While many aspects of blood production are now well understood, the spatial organization of myeloid differentiation in the bone marrow (BM) remains unknown. Here, we use imaging to track granulocyte/macrophage progenitor (GMP) behavior during emergency and leukemic myelopoiesis. At steady state, we find individual GMPs scattered throughout the BM. During regeneration, we observe expanding GMP patches forming defined GMP clusters, which, in turn, locally differentiate into granulocytes. We describe how the timed release of important BM niche signals (SCF, IL-1β, G-CSF, TGF-β, CXCL4) and activation of an inducible Irf8/β-catenin progenitor self-renewal network controls the transient formation of regenerating GMP clusters. In leukemia, we show that GMP clusters are constantly produced due to persistent activation of the self-renewal network and lack of termination cytokines that normally restore stem cell quiescence. Our results uncover a previously unrecognized dynamic behavior of GMPs in situ, which tunes emergency myelopoiesis and is hijacked in leukemia.

Intracochlear perfusion and gross potential recording of sound-evoked neural and hair cell responses were used to study the site of action of the L-type Ca(2+) channel blocker nimodipine in the guinea pig inner ear. In agreement with previous work nimodipine (1-10 microM) caused changes in both the compound auditory nerve action potential (CAP) and the DC component of the hair cell receptor potential (summating potential, or SP) in normal cochleae. For 20-kHz stimulation, the effect of nimodipine on the CAP threshold was markedly greater than the effect on the threshold of the negative SP. This latter result was consistent with a dominant action of nimodipine at the final output stage of cochlear transduction: either the release of transmitter from inner hair cells (IHCs) or the postsynaptic spike generation process. In animals in which the outer hair cells (OHCs) had been destroyed by prior administration of kanamycin, nimodipine still caused a large change in the 20-kHz CAP threshold, but even less change was observed in the negative SP threshold than in normal cochleae. When any neural contamination of the SP recording in kanamycin-treated animals was removed by prior intracochlear perfusion with TTX, nimodipine caused no significant change in SP threshold. Some features of the data also suggest a separate involvement of nimodipine-sensitive channels in OHC function. Perfusion of the cochlea with solutions containing Ni(2+) (100 microM) caused no measurable change in either CAP or SP. These results are consistent with, but do not prove, the notion that L-type channels are directly involved in controlling transmitter release from the IHCs and that T-type Ca(2+) channels are not involved at any stage of cochlear transduction.

Hematopoietic aging is marked by a loss of regenerative capacity and skewed differentiation from hematopoietic stem cells (HSC) leading to impaired blood production. Signals from the bone marrow (BM) niche tailor blood production, but the contribution of the old niche to hematopoietic aging remains unclear. Here, we characterize the in ammatory milieu that drives both niche and hematopoietic remodeling. We nd decreased numbers and functionality of osteoprogenitors (OPr) and expansion of pro-in ammatory perisinusoidal mesenchymal stromal cells (MSC) with deterioration of the sinusoidal vasculature, which together create a degraded and in amed old BM niche. Niche in ammation, 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 all be ameliorated by blocking IL-1 signaling. Our results demonstrate that targeting IL-1 as a key mediator of niche in ammation is a tractable strategy to improve blood production during aging. HighlightsBoth endosteal and central marrow niche populations are remodeled with age Old niche populations show disruption of cell identity and enrichment of in ammatory response genes Emergency myelopoiesis pathways are chronically activated in response to niche in ammation Targeting niche-mediated IL-1 signaling attenuates stromal and blood aging Etoc BlurbPassegué and colleagues examine the aged bone marrow niche microenvironment to understand its contribution to blood aging and identify targetable factor(s) for functional anti-aging interventions. They show that crosstalk between the in amed niche and the in amed hematopoietic system leads to degraded blood production both at steady state and during regeneration, and identify IL-1 as a major targetable driver of age-related niche and blood system deterioration.