Inflammation coordinates tissue regeneration via damaged cell removal and stem cell activation. Hematopoietic stem cells (HSCs) survive inflammatory stress that kills other blood cells, but the ...mechanisms underlying this effect remain poorly understood. Here, we find that tumor necrosis factor α (TNF-α) acts differently on HSCs and progenitors, thus facilitating hematopoietic clearance and promoting regeneration. We show that while inducing myeloid progenitor apoptosis, TNF-α promotes HSC survival and myeloid differentiation by activating a strong and specific p65-nuclear factor κB (NF-κB)-dependent gene program that primarily prevents necroptosis rather than apoptosis, induces immunomodulatory functions, and poises HSCs for myeloid cell production. These TNF-α-driven mechanisms are critical for HSC response to inflammatory stress but are also hijacked in aged and malignant HSCs. Our results reveal several TNF-α-mediated pro-survival mechanisms unique to HSCs, highlight an important role for necroptosis in HSC killing, and establish TNF-α as a major pro-survival and pro-regeneration factor for HSCs.
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•A TNF-α-p65-cIAP2 axis supports HSC survival during inflammation•TNF-α drives PU.1 upregulation and myeloid regeneration from HSCs•TNF-α prevents HSC necroptosis and induces T cell suppression activity•The HSC-specific TNF-α signature is upregulated in aged and malignant HSCs
Passegué and colleagues reveal a complex role for TNF-α in hematopoietic regeneration. Inflammation-induced TNF-α eliminates myeloid progenitors but prevents HSC necroptosis and initiates emergency myelopoiesis through NF-κB-dependent mechanisms, hence promoting HSC survival and hematopoietic regeneration. Persistent TNF-α-driven hematopoietic regeneration underlies chronic inflammation and can contribute to aging and malignant hematopoiesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract SCI-41
Blood development is organized hierarchically, starting with a rare but well-defined population of hematopoietic stem cells (HSC) that give rise to a series of committed progenitors ...and mature cells with exclusive functional and immunophenotypic properties. HSC are the only cells within the hematopoietic system that self-renew for life, whereas other hematopoietic cells are short-lived and committed to the transient production of mature blood cells. Under steady-state conditions, HSC are a largely quiescent, slowly cycling cell population that, in response to environmental cues, is capable of dramatic expansion and contraction to ensure proper homeostatic replacement of all blood cells. While considerable work has deciphered the molecular networks controlling HSC activity, still little is known about how these mechanisms are integrated at the cellular level to ensure life-long maintenance of a functional HSC compartment. HSC reside in hypoxic niches in the bone marrow microenvironment, and are mostly kept quiescent in order to minimize stress and the potential for damage associated with cellular respiration and cell division. Recently, we have shown that HSC can also engage specialized response mechanisms that protect them from the killing effect of environmental stresses such as ionizing radiation (IR). We demonstrated that long-lived HSC, in contrast to short-lived myeloid progenitors, have enhanced expression of pro-survival members of the bcl2 gene family and robust induction of p53-mediated DNA damage response, which ensures their specific survival and repair following IR exposure. We reasoned that HSC have other unique protective features, which allow them to contend with a variety of cellular insults and damaged cellular components while maintaining their lifelong functionality and genomic integrity. We will present some of our recent findings on the fundamental mechanisms of stress-response that preserve HSC fitness during periods of metabolic stress, and allow for survival and repair following environmental stress associated with DNA damaging agents. It is now clear that oncogenic insults in diseases such as myeloproliferative neoplasms (MPN) can transform HSC and dramatically alter their biological functions leading to the emergence of leukemia-initiating stem cells (LSC), which are left untouched by most current therapies and can thereby mediate disease relapse. We will also discuss how transformed HSC may take advantage of some deregulated features of these normal stress-response mechanisms to escape therapeutic killing.
No relevant conflicts of interest to declare.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Highlights • A dynamic metabolic state underlies fate transitions in HSCs. • A glycolytic bias enforces quiescence whereas fatty acid oxidation influences commitment. • Mitochondria and ROS control ...the balance between self-renewal and differentiation. • Metabolic energetics offer new strategies to target blood malignancies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Genetically modified mice have provided important insights into the biological functions of the dimeric transcription factor complex AP-1. Extensive analyses of mice and cells with genetically ...modified Fos or Jun proteins provide novel insights into the physiological functions of AP-1 proteins. Using knock-out strategies it was found that some components, such as c-Fos, FosB and JunD are dispensable, whereas others, like c-Jun, JunB and Fra-1 are essential in embryonic development and/or in the adult organism. Besides the specific roles of AP-1 proteins in developmental processes, we are beginning to obtain a better molecular understanding of the cell-context dependent function of AP-1 in cell proliferation and apoptosis, in bone biology as well as in multistep tumorigenesis.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In the adult brain, the neural stem cell (NSC) pool comprises quiescent and activated populations with distinct roles. Transcriptomic analysis revealed that quiescent and activated NSCs exhibited ...differences in their protein homeostasis network. Whereas activated NSCs had active proteasomes, quiescent NSCs contained large lysosomes. Quiescent NSCs from young mice accumulated protein aggregates, and many of these aggregates were stored in large lysosomes. Perturbation of lysosomal activity in quiescent NSCs affected protein-aggregate accumulation and the ability of quiescent NSCs to activate. During aging, quiescent NSCs displayed defects in their lysosomes, increased accumulation of protein aggregates, and reduced ability to activate. Enhancement of the lysosome pathway in old quiescent NSCs cleared protein aggregates and ameliorated the ability of quiescent NSCs to activate, allowing them to regain a more youthful state.
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
Hematopoietic stem cells (HSCs) rely on instructive cues from the bone marrow (BM) niche to maintain their quiescence and adapt blood production to the organism’s needs. Alterations in the BM niche ...are commonly observed in blood malignancies and directly contribute to the aberrant function of disease-initiating leukemic stem cells (LSCs). Here, we review recent insights into the cellular and molecular determinants of the normal HSC niche and describe how genetic changes in stromal cells and leukemia-induced BM niche remodeling contribute to blood malignancies. Moreover, we discuss how these findings can be applied to non-cell-autonomous therapies targeting the LSC niche.
Passegué and colleagues review recent insights into the cellular and molecular determinants of the normal hematopoietic stem cell niche and describe how genetic changes in stromal cells and leukemia-induced niche remodeling contribute to blood malignancies. They also discuss strategies for developing non-cell-autonomous therapies targeting the leukemia stem cell niche.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
With age, haematopoietic stem cells lose their ability to regenerate the blood system, and promote disease development. Autophagy is associated with health and longevity, and is critical for ...protecting haematopoietic stem cells from metabolic stress. Here we show that loss of autophagy in haematopoietic stem cells causes accumulation of mitochondria and an activated metabolic state, which drives accelerated myeloid differentiation mainly through epigenetic deregulations, and impairs haematopoietic stem-cell self-renewal activity and regenerative potential. Strikingly, most haematopoietic stem cells in aged mice share these altered metabolic and functional features. However, approximately one-third of aged haematopoietic stem cells exhibit high autophagy levels and maintain a low metabolic state with robust long-term regeneration potential similar to healthy young haematopoietic stem cells. Our results demonstrate that autophagy actively suppresses haematopoietic stem-cell metabolism by clearing active, healthy mitochondria to maintain quiescence and stemness, and becomes increasingly necessary with age to preserve the regenerative capacity of old haematopoietic stem cells.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
Hematopoiesis is the hierarchical process in which all lineages of blood cells are produced by self-renewing hematopoietic stem cells (HSCs) in the bone marrow (BM). While the regulatory factors that ...maintain proper HSC function and lineage output under normal conditions are well understood, significantly less is known about how HSC fate is regulated in response to inflammation or disease. As many blood disorders are associated with overproduction of pro-inflammatory cytokines, significant interest has emerged in understanding the impact of these factors on HSC function. In this review we highlight key advances demonstrating the impact of pro-inflammatory cytokines on the biology of HSCs and the BM niche, and address ongoing questions regarding their role in normal and pathogenic hematopoiesis.
•Emerging work identifies how pro-inflammatory cytokines impact HSC biology.•Significant interest lies in how inflammation remodels the BM niche in disease.•Identifying how chronic inflammation alters HSC function is a critical new frontier.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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.
Metabolic activation and epigenetic alterations emerge as major contributors to the decline of hematopoietic stem cell (HSC) function with age. It has also become evident that epigenetic and metabolic regulation of HSCs are tightly linked.Recent data provide new insights into the role of the bone marrow niche microenvironment in regulating HSC function. In particular, the role of the inflammatory microenvironment in enforcing the preferential transformation and survival of mutation-bearing clones has emerged during aging and leukemogenesis.Mutations in epigenetic modifier and metabolic genes are associated with age-related clonal hematopoiesis (ARCH). Specific mutational signatures of ARCH can predict leukemia onset years before diagnosis and ARCH has been found associated with a range of nonhematopoietic morbidities and high mortality.Restoration of metabolic and epigenetic profiles and blocking of inflammatory signaling have been shown to be prime targets for the rejuvenation of aged HSCs and prevention of leukemic transformation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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