Linking cell cycle to hematopoietic stem cell fate decisions

A major next step in hematopoietic stem cell (HSC) biology is to obtain a thorough quantitative understanding of cellular and evolutionary dynamics involved in undisturbed hematopoiesis. Mathematical models are key in this respect, and are most powerful when parameterized experimentally and containing sufficient biological complexity. Mathematical models of hematopoiesis have either been parameterized experimentally without non-linear dynamics, or they include these complexities but have not been parameterized to the same extent. We bridge this gap using mouse data to parameterize a mathematical model of hematopoiesis that includes homeostatic control mechanisms as well as clonal evolution. We find that non-linear feedback control drastically changes the interpretation of kinetic estimates at homeostasis. This suggests that short-term HSC and multipotent progenitors (MPPs) can dynamically adjust to sustain themselves in the absence of long-term HSCs, even if they differentiate more often than they self-renew in undisturbed homeostasis. Additionally, the presence of feedback control in the model renders the system resilient against mutant invasion. Invasion barriers, however, can be overcome by a combination of age-related changes in stem cell differentiation and a mutant-associated inflammatory environment. This helps us understand the evolution of e.g.TET2, DNMT3A, orJAK2mutants, and how to potentially reduce mutant burden.

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Asymmetric cell division of hematopoietic stem cells: recent advances, emerging concepts, and future perspectives

Nunes,

Loeffler

2024

Front. Hematol.

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Hematopoietic stem cells (HSCs) can self-renew and differentiate for the entire life of an organism to produce new blood cells when needed. This process is regulated by asymmetric cell division (ACD), an evolutionarily conserved mechanism whereby cell fate determinants are unequally segregated into the daughter cells during division to instruct different cell fates. After many years of controversy, recent technical advances in microscopy, imaging, and bioinformatics make it now possible to visualize and quantify how factors segregate asymmetrically in dividing HSCs and lead to predictable changes in daughter cell fates many days later. While the molecular processes behind ACD in HSCs are still poorly understood, accumulating evidence suggests that lysosomes and other organelles, including mitochondria, autophagosomes, mitophagosomes, and recycling endosomes can segregate asymmetrically and act as cell fate determinants during divisions. Asymmetric segregation of lysosomes and mitochondria has been shown to predict mitochondrial activity, translation, and differentiation of HSC daughter cells and their offspring. This discovery and recent seminal findings show that lysosomes, once considered to be merely the trash bin of the cell, regulate many aspects of HSC biology and are crucial for the maintenance of quiescence and stem cell function. Here we provide a historical perspective and discuss the recent advances in our understanding of ACD and the role of lysosomes in HSC function. We discuss the limitations of past studies, talk about emerging concepts, and suggest critical next steps required to move the field forward.

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Linking cell cycle to hematopoietic stem cell fate decisions

Cited by 3 publications

References 108 publications

Tetrahydroxy stilbene glucoside rejuvenates aging hematopoietic stem cells with predilection for lymphoid differentiation via AMPK and Tet2

Tetrahydroxy stilbene glucoside rejuvenates aging hematopoietic stem cells with predilection for lymphoid differentiation via AMPK and Tet2

Dynamically adjusted cell fate decisions and resilience to mutant invasion during steady state hematopoiesis revealed by an experimentally parameterized mathematical model

Asymmetric cell division of hematopoietic stem cells: recent advances, emerging concepts, and future perspectives

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