Maternal inflammation regulates fetal emergency myelopoiesis.

Neonates are highly susceptible to inflammation and infection. Here, we investigate how late fetal liver (FL) mouse hematopoietic stem and progenitor cells (HSPCs) respond to inflammation, testing the hypothesis that deficits in the engagement of emergency myelopoiesis (EM) pathways limit neutrophil output and contribute to perinatal neutropenia. We show that fetal HSPCs have limited production of myeloid cells at steady state and fail to activate a classical adult-like EM transcriptional program. Moreover, we find that fetal HSPCs can respond to EM-inducing inflammatory stimuli in vitro but are restricted by maternal anti-inflammatory factors, primarily interleukin-10 (IL-10), from activating EM pathways in utero. Accordingly, we demonstrate that the loss of maternal IL-10 restores EM activation in fetal HSPCs but at the cost of fetal demise. These results reveal the evolutionary trade-off inherent in maternal anti-inflammatory responses that maintain pregnancy but render the fetus unresponsive to EM activation signals and susceptible to infection.

Maternal IL-10 restricts fetal emergency myelopoiesis.

Neonates, in contrast to adults, are highly susceptible to inflammation and infection. Here we investigate how late fetal liver (FL) mouse hematopoietic stem and progenitor cells (HSPC) respond to inflammation, testing the hypothesis that deficits in engagement of emergency myelopoiesis (EM) pathways limit neutrophil output and contribute to perinatal neutropenia. We show that despite similar molecular wiring as adults, fetal HSPCs have limited production of myeloid cells at steady state and fail to activate a classical EM transcriptional program. Moreover, we find that fetal HSPCs are capable of responding to EM-inducing inflammatory stimuli in vitro , but are restricted by maternal anti-inflammatory factors, primarily interleukin-10 (IL-10), from activating EM pathways in utero . Accordingly, we demonstrate that loss of maternal IL-10 restores EM activation in fetal HSPCs but at the cost of premature parturition. These results reveal the evolutionary trade-off inherent in maternal anti-inflammatory responses that maintain pregnancy but render the fetus unresponsive to EM activation signals and susceptible to infection. HIGHLIGHTS: The structure of the HSPC compartment is conserved from late fetal to adult life.Fetal HSPCs have diminished steady-state myeloid cell production compared to adult.Fetal HSPCs are restricted from engaging in emergency myelopoiesis by maternal IL-10.Restriction of emergency myelopoiesis may explain neutropenia in septic neonates. eTOC BLURB: Fetal hematopoietic stem and progenitor cells are restricted from activating emergency myelopoiesis pathways by maternal IL-10, resulting in inadequate myeloid cell production in response to inflammatory challenges and contributing to neonatal neutropenia.

Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells.

Aging of the hematopoietic system promotes various blood, immune and systemic disorders and is largely driven by hematopoietic stem cell (HSC) dysfunction ( 1 ). Autophagy is central for the benefits associated with activation of longevity signaling programs ( 2 ), and for HSC function and response to nutrient stress ( 3,4 ). With age, a subset of HSCs increases autophagy flux and preserves some regenerative capacity, while the rest fail to engage autophagy and become metabolically overactivated and dysfunctional ( 4 ). However, the signals that promote autophagy in old HSCs and the mechanisms responsible for the increased regenerative potential of autophagy-activated old HSCs remain unknown. Here, we demonstrate that autophagy activation is an adaptive survival response to chronic inflammation in the aging bone marrow (BM) niche ( 5 ). We find that inflammation impairs glucose metabolism and suppresses glycolysis in aged HSCs through Socs3-mediated impairment of AKT/FoxO-dependent signaling. In this context, we show that inflammation-mediated autophagy engagement preserves functional quiescence by enabling metabolic adaptation to glycolytic impairment. Moreover, we demonstrate that transient autophagy induction via a short-term fasting/refeeding paradigm normalizes glucose uptake and glycolytic flux and significantly improves old HSC regenerative potential. Our results identify inflammation-driven glucose hypometabolism as a key driver of HSC dysfunction with age and establish autophagy as a targetable node to reset old HSC glycolytic and regenerative capacity. One-Sentence Summary: Autophagy compensates for chronic inflammation-induced metabolic deregulation in old HSCs, and its transient modulation can reset old HSC glycolytic and regenerative capacity.

Stromal niche inflammation mediated by IL-1 signalling is a targetable driver of haematopoietic ageing.

Haematopoietic ageing is marked by a loss of regenerative capacity and skewed differentiation from haematopoietic stem cells (HSCs), leading to impaired blood production. Signals from the bone marrow niche tailor blood production, but the contribution of the old niche to haematopoietic ageing remains unclear. Here we characterize the inflammatory milieu that drives both niche and haematopoietic remodelling. We find decreased numbers and functionality of osteoprogenitors at the endosteum and expansion of central marrow LepR+ mesenchymal stromal cells associated with deterioration of the sinusoidal vasculature. Together, they create a degraded and inflamed old bone marrow niche. Niche inflammation in turn drives the chronic activation of emergency myelopoiesis pathways in old HSCs and multipotent progenitors, which promotes myeloid differentiation and hinders haematopoietic regeneration. Moreover, we show how production of interleukin-1ß (IL-1ß) by the damaged endosteum acts in trans to drive the proinflammatory nature of the central marrow, with damaging consequences for the old blood system. Notably, niche deterioration, HSC dysfunction and defective regeneration can all be ameliorated by blocking IL-1 signalling. Our results demonstrate that targeting IL-1 as a key mediator of niche inflammation is a tractable strategy to improve blood production during ageing.

Aged hematopoietic stem cells are refractory to bloodborne systemic rejuvenation interventions.

While young blood can restore many aged tissues, its effects on the aged blood system itself and old hematopoietic stem cells (HSCs) have not been determined. Here, we used transplantation, parabiosis, plasma transfer, exercise, calorie restriction, and aging mutant mice to understand the effects of age-regulated systemic factors on HSCs and their bone marrow (BM) niche. We found that neither exposure to young blood, nor long-term residence in young niches after parabiont separation, nor direct heterochronic transplantation had any observable rejuvenating effects on old HSCs. Likewise, exercise and calorie restriction did not improve old HSC function, nor old BM niches. Conversely, young HSCs were not affected by systemic pro-aging conditions, and HSC function was not impacted by mutations influencing organismal aging in established long-lived or progeroid genetic models. Therefore, the blood system that carries factors with either rejuvenating or pro-aging properties for many other tissues is itself refractory to those factors.

Dysregulated haematopoietic stem cell behaviour in myeloid leukaemogenesis.

Haematopoiesis is governed by haematopoietic stem cells (HSCs) that produce all lineages of blood and immune cells. The maintenance of blood homeostasis requires a dynamic response of HSCs to stress, and dysregulation of these adaptive-response mechanisms underlies the development of myeloid leukaemia. Leukaemogenesis often occurs in a stepwise manner, with genetic and epigenetic changes accumulating in pre-leukaemic HSCs prior to the emergence of leukaemic stem cells (LSCs) and the development of acute myeloid leukaemia. Clinical data have revealed the existence of age-related clonal haematopoiesis, or the asymptomatic clonal expansion of mutated blood cells in the elderly, and this phenomenon is connected to susceptibility to leukaemic transformation. Here we describe how selection for specific mutations that increase HSC competitive fitness, in conjunction with additional endogenous and environmental changes, drives leukaemic transformation. We review the ways in which LSCs take advantage of normal HSC properties to promote survival and expansion, thus underlying disease recurrence and resistance to conventional therapies, and we detail our current understanding of leukaemic 'stemness' regulation. Overall, we link the cellular and molecular mechanisms regulating HSC behaviour with the functional dysregulation of these mechanisms in myeloid leukaemia and discuss opportunities for targeting LSC-specific mechanisms for the prevention or cure of malignant diseases.

Losing Sense of Self and Surroundings: Hematopoietic Stem Cell Aging and Leukemic Transformation.

Aging leads to functional decline of the hematopoietic system, manifested by an increased incidence of hematological disease in the elderly. Deterioration of hematopoietic integrity with age originates in part from the degraded functionality of hematopoietic stem cells (HSCs). Here, we review recent findings identifying changes in metabolic programs and loss of epigenetic identity as major drivers of old HSC dysfunction and their role in promoting leukemia onset in the context of age-related clonal hematopoiesis (ARCH). We discuss how inflammatory and growth signals from the aged bone marrow (BM) microenvironment contribute to cell-intrinsic HSC aging phenotypes and favor leukemia development. Finally, we address how metabolic, epigenetic, and inflammatory pathways could be targeted to enhance old HSC fitness and prevent leukemic transformation.