Quantifying cell dynamics in myelopoiesis during immune responses

Although changes in immune blood cell number is commonly used as a sign of infection or inflammation in the clinics, the cell dynamics parameters controlling cell numbers during an immune response (division, differentiation, and death) are not well understood. As myeloid cells are short lived, changes in myeloid cell numbers comes from cell production by myelopoiesis.

Given the importance of cell dynamics in immune response, we propose to unravel the cell dynamics of myelopoiesis during inflammation. However, few methods allow to measure in vivo the cell dynamics parameters.

Methods to study division in vivo can trace up 10 divisions, apart for the telomere measures that have no maximum but is restricted to cell types without telomerase activity, unlike our cells of interest.

As we estimate a minimum of 14 divisions from hematopoietic stem cells to myeloid cells, a new method to follow over 10 divisions is required.

This proposal will overcome this methodological barrier by developing the DivCounter a new method, to count division in vivo in mice.

Our innovation is: 1/ to implement a quantitative counter of division combining wet and dry lab. 2/ compatible with single cell transcriptomics to measure cell differentiation status with the required granularity. 3/ creating a new mouse model. Using the DivCounter, we will quantify for the first time the number of divisions in homeostatic myelopoiesis.

We will also infer division, differentiation and death rate, uncovering the understudied role of death in myelopoiesis.

We will also unravel how division and death change during emergency myelopoiesis and when and how myelopoiesis returns to homeostasis after inflammatory stimulations.

This knowledge will shed light on which of the cell dynamics parameters to intervene to change myeloid cell numbers, opening therapeutic perspective for the design of vaccines and immunotherapies. The DivCounter will serve other fields in which cell dynamics is key (cancer, development).