Hematopoiesis and the behavior of hematopoietic stem and progenitor cells (HSPCs) are regulated by the bone marrow niche. Here, we introduce the major niche cell types in bone marrow and their response to stress condition. We highlight the hematopoietic response and bone marrow niche adaptation to inflammatory condition and non-hematopoietic diseases, which are not systematically summarized. These emerging data suggest targeting hematopoiesis and bone marrow niche may provide novel therapeutic target to precisely control the progression of the diseases.

Sepsis is a life-threatening multiple organ dysfunction resulting from a dysregulated host response to infection, and patients with sepsis always exhibit a state of immune disorder characterized by both overwhelming inflammation and immunosuppression. The aging of immune system, namely "immunosenescence", has been reported to be correlated with high morbidity and mortality in elderly patients with sepsis. Initially, immunosenescence was considered as a range of age-related alterations in the immune system. However, increasing evidence has proven that persistent inflammation or even a short-term inflammatory challenge during sepsis could trigger accelerated aging of immune cells, which might further exacerbate inflammatory cytokine storm and promote the shift towards immunosuppression. Thus, premature immunosenescence is found in young sepsis individuals, which further aggravates immune disorders and induces the progression of sepsis. Furthermore, in old sepsis patients, the synergistic effects of both sepsis and aging may cause immunosenescence-associated alterations more significantly, resulting in more severe immune dysfunction and a worse prognosis. Therefore, it is necessary to explore the potential therapeutic strategies targeting immunosenescence during sepsis.

Rapid hematopoietic adaptations are important for building and sustaining the biological response to β-glucan. The signals involved in these early events have not yet been fully explored. Given that type I interferons are produced in response to β-glucan and can profoundly impact hematopoietic stem cell (HSC) function, we hypothesized that this pathway may be involved in the early bone marrow response to β-glucan. In vivo administration of β-glucan led to local interferon-α production in the peritoneal cavity and bone marrow, upregulation of its receptor, IFNAR1, specifically on long-term hematopoietic stem cells (LT-HSCs), and broad expansion of downstream progenitor subpopulations. We demonstrate that intact type I interferon signaling is critical for β-glucan-mediated LT-HSC proliferation, mitochondrial activity, and glycolytic commitment. By determining that type I interferon signaling is important for LT-HSCs, which sit at the apex of the hematopoietic hierarchy, we uncover an important component of the early inflammatory response to β-glucan.

Ginsenoside Rg1 is a key bioactive compound in ginseng, a traditional herbal medicine known for tonifying qi and nourishing blood, traditionally used to replenish "qi" by regulating hematopoietic function. But its underlying mechanism remains to be elucidated.

This study aims to delve into the role of Rg1 on senescent hematopoiesis and its mechanisms.

A model of D-galactose-induced hematopoietic injury was established with ginsenoside Rg1. The hematopoietic supportive effect of Rg1 was assessed by quantifying the levels of hematopoietic supportive factors VCAM1, CXCL12 and SCF, CFU-Mix formation and cellular senescence; and the levels of inflammatory factors and oxidative stress were measured by ELISA in the serum and cellular supernatant of mice. Co-culture technique was used to examine the ability of Rg1 to restore impaired hematopoiesis by improving the inflammatory hematopoietic microenvironment. For mechanism exploration, RNA-Seq was used to detect differential genes in Rg1-treated MSCs, GO- and KEGG-based enrichment analyses were used to screen the key pathways in which Rg1 exerts its effects, and molecular docking was used to demonstrate the feasibility of molecular interconnections between Rg1 and TLR2. To further explore the mechanism, pathway activators were further used and the expression levels of target proteins downstream of the TLR2 pathway were quantified using Western blotting.

Rg1 decreased the levels of inflammatory factors IL-1β, IL-6 and TNFα, while enhancing the expression of hematopoietic support factors in senescent MSCs, thereby improving the self-renewal and differentiation of aged HSPCs. Additionally, Rg1 also delayed HSPC senescence and reduced the level of oxidative stress. KEGG and GO were enriched for the Toll/NF-κB signaling pathway, based on differential genes obtained by transcriptional sequencing. Rg1 could inhibit the elevated levels of MyD88, NF-κB-p65 and IκBα proteins, and their phosphorylation levels by binding to TLR2 protein and inhibiting them. In conclusion, Rg1 ameliorates the inflammatory hematopoietic microenvironment induced by MSCs senescence via the TLR2/NF-κB-p65 signaling pathway, alleviating HSPCs senescence.

Our results reveal the mechanism by which Rg1 regulates HSPCs function and represent a potential therapeutic strategy for hematopoietic dysfunction, highlighting the potential value of traditional Chinese medicine extracts in clinical applications.

Tumor-induced systemic accumulation and polarization of neutrophils to an immunosuppressive phenotype is a potent driver of metastasis formation. Yet, how mammary tumors reprogram granulopoiesis at the molecular level and when tumor imprinting occurs during neutrophil development remains underexplored. Here, we combined single-cell, chromatin and functional analyses to unravel the tumor-driven reprogramming of granulopoiesis in the bone marrow, along with intervention studies aimed at reversing this process. We observe that mammary tumors accelerate commitment to the neutrophil lineage at the expense of lymphopoiesis and erythropoiesis without stimulating the development of a novel myeloid lineage. Moreover, tumor-directed immunosuppressive imprinting of neutrophils starts early in hematopoiesis. Treatment with anti-IL-1β normalizes tumor-induced granulopoiesis, reducing neutrophil immunosuppressive phenotype and mitigating metastatic spread. Together, these data provide molecular insights into the aberrant, tumor-driven neutrophil differentiation pathway leading to metastasis-promoting chronic inflammation and how it can be reversed to reduce metastatic spread.

Inflammation is a driving force of hematopoietic stem cells (HSCs) aging, causing irreversible exhaustion of functional HSCs. However, the underlying mechanism of HSCs erosion by inflammatory insult remains poorly understood. Here, we find that transient LPS exposure primes aged HSCs to undergo accelerated differentiation at the expense of self-renewal, leading to depletion of HSCs. Meanwhile, the central regulator nuclear factor kappa B (NF-κB) mediating functional impairment by inflammation insult induces differential transcriptional response in aged HSCs compared with young HSCs, with precocious activation of myeloid lineage genes. Altered compartmentalization and chromatin loop formation are associated with aging-related differential transcriptional response in HSCs upon lipopolysaccharide (LPS) stimulation. Mechanistically, enhancer and promoter regions of myeloid lineage genes in aged HSCs are more accessible and display more rapid and prominent CTCF occupancy upon LPS stimulation. Our study provides comprehensive resources for the three-dimensional (3D) genome structure of HSCs and sheds light into the ordered genome organization and the associated transcriptome signature underlying HSCs aging.

Upon inflammation, the bone marrow (BM) landscape undergoes significant architectural and functional modifications. Stimulation of the hematopoietic niche triggers a series of lightning events, which begin with stem/progenitor blood elements mobilization and culminates with the activation of immune responses. Ageing partially mirrors this process, albeit with a propensity towards chronic inflammation and immune dysfunction. Age-related chronic inflammation disrupts bone homeostasis and accompanies impaired tissue regeneration. Thus, focusing on the bone marrow's dynamics during inflammatory bone diseases could lay the way for the development of novel therapeutic platforms aimed at niche reprogramming. Herein, we summarize inflammatory and age-induced processes in multiple BM compartments, with particular reference to hematopoietic, stromal stem/progenitor cells, and mature immunocytes. Finally, we focus on autophagy and its potential to clinically re-modulate the pathological "flogistic" bias, possibly by restoring functional phenotypes within the bone marrow niche elements.

Adenosine signaling is emerging as a key regulator of hematopoietic lineage commitment, influencing both erythropoiesis and myelopoiesis. This review explores the distinct roles of adenosine receptors in balancing these processes, particularly under stress conditions. Since adenosine extracellular levels are increased in multiple hematological disorders, including sickle cell disease, deciphering the mechanisms downstream of adenosine receptor activation is crucial to understand the pathophysiology of these conditions.

Extracellular adenosine levels in the bone marrow microenvironment are tightly regulated by CD39/CD73 activity and ENT1 uptake. Recent studies have shown that ENT1-mediated adenosine transport is crucial for adenosine intracellular metabolism and normal erythropoiesis, while increased extracellular adenosine levels impact hematopoietic differentiation through adenosine receptor activation.. High dose of exogenous adenosine inhibits erythroid proliferation by inducing G1 arrest and p53-mediated apoptosis. Furthermore, A2B and A3 receptor signaling inhibits erythroid differentiation, while adenosine signaling through A3 also favors granulopoiesis.

Collectively, these findings highlight adenosine signaling as a critical and multifaceted regulator of hematopoietic balance, offering novel insights into its therapeutic potential for managing disorders characterized by ineffective erythropoiesis and aberrant myelopoiesis.

SARS-CoV-2 can cause a variety of post-acute sequelae including Long COVID19 (LC), a complex, multisystem disease characterized by a broad range of symptoms including fatigue, cognitive impairment, and post-exertional malaise. The pathogenesis of LC is incompletely understood. In this study, we performed comprehensive cellular and transcriptional immunometabolic profiling within a cohort that included SARS-CoV-2-naïve controls (NC, N=30) and individuals with prior COVID-19 (~4-months) who fully recovered (RC, N=38) or went on to experience Long COVID symptoms (N=58). Compared to the naïve controls, those with prior COVID-19 demonstrated profound metabolic and immune alterations at the proteomic, cellular, and epigenetic level. Specifically, there was an enrichment in immature monocytes with sustained inflammasome activation and oxidative stress, elevated arachidonic acid levels, decreased tryptophan, and variation in the frequency and phenotype of peripheral T-cells. Those with LC had increased CD8 T-cell senescence and a distinct transcriptional profile within CD4 and CD8 T-cells and monocytes by single cell RNA sequencing. Our findings support a profound and persistent immunometabolic dysfunction that follows SARS-CoV-2 which may form the pathophysiologic substrate for LC. Our findings suggest that trials of therapeutics that help restore immune and metabolic homeostasis may be warranted to prevent, reduce, or resolve LC symptoms.

Clonal dominance characterizes hematopoiesis during aging and increases susceptibility to blood cancers and common nonmalignant disorders. VEXAS syndrome is a recently discovered, adult-onset, autoinflammatory disease burdened by a high mortality rate and caused by dominant hematopoietic clones bearing somatic mutations in the UBA1 gene. However, pathogenic mechanisms driving clonal dominance are unknown. Moreover, the lack of disease models hampers the development of disease-modifying therapies. In the present study, we performed immunophenotype characterization of hematopoiesis and single-cell transcriptomics in a cohort of nine male patients with VEXAS syndrome, revealing pervasive inflammation across all lineages. Hematopoietic stem and progenitor cells (HSPCs) in patients are skewed toward myelopoiesis and acquire senescence-like programs. Humanized models of VEXAS syndrome, generated by inserting the causative mutation in healthy HSPCs through base editing, recapitulated proteostatic defects, cytological alterations and senescence signatures of patients' cells, as well as hematological and inflammatory disease hallmarks. Competitive transplantations of human UBA1-mutant and wild-type HSPCs showed that, although mutant cells are more resilient to the inflammatory milieu, probably through the acquisition of the senescence-like state, wild-type ones are progressively exhausted and overwhelmed by VEXAS clones, overall impairing functional hematopoiesis and leading to bone marrow failure. Our study unveils the mechanism of clonal dominance and provides models for preclinical studies and preliminary insights that could inform therapeutic strategies.

Inflammatory cytokines are fundamental mediators of the organismal response to injury, infection, or other harmful stimuli. To elucidate the early and mostly direct transcriptional signatures of inflammatory cytokines, we profiled all immunologic cell types by RNAseq after systemic exposure to IL1β, IL6, and TNFα. Our results revealed a significant overlap in the responses, with broad divergence between myeloid and lymphoid cells, but with very few cell-type-specific responses. Pathway and motif analysis identified several main controllers (NF-κB, IRF8, and PU.1), but the largest portion of the response appears to be mediated by MYC, which was also implicated in the response to γc cytokines. Indeed, inflammatory and γc cytokines elicited surprisingly similar responses (∼50% overlap in NK cells). Significant overlap with interferon-induced responses was observed, paradoxically in lymphoid but not myeloid cell types. These results point to a highly redundant cytokine network, with intertwined effects between disparate cytokines and cell types.

Signaling responses to cytokines are disrupted in clonal hematopoiesis and myeloid malignancies. To better identify specific signaling response alterations in the presence or absence of TET2, we developed a 36-parameter cytometry by time-of-flight (CyTOF) panel of both surface marker and phosphoprotein antigens in murine bone marrow (BM). We show diverse, cell-type specific inflammatory cytokine responses in healthy hematopoietic cells. We next investigated changes associated with BM cells from Tet2KO mice. High-dimensional surface marker phenotyping revealed expansion of hematopoietic stem and progenitor cells (HSPCs), committed cKIT+Ly6C+ myeloid progenitors, and monocytes. Loss of TET2 function increased the magnitude of response to extracellular perturbations, including interferon (IFN)γ and H2O2. Response time courses revealed that IFNγ-mediated pSTAT1 remains elevated over time in Tet2KO. Further, IFNγ resulted in a more significant increase in major histocompatibility complex class II (MHCII) expression in Tet2KO immortalized progenitor cells than in Tet2WT. Inhibition of Janus kinase 1 and 2 (JAK1/2) with ruxolitinib significantly reduced STAT1 phosphorylation and MHCII expression in Tet2KO cells. Our results identify targetable disrupted signaling responses in Tet2KO cells.

Among various types of candidate cells, including osteoblasts and Nestin+ periarteriolar cells, several lines of histological and genetic evidence have demonstrated that the single population of mesenchymal stem cells, termed CXC chemokine ligand 12 (CXCL12)-abundant reticular (CAR) cells, which overlap strongly with leptin receptor-expressing (LepR+) cells, is the major cellular component of niches for hematopoietic stem cells (HSCs) and hematopoiesis in the bone marrow (BM). Expression of p16, a marker for senescent cells, and interleukin (IL)-1β and γH2AX foci, a marker for DNA damage, were increased in CAR/LepR+ cells and osteoblasts with age. However, the most striking phenotype of aging in the human BM is yellow marrow, which consists predominantly of adipocytes, causing the decreased volume of the principal site of hematopoiesis probably with the decreased numbers of HSCs in the total body. BM adipocytes are derived from CAR/LepR+ cells and act as negative or positive regulators of HSCs during homeostasis and myelosuppressive condition. Therefore, a fundamental question is how a portion of BM CAR/LepR+ cells differentiate into adipocytes during aging. Many rounds of inflammatory stress induced yellow marrow in mice. On the other hand, type H vessels found in the metaphysis and peripheral nerves running along the arteries were markedly reduced in the marrow of aged mice, which might affect HSCs and/or their niche cells. Understanding the cellular and molecular function of aged HSC niches could enable pharmacological regulation of niche functions to facilitate control of disease caused by BM aging.

Leukemia-initiating cells (LICs) are a critical subset of cells driving acute myeloid leukemia (AML) relapse and resistance to therapy. They possess unique properties, including metabolic, epigenetic, and microenvironmental dependencies, making them promising therapeutic targets.

This review summarizes preclinical advances in targeting AML LICs, including strategies to exploit metabolic vulnerabilities, such as the reliance on oxidative phosphorylation (OXPHOS), through the use of mitochondrial inhibitors; target epigenetic regulators like DOT1L (Disruptor of Telomeric Silencing 1-like) to disrupt LIC survival mechanisms; develop immunotherapies, including CAR (chimeric antigen receptor) T-cell therapy, and bispecific antibodies; and disrupt LIC interactions with the bone marrow microenvironment by inhibiting supportive niches.

LIC-targeted therapies hold significant promise for revolutionizing AML treatment by reducing relapse rates and improving long-term outcomes. However, challenges such as LIC heterogeneity, therapy resistance, and associated toxicity persist. Recent studies have illuminated the distinct biological characteristics of LICs, advancing our understanding of their behavior and vulnerabilities. These insights offer new opportunities to target LICs at earlier disease stages and to explore combination therapies with other targeted treatments, ultimately enhancing therapeutic efficacy and improving patient outcomes.

Severe infections such as malaria are on the rise worldwide, driven by both climate change and increasing drug resistance. It is therefore paramount that we better understand how the host responds to severe infection. Hematopoiesis is particularly of interest in this context because hematopoietic stem and progenitor cells (HSPCs) maintain the turnover of all blood cells, including all immune cells. Severe infections have been widely acknowledged to affect HSPCs; however, this disruption has been mainly studied during the acute phase, and the process and level of HSPC recovery remain understudied. Using a self-resolving model of natural rodent malaria, infection by Plasmodium chabaudi, here we systematically assess phenotypically defined HSPCs' acute response and recovery upon pathogen clearance. We demonstrate that during the acute phase of infection the most quiescent and functional stem cells are depleted, multipotent progenitor compartments are drastically enlarged, and oligopotent progenitors virtually disappear, underpinned by dramatic, population-specific and sometimes unexpected changes in proliferation rates. HSPC populations return to homeostatic size and proliferation rate again through specific patterns of recovery. Overall, our data demonstrate that HSPC populations adopt different responses to cope with severe infection and suggest that the ability to adjust proliferative capacity becomes more restricted as differentiation progresses.

Aging and chronic inflammation are associated with overabundant myeloid-primed multipotent progenitors (MPPs) among hematopoietic stem and progenitor cells (HSPCs). Although hematopoietic stem cell (HSC) differentiation bias has been considered a primary cause of myeloid bias, whether it is sufficient has not been quantitatively evaluated. Here, we analyzed bone marrow data from the IκB- (Nfkbia+/-Nfkbib-/-Nfkbie-/-) mouse model of inflammation with elevated NFκB activity, which reveals increased myeloid-biased MPPs. We interpreted these data with differential equation models of population dynamics to identify alterations of HSPC proliferation and differentiation rates. This analysis revealed that short-term HSC differentiation bias alone is likely insufficient to account for the increase in myeloid-biased MPPs. To explore additional mechanisms, we used single-cell RNA sequencing (scRNA-seq) measurements of IκB- and wild-type HSPCs to track the continuous differentiation trajectories from HSCs to erythrocyte/megakaryocyte, myeloid, and lymphoid primed progenitors. Fitting a partial differential equations model of population dynamics to these data revealed not only less lymphoid-fate specification among HSCs but also increased expansion of early myeloid-primed progenitors. Differentially expressed genes along the differentiation trajectories supported increased proliferation among these progenitors. These findings were conserved when wild-type HSPCs were transplanted into IκB- recipients, indicating that an inflamed bone marrow microenvironment is a sufficient driver. We then applied our analysis pipeline to scRNA-seq measurements of HSPCs isolated from aged mice and human patients with myeloid neoplasms. These analyses identified the same myeloid-primed progenitor expansion as in the IκB- models, suggesting that it is a common feature across different settings of myeloid bias.

Neutrophils are traditionally viewed as uncomplicated exterminators that arrive quickly at sites of infection, kill pathogens, and then expire. However, recent studies employing modern transcriptomics coupled with novel imaging modalities have discovered that neutrophils exhibit significant heterogeneity within organs and have complex functional roles ranging from tissue homeostasis to cancer and chronic pathologies. This has revised the view that neutrophils are simplistic butchers, and there has been a resurgent interest in neutrophils. The spleen was described as a granulopoietic organ more than 4 decades ago, and studies indicate that neutrophils are briefly retained in the spleen before returning to circulation after proliferation. Transcriptomic studies have discovered that splenic neutrophils are heterogeneous and distinct compared with those in blood. This suggests that a unique hematopoietic niche exists in the splenic microenvironment, i.e., capable of programming neutrophils in the spleen. During severe systemic inflammation with an increased need of neutrophils, the spleen can adapt by producing neutrophils through emergency granulopoiesis. In this review, we describe the structure and microanatomy of the spleen and examine how cells within the splenic microenvironment help to regulate splenic granulopoiesis. A focus is placed on exploring the increase in splenic granulopoiesis to meet host needs during infection and inflammation. Emerging technologies such as single-cell RNA sequencing, which provide valuable insight into splenic neutrophil development and heterogeneity, are also discussed. Finally, we examine how tumors subvert this natural pathway in the spleen to generate granulocytic suppressor cells to promote tumor growth.

The bone marrow (BM) is a multifactorial, highly dynamic, still not fully "mapped," reservoir. The BM labyrinthine landscape is subject to a relentless debate on the specialized and stem/progenitor cells' scattering within designated microareas. Certainly, BM tissue plays a watchdog role in bone modeling and remodeling, hematopoiesis, immune surveillance, and endocrine response integration. Parameters like tissue topographical distinctiveness, stiffness and porosity grade, and cells' behavioral idiosyncrasies in terms of stem/progenitor cell housing, activation, and motility represent a knotty problem not easily solved. Given that the disruption of BM microdomains has been associated with a number of severe pathological disorders, the comprehension and preservation of the BM workspace at multiple levels have become mandatory. Solid evidence has showed the existence of an intricate and tightly regulated cross-talk between the BM cellular occupants. Direct physical cell-cell connections and soluble mediators, including cytokines, chemokines, growth factors, exosomes and microvesicles, orchestrate composite intracellular signaling routes. The spatiotemporal action of definite biofactors ensures a functional blood-producing organ with a physiological bone turnover and prompts the action of multipotent stromal/hematopoietic cells. Recently, significant research efforts have been addressed to build bioengineered niche-mimic models based on biofunctionalized scaffolds and organoid-like constructs. These artificial BM niches combine and transduce various aspects of bioinformatics and tissue engineering to unravel the complexities of BM organization. This chapter aims to unfold the recent breakthroughs in the understanding of a BM intramural cell-cell dialogue in a physiological and, in some cases, within an inflammatory background. BM maze is gradually being discovered, but there is still a long way to go.

Aging exerts a profound impact on the hematopoietic system, leading to increased susceptibility to infections, autoimmune diseases, chronic inflammation, anemia, thrombotic events, and hematologic malignancies. Within the field of experimental hematology, the functional decline of hematopoietic stem cells (HSCs) is often regarded as a primary driver of age-related hematologic conditions. However, aging is clearly a complex multifaceted process involving not only HSCs but also mature blood cells and their interactions with other tissues. This review reappraises an HSC-centric view of hematopoietic aging by exploring how the entire hematopoietic hierarchy, from stem cells to mature cells, contributes to age-related disorders. It highlights the decline of both innate and adaptive immunity, leading to increased susceptibility to infections and cancer, and the rise of autoimmunity as peripheral immune cells undergo aging-induced changes. It explores the concept of "inflammaging," where persistent, low-grade inflammation driven by old immune cells creates a cycle of tissue damage and disease. Additionally, this review delves into the roles of inflammation and homeostatic regulation in age-related conditions such as thrombotic events and anemia, arguing that these issues arise from broader dysfunctions rather than stemming from HSC functional attrition alone. In summary, this review highlights the importance of taking a holistic approach to studying hematopoietic aging and its related pathologies. By looking beyond just stem cells and considering the full spectrum of age-associated changes, one can better capture the complexity of aging and attempt to develop preventative or rejuvenation strategies that target multiple facets of this process.

Hematopoiesis is a finely tuned process that generates all blood cell types through self-renewal and differentiation, which is crucial for maintaining homeostasis. Acute infections can prompt a hematopoietic response known as emergency myelopoiesis. In this study, using a Candida albicans (C. albicans) infection model, we demonstrated for the first time that disruption of Fhl2 led to increased fungal burden, heightened inflammatory response and reduced survival rates. Impaired myeloid hematopoiesis and immune cell production were evident, as proved by the decreased numbers of hematopoietic stem and progenitor cells (HSPCs) and granulocytes in the bone marrow of Fhl2-deficient mice. In conclusion, FHL2 regulated emergency myelopoiesis in response to C. albicans, affecting the host's defense against pathogens.

A decade after the term 'trained immunity' (TRIM) was coined to reflect the long-lasting hyper-responsiveness of innate immune cells with an epigenetically imprinted 'memory' of earlier stimuli, our understanding has broadened to include the potential implications of TRIM in health and disease. Here, after summarizing the well-documented beneficial effects of TRIM against infections, we discuss emerging evidence that TRIM is also a major underlying mechanism in chronic inflammation-related disorders such as periodontitis, rheumatoid arthritis and cardiovascular disease. Furthermore, mounting evidence indicates that the induction of TRIM by certain agonists confers protective antitumour responses. Although the mechanisms underlying TRIM require further study, the current knowledge enables the experimental development of innovative therapeutic approaches to stimulate or inhibit TRIM in a context-appropriate manner, such as the stimulation of TRIM in cancer or its inhibition in inflammatory disorders.

Chronic low-grade inflammation observed in older adults, termed inflammaging, is a common feature underlying a multitude of aging-associated maladies including a decline in hematopoietic activity. However, whether suppression of inflammaging can preserve hematopoietic health span remains unclear, in part because of a lack of tools to measure inflammaging within hematopoietic stem cells (HSCs). Here, we identify thrombospondin-1 (Thbs1) as an essential regulator of inflammaging within HSCs. We describe a transcriptomics-based approach for measuring inflammaging within stem cells and demonstrate that deletion of Thbs1 is sufficient to prevent HSC inflammaging. Our results demonstrate that suppression of HSC inflammaging prevents aging-associated defects in hematopoietic activity including loss of HSC self-renewal, myeloid-biased HSC differentiation, and anemia. Our findings indicate that suppression of HSC inflammaging may also prolong overall systemic health span.

Blood production depends on rare haematopoietic stem cells (HSCs) and haematopoietic stem and progenitor cells (HSPCs) that ultimately take up residence in the bone marrow during development. HSPCs and HSCs are subject to extrinsic regulation by the bone marrow microenvironment, or niche. Studying the interactions between HSCs and their niche is critical for improving ex vivo culturing conditions and genetic manipulation of HSCs, which is pivotal for improving autologous HSC therapies and transplantations. Additionally, understanding how the complex molecular network in the bone marrow is altered during ageing is paramount for developing novel therapeutics for ageing-related haematopoietic disorders. HSCs are unique amongst stem and progenitor cell pools in that they engage with multiple physically distinct niches during their ontogeny. HSCs are specified from haemogenic endothelium in the aorta, migrate to the fetal liver and, ultimately, colonize their final niche in the bone marrow. Recent studies employing single-cell transcriptomics and microscopy have identified novel cellular interactions that govern HSC specification and engagement with their niches throughout ontogeny. New lineage-tracing models and microscopy tools have raised questions about the numbers of HSCs specified, as well as the functional consequences of HSCs interacting with each developmental niche. Advances have also been made in understanding how these niches are modified and perturbed during ageing, and the role of these altered interactions in haematopoietic diseases. In this Review, we discuss these new findings and highlight the questions that remain to be explored.

The inflammasome plays multifaceted roles in cancer, but less is known about its function during premalignancy upon initial cell transformation. We report a homeostatic function of the inflammasome in suppressing malignant transformation through Ras inhibition. We identified increased hematopoietic stem cell (HSC) proliferation within the bone marrow of inflammasome-deficient mice. HSCs within an inflammasome-deficient stroma expressed a Ras signature associated with increased Ras pathway- and cancer-related transcripts and heightened levels of cytokine, chemokine and growth factor receptors. Stromal inflammasome deficiency established a poised Ras-dependent mitogenic state within HSCs, which fueled progeny B cell lymphomagenesis upon Myc deregulation in a spontaneous model of B cell lymphoma, and shortened its premalignant stage leading to faster onset of malignancy. Thus, the stromal inflammasome preserves tissue balance by restraining Ras to disrupt the most common oncogenic Myc-Ras cooperation and establish a natural defense against transition to malignancy. These findings should inform preventative therapies against hematological malignancies.

Fanconi anemia (FA) is generally classified as a DNA repair disorder, conferring a genetic predisposition to cancer and prominent bone marrow failure (BMF) in early childhood. Corroborative human and murine studies point to a fetal origin of hematopoietic stem cell (HSC) attrition under replicative stress. Along with intriguing recent insights into non-canonical roles and domain-specific functions of FA proteins, these studies have raised the possibility of a DNA repair-independent BMF etiology. However, deeper mechanistic insight is critical as current curative options of allogeneic stem cell transplantation and emerging gene therapy have limited eligibility, carry significant side effects, and involve complex procedures restricted to resource-rich environments. To develop rational and broadly accessible therapies for FA patients, the field will need more faithful disease models that overcome the scarcity of patient samples, leverage technological advances, and adopt investigational clinical trial designs tailored for rare diseases.

Hematopoietic stem cells (HSCs) are a rare, long-lived and multipotent population that give rise to majority of blood cells and some tissue-resident immune cells. There is growing evidence that inflammatory stimuli can trigger persistent reprogramming in HSCs that enhances or inhibits the cellular functions of these HSCs and their progeny in response to subsequent infections. This newly discovered property makes HSCs a reservoir for innate immune memory. The molecular mechanisms underlying innate immune memory in HSCs are similar to those observed in innate immune cells, although their full elucidation is still pending. In this review, we examine the current state of knowledge on how an inflammatory response leads to reprogramming of HSCs. Understanding the full spectrum of consequences of reshaping early hematopoiesis is critical for assessing the potential benefits and risks under physiological and pathological conditions.

Hematopoiesis is a complex physiological process that ensures renewal of blood cells to maintain normal blood circulation and immune function. Wujin pigs exhibit distinct characteristics such as tender meat, high fat storage, strong resistance to roughage, robust disease resistance, and oxidation resistance. Therefore, using Wujin pigs as models may offer valuable insights for hematopoietic-related studies. In this study, twelve healthy 35-day-old piglets, including six Wujin and six Duroc piglets of similar weight, were selected from each of the Wujin and Duroc pig groups and housed in single cages. After 30 days of feeding, blood and bone marrow samples were collected. Routine blood indices and hematopoietic-related serum biochemical indexes of Wujin and Duroc pigs were determined, and bone marrow gene expression levels were analyzed using transcriptomics. (1) Hemoglobin (Hb) and Mean Corpuscular Hemoglobin Concentration (MCHC) levels in Wujin pigs were significantly higher than in Duroc pigs (p < 0.05), and platelet counts and serum Hb levels in Wujin pigs were significantly lower than in Duroc pigs (p < 0.05). (2) A total of 312 significantly differentially expressed genes were identified between the pigs. Their functions were mainly related to blood systems, inflammation, and oxidation. Six differentially expressed genes may be related to hematopoietic function. (3) By combining the differential genes screened through sequencing with Weighted Gene Co-expression Network Analysis results, 16 hematopoietic function differential genes were obtained, mainly focusing on immunity, inflammation, and induction of apoptosis functions. Differences were present in the immune and inflammatory responses between Wujin pigs and Duroc pigs, suggesting that differences in hematopoietic function between the two breeds were related to antioxidant capacity and disease resistance.

Hematopoietic stem cells (HSC) reside within specialized microenvironments that undergo dynamic changes throughout development and aging to support HSC function. However, the evolving cell-cell communication networks within these niches remain largely unexplored. This study integrates single-cell RNA sequencing datasets to systematically characterize the HSC niche interactome from ontogeny to aging. We reconstructed single-cell atlases of HSC niches at different developmental stages, revealing stage-specific cellular compositions and interactions targeting HSC. During HSC maturation, our analysis identified distinct patterns of ligand-receptor interactions and signaling pathways that govern HSC emergence, expansion, and maintenance. HSC aging was accompanied by a decrease in supportive niche interactions, followed by an adaptive increase in interaction strength in old adult bone marrow. This complex aging process involved the emergence of interactions associated with inflammation, altered stem cell function, and a decline in the efficacy of key signaling pathways. Our findings provide a comprehensive understanding of the dynamic remodeling of the HSC niche interactome throughout life, paving the way for targeted interventions to maintain HSC function and promote healthy aging. This study offers valuable insights into the intricate cell-cell communication networks that govern HSC behavior and fate, with implications for hematological disorders and regenerative medicine.

The proinflammatory cytokine interferon gamma (IFNγ) is upregulated in a variety of infections and contributes to bone marrow failure through hematopoietic stem cell (HSC) activation and subsequent exhaustion. The cell-surface protein, bone marrow stromal antigen 2 (BST2), is a key mediator of this process, because it is induced upon IFN stimulation and required for IFN-dependent HSC activation. To identify the mechanism by which BST2 promotes IFN-dependent HSC activation, we evaluated its role in niche localization, immune cell function, lipid raft formation, and intracellular signaling. Our studies indicated that knockout (KO) of BST2 in a murine model does not disrupt immune cell responses to IFN-inducing mycobacterial infection. Furthermore, intravital imaging studies indicate that BST2 KO does not disrupt localization of HSCs relative to endothelial or osteoblastic niches in the bone marrow. However, using imaging-based flow cytometry, we found that IFNγ treatment shifts the lipid raft polarity of wild-type (WT) but not Bst2-/- hematopoietic stem and progenitor cells (HSPCs). Furthermore, RNAseq analysis, reverse-phase protein array and western blot analysis of HSPCs indicate that BST2 promotes ERK1/2 phosphorylation during IFNγ-mediated stress. Overall, we find that BST2 facilitates HSC division by promoting cell polarization and ERK activation, thus elucidating a key mechanism of IFN-dependent HSPC activation. These findings inform future approaches in the treatment of cancer and bone marrow failure.

In work spanning several decades, extensive studies have focused on the properties of malignant stem cells that drive the pathogenesis of acute myeloid leukemia (AML). However, relatively little attention has been devoted to several serious myeloid malignancies that occur prior to the onset of frank leukemia, including myelodysplastic syndrome (MDS). Like leukemia, MDS is hypothesized to arise from a pool of immature malignant stem and progenitor cells (MDS-SCs) that serve as a reservoir for disease evolution and progression1. While multiple studies have sought to identify and characterize the biology and vulnerabilities of MDS-SCs, yet translation of scientific concepts to therapeutically impactful regimens has been limited. Here, we evaluate the currently known properties of MDS-SCs as well as the post-transcriptional mechanisms that drive MDS pathogenesis at a stem and progenitor level. We highlight limits and gaps in our characterization and understanding of MDS-SCs and address the extent to which the properties of MDS-SC are (and can be) inferred from the characterization of LSCs.

Inflammation is a key driver of the progression of preleukemic myeloid conditions, such as clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS), to myelodysplastic syndromes (MDS). Inflammation is a critical mediator in the complex interplay of the genetic, epigenetic, and microenvironmental factors contributing to clonal evolution. Under inflammatory conditions, somatic mutations in TET2, DNMT3A, and ASXL1, the most frequently mutated genes in CHIP and CCUS, induce a competitive advantage to hematopoietic stem and progenitor cells, which leads to their clonal expansion in the bone marrow. Chronic inflammation also drives metabolic reprogramming and immune system deregulation, further promoting the expansion of malignant clones. This review underscores the urgent need to fully elucidate the role of inflammation in MDS initiation and highlights the potential of the therapeutical targeting of inflammatory pathways as an early intervention in MDS.

Bone marrow-mesenchymal stromal cells (BM-MSCs) are key components of the BM niche, where they regulate hematopoietic stem progenitor cell (HSPC) homeostasis by direct contact and secreting soluble factors. BM-MSCs also protect the BM niche from excessive inflammation by releasing anti-inflammatory factors and modulating immune cell activity. Thanks to these properties, BM-MSCs were successfully employed in pre-clinical HSPC transplantation models, increasing the rate of HSPC engraftment, accelerating the hematological reconstitution, and reducing the risk of graft failure. However, their clinical use requires extensive in vitro expansion, potentially altering their biological and functional properties. In this work, we analyzed the transcriptomic profile of human BM-MSCs sorted as CD45-, CD105+, CD73+, and CD90+ cells from the BM aspirates of heathy-donors and corresponding ex-vivo expanded BM-MSCs. We found the expression of immune and inflammatory genes downregulated upon cell culture and selected the transcription factor EGR1 to restore the MSC properties. We overexpressed EGR1 in BM-MSCs and performed in vitro tests to study the functional properties of EGR1-overexpressing BM-MSCs. We concluded that EGR1 increased the MSC response to inflammatory stimuli and immune cell control and potentiated the MSC hematopoietic supportive activity in co-culture assay, suggesting that the EGR1-based reprogramming may improve the BM-MSC clinical use.

Stem cells are a unique class of cells that possess the ability to differentiate and self-renew, enabling them to repair and replenish tissues. To protect and maintain the potential of stem cells, the cells and the environment surrounding these cells (stem cell niche) are highly responsive and tightly regulated. However, various stresses can affect the stem cells and their niches. These stresses are both systemic and cellular and can arise from intrinsic or extrinsic factors which would have strong implications on overall aging and certain disease states. Therefore, understanding the breadth of drivers, namely epigenetic alterations, involved in cellular stress is important for the development of interventions aimed at maintaining healthy stem cells and tissue homeostasis. In this review, we summarize published findings of epigenetic responses to replicative, oxidative, mechanical, and inflammatory stress on various types of adult stem cells.

Bronchitis is a common respiratory disease characterized by acute inflammation, edema, and necrosis of the small airways, leading to a significant pathological burden. Immune cells play a crucial role in combating bronchitis. This study aims to explore the causal relationship between immune cells and bronchitis using the Mendelian randomization approach. In this study, we screened 18,183 single nucleotide polymorphisms highly associated with immune cells and employed 5 Mendelian randomization methods to assess the potential causal link between different types of immune cells and bronchitis. Additionally, the study utilized inverse variance weighting and MR-Egger regression analysis to evaluate the heterogeneity and robustness of the causal estimates. The study found a significant causal association between 28 types of immune cells and the risk of bronchitis. These cell types mainly included T cells, monocytes, and B cells. For instance, CD25 on B cells and CD25 on IgD+ were associated with an increased risk of bronchitis, whereas IgD+ CD24- B cells and CD33- HLA DR- AC showed a protective effect against bronchitis. Moreover, the study validated the robustness of these findings through leave-one-out analysis and the MR-Egger method, and quantitatively illustrated the impact of immune cells on the risk of bronchitis through forest plots. This study reveals the dual role of immune cells in bronchitis. The identified types of immune cells may increase the risk of bronchitis by promoting inflammatory responses and cell-mediated immune reactions, while other cell types may offer protection by promoting immune balance and effective defense.

Myeloablative pre-conditioning facilitates the differentiation of transplanted hematopoietic stem and progenitor cells (HSPCs). However, the factors in the stress environment that regulate HSPC behavior remain elusive. Here, we investigated the mechanisms that shaped the cell fates of transplanted murine multipotent progenitors (MPPs) expressing the Fms-related receptor tyrosine kinase 3 gene (Flt3). Using lineage tracing, clonal analysis, and single-cell RNA sequencing (RNA-seq), we showed that the myeloablative environment increased lymphoid priming of Flt3+ MPPs and that their efficient B cell output required intact interleukin 1 (IL-1) signaling. The Flt3+ MPPs with short-term exposure to IL-1β underwent a myeloid-biased to lymphoid-biased cell fate switch and produced more lymphoid-biased progeny with a stronger B lymphopoiesis capacity in vitro. Correspondingly, a brief exposure to IL-1β facilitated the B cell output of transplanted Flt3+ MPPs in vivo. Together, our study demonstrated an unrecognized function of IL-1β in promoting B lymphopoiesis and highlighted a latent effect of IL-1β in regulating MPP cell fate dynamics.

In myelodysplastic syndromes (MDS), the IL-1β pathway is upregulated, and previous studies using mouse models of founder MDS mutations demonstrated that it enhances hematopoietic stem and progenitor cells' (HSPCs') aberrant differentiation towards the myeloid lineage at the expense of erythropoiesis. To evaluate whether targeting the IL-1β signaling pathway can rescue ineffective erythropoiesis in patients with MDS, we designed a phase 2 non-randomized single-arm clinical trial (NCT04239157) to assess the safety profile and efficacy of the IL-1β inhibitor canakinumab in previously treated lower-risk MDS patients. We enrolled 25 patients with a median age of 74 years; 60% were male, 16% had lower-risk MDS, 84% had intermediate-1 risk MDS according to the International Prognostic Scoring System score, and 80% failed hypomethylating agent therapy. The study met the primary endpoint of defining the clinical activity of canakinumab, and the secondary objective of determining the safety profile, including the rate of transfusion independence, the duration of response, progression-free survival, leukemia-free survival, and overall survival. The overall response rate was 17.4%, with all responses including hematological improvement. Sequential post-hoc prospective single-cell RNA sequencing analyses of HSPCs and bone marrow mononuclear cells at different time points during therapy showed that canakinumab's on-target effects in hematopoietic populations expressing the IL-1β receptor decreased the TNF-mediated inflammatory signaling pathway but rescued ineffective erythropoiesis only in the context of lower genetic complexity. This study demonstrates that better stratification strategies could target lower-risk MDS patients more effectively.

Therapies for acute myeloid leukemia (AML) face formidable challenges due to relapse, often driven by leukemia stem cells (LSCs). Strategies targeting LSCs hold promise for enhancing outcomes, yet paired comparisons of functionally defined LSCs at diagnosis and relapse remain underexplored. We present transcriptome analyses of functionally defined LSC populations at diagnosis and relapse, revealing significant alterations in IL-1 signaling. Interleukin-1 receptor type I (IL1R1) and interleukin-1 receptor accessory protein (IL1RAP) were notably upregulated in leukemia stem and progenitor cells at both diagnosis and relapse. Knockdown of IL1R1 and IL1RAP reduced the clonogenicity and/or engraftment of primary human AML cells. In leukemic MLL-AF9 mice, Il1r1 knockout reduced LSC frequency and extended survival. To target IL-1 signaling at both diagnosis and relapse, we developed UR241-2, a novel interleukin-1 receptor-associated kinase 1 and 4 (IRAK1/4) inhibitor. UR241-2 robustly suppressed IL-1/IRAK1/4 signaling, including NF-κB activation and phosphorylation of p65 and p38, following IL-1 stimulation. UR241-2 selectively inhibited LSC clonogenicity in primary human AML cells at both diagnosis and relapse, while sparing normal hematopoietic stem and progenitor cells. It also reduced AML engraftment in leukemic mice. Our findings highlight the therapeutic potential of UR241-2 in targeting IL-1/IRAK1/4 signaling to eradicate LSCs and improve AML outcomes.

Both cell-intrinsic and niche-derived, cell-extrinsic cues drive the specification of hematopoietic multipotent progenitors (MPPs) in the bone marrow, which comprise multipotent MPP1 cells and lineage-restricted MPP2, MPP3, and MPP4 subsets. Patients with WHIM syndrome, a rare congenital immunodeficiency caused by mutations that prevent desensitization of the chemokine receptor CXCR4, have an excess of myeloid cells in the bone marrow. Here, we investigated the effects of increased CXCR4 signaling on the localization and fate of MPPs. Knock-in mice bearing a WHIM syndrome-associated CXCR4 mutation (CXCR41013) phenocopied the myeloid skewing of bone marrow in patients. Whereas MPP4 cells in wild-type mice differentiated into lymphoid cells, MPP4s in CXCR41013 knock-in mice differentiated into myeloid cells. This myeloid rewiring of MPP4s in CXCR41013 knock-in mice was associated with enhanced signaling mediated by the kinase mTOR and increased oxidative phosphorylation (OXPHOS). MPP4s also localized further from arterioles in the bone marrow of knock-in mice compared with wild-type mice, suggesting that the loss of extrinsic cues from the perivascular niche may also contribute to their myeloid skewing. Chronic treatment with the CXCR4 antagonist AMD3100 or the mTOR inhibitor rapamycin restored the lymphoid potential of MPP4s in knock-in mice. Thus, CXCR4 desensitization drives the lymphoid potential of MPP4 cells by dampening the mTOR-dependent metabolic changes that promote myeloid differentiation.