Biology subjects

Kathrein, K. L.

Publications and source records attributed to Kathrein, K. L..

3 recordsLinked to original sources

bioRxiv2025

Stochastic Modeling of Hematopoietic Stem Cell Dynamics

The study of hematopoietic stem cell (HSCs) maintenance and differentiation to supply the hematopoietic system presents unique challenges, given the complex regulation of the process and the difficulty in observing cellular interactions in the stem cell niche. Quantitative methods and tools have emerged as valuable mechanisms to address this issue; however, the stochasticity of HSCs presents significant challenges for mathematical modeling, especially when bridging the gap between theoretical models and experimental validation. In this work, we have built a flexible and user-friendly stochastic dynamical and spatial model for long-term HSCs (LT-HSCs) and short-term HSCs (ST-HSCs) that captures experimentally observed cellular variability and heterogeneity. Our model implements the behavior of LT-HSCs and ST-HSCs and predicts their homeostatic dynamics. Furthermore, our model can be modified to explore various biological scenarios, such as stress-induced perturbations mediated by apoptosis, and successfully implement these conditions. Finally, the model incorporates spatial dynamics, simulating cell behavior in a 2D environment by combining Brownian motion with spatially graded parameters. *Summary StatementThis study addresses the challenge of characterizing hematopoietic stem cell (HSC) dynamics by developing a flexible, user-friendly stochastic spatial model of long-term and short-term HSCs. The model captures observed cellular variability and heterogeneity, predicts homeostatic dynamics, can be adapted to simulate stress-induced perturbations like apoptosis, and incorporates a spatial component to analyze HSC movement within a bone marrow niche.

developmental biology↗

bioRxiv2024

Loss of Ing4 enhances hematopoietic regeneration in multipotent progenitor cells

Despite its critical role in survival, many aspects of hematopoiesis remain unresolved. In the classical model of the hematopoietic program, quiescent hematopoietic stem cells (HSCs) sit at the top of the hematopoietic hierarchy, with the ability to self-renew and differentiate as needed. HSCs give rise to more proliferative progenitor cells, which possess multipotent potential, but have largely or completely lost self-renewal capabilities. Here, we have identified the tumor suppressor, Inhibitor of Growth 4 (Ing4), as a critical regulator of multipotent progenitor (MPP) homeostasis. In the absence of Ing4, we show that MPPs express a transcriptional program of hematopoietic activation, yet they remain quiescent with low levels of reactive oxygen species. Functionally, Ing4-deficient MPPs are capable of robust regeneration following competitive bone marrow transplantation, resulting in substantially higher blood chimerism compared to wild-type MPPs. These data suggest Ing4 deficiency promotes a poised state in MPPs, quiescent, but transcriptionally primed for activation, and capable of converting the poised state into robust repopulation upon stress. Our model provides key tools for further identification and characterization of pathways that control quiescence and regeneration in MPPs.

molecular biology↗

bioRxiv2021

Ing4-deficiency enhances HSC quiescence and confers resistance to inflammatory stress

Hematopoiesis is tightly regulated by a network of transcription factors and complexes that are required for the development and maintenance of hematopoietic stem cells (HSCs). We recently identified the tumor suppressor, Ing4, as a critical regulator of HSC homeostasis. Though the Ing4 mechanism of action remains poorly characterized, it has been shown to promote stem-like cell characteristics in malignant cells. This activity is, in part, due to Ing4 mediated regulation of several major signaling pathways, including NF-{kappa}B and c-Myc. In murine hematopoiesis, Ing4 deficiency induces G0 arrest in HSCs, while simultaneously promoting gene expression signatures associated with differentiation. This results in a poised state for Ing4-deficient HSCs. Long term HSCs are unable to overcome this block, but short-term HSCs convert the poised state into regenerative capacity during hematopoietic challenges, including irradiation and transplantation. Overall, our findings suggest that Ing4 plays a crucial role in the regulation of hematopoiesis. Our model provides key tools for further identification and characterization of pathways that control quiescence and differentiation in HSCs.

cell biology↗