Myeloid progenitor cluster formation drives regenerative and leukemic myelopoiesis

Hérault, Aurélie; Leong, Stephanie; Calero, Fernando Sánchez; Zhang, Si Yi; Pietras, Eric M.; Chu, Haihua; Barry-Holson, Keegan; Armstrong, Scott A.; Göttgens, Berthold; Passegué, Emmanuelle

doi:10.1016/j.exphem.2016.06.157

Cited by 2 publications

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“…Finally, we observed the presence of GMP patches in the old marrow cavity ( Fig. 3e ), which are never found in young mice absent a regenerative challenge 37 . Together, these results demonstrate a profound hematopoietic remodeling with constitutive activation of emergency myelopoiesis pathways from old HSCs with increased production of MPP3, myeloid-reprogramming of MPP4, and GMP cluster formation likely caused by persistent exposure to niche inflammation.…”

Section: Inflammatory Remodeling Of the Old Blood Systemmentioning

confidence: 69%

Stromal inflammation is a targetable driver of hematopoietic aging

Verovskaya

Mitchell

Calero-Nieto

et al. 2021

Preprint

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Hematopoietic aging is marked by a loss of regenerative capacity and skewed differentiation from hematopoietic stem cells (HSC) leading to dysfunctional blood production. Signals from the bone marrow (BM) niche dynamically tailor hematopoiesis, but the effect of aging on the niche microenvironment and the contribution of the aging niche to blood aging still remains unclear. Here, we characterize the inflammatory milieu in the aged marrow cavity that drives both stromal and hematopoietic remodeling. We find decreased numbers and functionality of osteogenic mesenchymal stromal cells (MSC) at the endosteum and expansion of pro-inflammatory perisinusoidal MSCs with deterioration of sinusoidal endothelium in the central marrow, which together create a degraded and inflamed old niche. Molecular mapping at single cell resolution confirms disruption of cell identities and enrichment of inflammatory response genes in niche populations. Niche inflammation, in turn, drives chronic activation of emergency myelopoiesis pathways in old HSCs and multipotent progenitors (MPP), which promotes myeloid differentiation at the expense of lymphoid and erythroid commitment and hinders hematopoietic regeneration. Remarkably, niche deterioration, HSC dysfunction and defective hematopoietic regeneration, can be improved by blocking inflammatory IL-1 signaling. Our results demonstrate that targeting niche inflammation is a tractable strategy to restore blood production during aging.

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Section: Inflammatory Remodeling Of the Old Blood Systemmentioning

confidence: 69%

Stromal inflammation is a targetable driver of hematopoietic aging

Verovskaya

Mitchell

Calero-Nieto

et al. 2021

Preprint

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“…The MPP3 can proliferate or differentiate into the granulocyte-monocyte progenitor (GMP). GMPs can proliferate and/or physically cluster together into pGMP 97 . This clustering facilitates differentation into cGMP that, in turn, differentiate into promyelocytes (PM) and myelocytes (M), thereby forming clusters of these cells in the bone marrow 97 .…”

Section: Discussionmentioning

confidence: 99%

“…GMPs can proliferate and/or physically cluster together into pGMP 97 . This clustering facilitates differentation into cGMP that, in turn, differentiate into promyelocytes (PM) and myelocytes (M), thereby forming clusters of these cells in the bone marrow 97 . During these last differentiation steps the progenitors loose their propensity to proliferate (mediated by the expression of C/EBP   and continue to mature towards mature neutrophils via metamyelocytes and banded cells (see figure 2).…”

Section: Discussionmentioning

confidence: 99%

The journey of neutropoiesis: how complex landscapes in bone marrow guide continuous neutrophil lineage determination

Overbeeke

Tak

Koenderman

2022

Blood

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Neutrophils are the most abundant white blood cell, and differentiate in homeostasis in the bone marrow from hematopoietic stem cells (HSCs) via multiple intermediate progenitor cells into mature cells that enter the circulation. Recent findings support a continuous model of differentiation in the bone marrow of heterogeneous HSCs and progenitor populations. Cell fate decisions both at the level of proliferation and differentiation are enforced through expression of lineage-determining transcription factors (LDTFs) and their interactions, that are influenced by both intrinsic (intracellular) as well as extrinsic (extracellular) mechanisms. Neutrophil homeostasis is subjected to positive feedback loops, stemming from the gut microbiome, as well as negative feedback loops resulting from the clearance of apoptotic neutrophils by mature macrophages. Finally, the cellular kinetics regarding the replenishing of the mature neutrophil pool is discussed in light of recent, contradictory data.

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Myeloid progenitor cluster formation drives regenerative and leukemic myelopoiesis

Cited by 2 publications

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Stromal inflammation is a targetable driver of hematopoietic aging

Stromal inflammation is a targetable driver of hematopoietic aging

The journey of neutropoiesis: how complex landscapes in bone marrow guide continuous neutrophil lineage determination

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