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bioRxiv · 10.1101/2025.08.15.670507

In Silico Investigation of the Role of Local and Global Inflammation-Driven Feedback in Myelopoiesis and Clonal Cell Expansion

Umar, Y. J.·Savvopoulos, S. V.·Pitsalidis, C.·Mitroulis, I.·Hatzikirou, H.
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Abstract

Chronic inflammation perturbs hematopoietic homeostasis, promoting aberrant myelopoiesis and clonal expansion of mutated stem cells. Here, we develop a mathematical model that integrates both local (bone marrow-intrinsic) and global (systemic/peripheral) inflammation-driven feedback mechanisms to investigate their roles in hematopoietic regulation and disease progression. Our model captures the nonlinear interplay between self-renewal, progenitor proliferation, and inflammatory cues, enabling classification of healthy, myelodysplastic, and leukemic states based on stem cell population dynamics. We show that global inflammatory feedback enhances the resilience of hematopoiesis, while excessive feedback on progenitor cells under chronic inflammation drives instability and clonal dominance. Using sensitivity analysis and parameter space mapping, we identify critical feedback thresholds governing transitions between hematopoietic states and reveal how mutated clones exploit inflammation to outcompete wild-type cells. This systems-level framework offers mechanistic insights into the emergence of myeloid malignancies and provides a computational platform for exploring potential anti-inflammatory therapeutic strategies.

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Umar, Y. J., Savvopoulos, S. V., Pitsalidis, C., Mitroulis, I., Hatzikirou, H.. 2025-08-20. In Silico Investigation of the Role of Local and Global Inflammation-Driven Feedback in Myelopoiesis and Clonal Cell Expansion. https://doi.org/10.1101/2025.08.15.670507

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