Interleukin 17A Modulates Erythropoietic Control: Understanding How Inflammatory Signals Tune Stem Cell Systems

Abstract

Homeostasis, the maintenance of a stable internal environment despite external fluctuations, is a fundamental property of living systems. In stem cell biology, homeostatic control takes on particular significance as it governs the balance between self-renewal and differentiation or proliferation and quiescence, crucial for not only basal tissue function but for regeneration and stress response. This thesis investigates how inflammatory signals can tune this homeostatic control, using erythropoiesis as a model system. Erythropoiesis, the process of red blood cell production, offers several unique advantages for studying homeostatic control: well-characterized developmental stages, a single cell type as the product, and a clear physiological metric in oxygen-carrying capacity. Through integrating experimental approaches with mathematical modeling, we demonstrate that Interleukin-17A (IL-17A) functions as a context-dependent amplifier, modulating the sensitivity of erythroid progenitors to Erythropoietin (Epo), the primary regulator of erythropoiesis. We show that IL-17A synergizes with Epo to enhance erythroid output, while having minimal effects during homeostasis. Mathematical modeling reveals this sensitization mechanism as optimal for balancing rapid stress response against basal metabolic burden. Using single cell RNA sequencing, we demonstrate that IL-17A amplifies Epo-dependent transcriptional programs in early progenitors rather than directly stimulating their proliferation, consistent with an Epo sensitization mechanism. To enable future practical investigation of IL-17A function, we also developed an Fc-fusion protein that extends its in vivo half-life from 2 hours to 13 hours. By elucidating the role of IL-17A in erythropoiesis, this research not only advances our understanding of red blood cell production but also provides insights into broader principles of homeostatic control in stem cell systems. These findings establish a new framework for understanding how inflammatory signals regulate tissue homeostasis and have implications for therapeutic interventions in hematological disorders and other stem cell-related pathologies.