Contributions
Abstract: S1593
Type: Oral Presentation
Presentation during EHA23: On Sunday, June 17, 2018 from 08:45 - 09:00
Location: Room A10
Background
Hematopoietic stem cells (HSC) are responsible for the on demand production of mature blood cells both in homeostasis and in response to stress situations such as injury and infection. HSCs reside in specialized niches in bone marrow (BM), which regulate their function. These niches are perceived as dynamic entities with the capacity to sense and respond to specific requirements in blood cell production, but the mechanisms underlying this dynamic regulation remain unclear. Accumulating evidence indicate that HSCs are highly heterogeneous, and different BM niches have been proposed, potentially supporting different subsets of HSCs. We recently identified a distinct subset of HSCs, which are molecularly and functionally primed for platelet replenishment (Carrelha J. et al, Nature 2018). However, the role of the niche in the regulation of platelet-biased HSC function is still unknown.
Aims
This work aims at investigating the role of the BM niche in the response of platelet-biased HSCs to platelet depletion.
Methods
Thrombocytopenia was induced in mice by the administration of an antibody against the platelet GPIbα receptor, leading to fast and efficient platelet depletion. We used a RNA-sequencing approach to analyze different BM niche cell populations and HSCs in order to identify signals involved in the HSC response to platelet depletion.
Results
Platelet-biased HSCs are rapidly and selectively recruited into cell cycle in response to platelet depletion, through a feedback mechanism to replenish platelet numbers and homeostasis. Here we identified Interleukin-1 (IL-1) as a cytokine released upon acute platelet depletion and specifically sensed by niche LepR+ perivascular cells. Abrogation of IL-1 signaling specifically in LepR+ niche cells but not in hematopoietic cells impaired the platelet-biased HSC response to platelet depletion. This process was found to be dependent on platelet activation.
Conclusion
This work uncovers a molecular mechanism involving the pro-inflammatory signal IL-1 and the niche perivascular cell compartment in the rapid activation of platelet biased HSCs to thrombocytopenia, highlighting a mechanism by which a distinct subclass of HSCs senses and responds to the loss of the lineage for which it is intrinsically primed for.
Session topic: 24. Hematopoiesis, stem cells and microenvironment
Keyword(s): Hematopoietic microenvironment, Hematopoietic Stem Cell, inflammation, Thrombocytopenia
Abstract: S1593
Type: Oral Presentation
Presentation during EHA23: On Sunday, June 17, 2018 from 08:45 - 09:00
Location: Room A10
Background
Hematopoietic stem cells (HSC) are responsible for the on demand production of mature blood cells both in homeostasis and in response to stress situations such as injury and infection. HSCs reside in specialized niches in bone marrow (BM), which regulate their function. These niches are perceived as dynamic entities with the capacity to sense and respond to specific requirements in blood cell production, but the mechanisms underlying this dynamic regulation remain unclear. Accumulating evidence indicate that HSCs are highly heterogeneous, and different BM niches have been proposed, potentially supporting different subsets of HSCs. We recently identified a distinct subset of HSCs, which are molecularly and functionally primed for platelet replenishment (Carrelha J. et al, Nature 2018). However, the role of the niche in the regulation of platelet-biased HSC function is still unknown.
Aims
This work aims at investigating the role of the BM niche in the response of platelet-biased HSCs to platelet depletion.
Methods
Thrombocytopenia was induced in mice by the administration of an antibody against the platelet GPIbα receptor, leading to fast and efficient platelet depletion. We used a RNA-sequencing approach to analyze different BM niche cell populations and HSCs in order to identify signals involved in the HSC response to platelet depletion.
Results
Platelet-biased HSCs are rapidly and selectively recruited into cell cycle in response to platelet depletion, through a feedback mechanism to replenish platelet numbers and homeostasis. Here we identified Interleukin-1 (IL-1) as a cytokine released upon acute platelet depletion and specifically sensed by niche LepR+ perivascular cells. Abrogation of IL-1 signaling specifically in LepR+ niche cells but not in hematopoietic cells impaired the platelet-biased HSC response to platelet depletion. This process was found to be dependent on platelet activation.
Conclusion
This work uncovers a molecular mechanism involving the pro-inflammatory signal IL-1 and the niche perivascular cell compartment in the rapid activation of platelet biased HSCs to thrombocytopenia, highlighting a mechanism by which a distinct subclass of HSCs senses and responds to the loss of the lineage for which it is intrinsically primed for.
Session topic: 24. Hematopoiesis, stem cells and microenvironment
Keyword(s): Hematopoietic microenvironment, Hematopoietic Stem Cell, inflammation, Thrombocytopenia