits are essential for long term engraftment and HSCT efficiency. Our results support targeting SKP2 as a promising and novel strategy to rejuvenate aging HSCs and improve outcomes in regenerative therapies.

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