Research Highlight #3: IL-1 regulates haematopoietic stem cell pool size via PU.1

Today, we move to mouse adult haematopoiesis, with an elegant work on inflammation and stem cell biology. As always, feedback is more than welcome!

Chronic inflammation is one of the classic events underlying aging and infection response. When associated with loss of quiescence in haematopoietic stem cells (HSCs), it is commonly the initiating event in leukemia progression. Chavez and colleagues present the impact of chronic interleukin-1 (IL-1) exposure on the most immature HSCs. First of all, they exposed adult mice to IL-1β for 20 days, observing major changes in the HSCs transcriptome. In particular, IL-1β treatment reduced the expression of genetic programs associated with cell cycle progression and protein synthesis. In vitro short-term culture of the most immature HSCs (called LT-HSC), in the presence of IL-1β, confirmed a slower cell cycle entry. Using a genetic reporter for the myeloid master regulator Pu.1, the authors proved that IL-1 is directly linked to the transcription factor increased activity. Specifically, PU.1 is able to bind more than two-thirds of the genes downregulated by IL-1β exposure. Finally, the authors used a genetic mouse model for reduced Pu.1 activity, proving elegantly that an inefficient PU.1 opens the way to the aberrant increase in LT-HSCs cell cycle activity and protein synthesis, leading to an increased cellular pool of stem cells.

Taken altogether, those results describe an IL-1 – PU.1 system that physiologically contributes to stabilizing the number of LT-HSCs. Those results are relevant, because IL-1β prematurely initiate myeloid differentiation, and in general promote the expansion of white blood cells. How to conciliate therefore those apparently contradicting results? Here, the authors focused on a smaller subset of HSCs, and affirm that PU.1 in these cells acts as an activation barrier against unwanted proliferation, while still able to prime HSCs for myeloid differentiation. It will be interesting to assess if other signals could activate similar pool size regulation mechanisms for HSCs.

Chavez J et al. “PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress”

Doi: https://doi.org/10.1101/2020.05.18.102830

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