# Stable platelet production via the bypass pathway explains long-term hematopoietic stem cell reconstitution

## TL;DR

This study shows that the platelet-bypass pathway helps hematopoietic stem cells maintain long-term blood cell production, especially as they age.

## Contribution

The study introduces a mathematical model linking platelet-bypass dependence to long-term stem cell function and reconstitution.

## Key findings

- Myeloid cell production remains stable with age, while B cell production declines.
- Platelet-bypass dependence correlates with long-term hematopoietic stem cell reconstitution.
- The platelet-to-erythrocyte chimerism ratio at 8 weeks predicts HSC function.

## Abstract

In vivo differentiation pathways into several blood cell lineages of Hematopoietic stem cells (HSCs) remain challenging to track over time. Using data from single-cell transplantation assays and mathematical modeling, we examined HSC differentiation kinetics, including the myeloid bypass pathway. We found that myeloid cell production was unchanged with age, whereas B cell production declined, quantitatively confirming myeloid lineage skewing. Estimated dependence on the platelet-bypass correlated with the long-term reconstitution capacity of HSCs. Time-dependent blood cell production patterns calculated by our model distinguished the reconstitution potential of HSCs into subgroups, suggesting a link between the bypass pathway and the multilineage differentiation dynamics of HSCs. Notably, platelet bypass dependence could be determined by the platelet-to-erythrocyte chimerism ratio at 8 weeks after transplantation, serving as a predictive indicator of long-term HSC function. These findings provide quantitative insights into HSC aging and differentiation dynamics, emphasizing the role of the bypass pathway in defining HSC properties.

•The differentiation of single-HSC clones was analyzed in a mathematical model•Dependence on the platelet bypass correlates with long-term HSC reconstitution•Blood cell production patterns distinguished the reconstitution potential of HSCs•Early platelet-to-erythrocyte chimerism ratio predicted HSC characteristics

The differentiation of single-HSC clones was analyzed in a mathematical model

Dependence on the platelet bypass correlates with long-term HSC reconstitution

Blood cell production patterns distinguished the reconstitution potential of HSCs

Early platelet-to-erythrocyte chimerism ratio predicted HSC characteristics

Stem cells research; Mathematical biosciences; Biological constraints