Tumor-initiating cells (TICs) share features and regulatory pathways with normal stem cells, yet how the stem cell niche contributes to tumorigenesis remains unclear. Here, we identify CXCR4+ macrophages as a niche population enriched in normal mammary ducts, where they promote the regenerative activity of basal cells in response to luminal cell-derived CXCL12. CXCL12 triggers AKT-mediated stabilization of β-catenin, which induces Wnt ligands and pro-migratory genes, enabling intraductal macrophage infiltration and supporting regenerative activity of basal cells. Notably, these same CXCR4+ niche macrophages regulate the tumor-initiating activity of various breast cancer subtypes by enhancing TIC survival and tumor-forming capacity, while promoting early immune evasion through regulatory T cell induction. Furthermore, a CXCR4+ niche macrophage gene signature correlates with poor prognosis in human breast cancer. These findings highlight the pivotal role of the CXCL12-CXCR4 axis in orchestrating interactions between niche macrophages, mammary epithelial cells, and immune cells, thereby establishing a supportive niche for both normal tissue regeneration and mammary tumor initiation.

Adoptive transfer of regulatory T cells (Tregs) has been proposed as a next-generation treatment approach for the treatment of various inflammatory or autoimmune disorders(Amini et al., 2022; Bluestone et al., 2023, 2015; Dall'Era et al., 2019; Chandran et al., 2017; Laukova and Glatman Zaretsky, 2023; Voskens et al., 2023; Canavan et al., 20161-8), inclusive of inflammatory bowel diseases (IBD). Identification of the appropriate Treg populations as donor sources for effective cell therapy is of great importance. We have recently identified specialized Tregs that localize within the hematopoietic stem cell (HSC) microenvironments(Fujisaki et al., 2011; Hirata et al., 2018, 2019, 2015; Kakiuchi et al., 2021a, 2021b; Furuhashi et al., 20259-16) of bone marrow (BM), termed HSC niches. These BM niche Tregs exhibit robust anti-inflammatory and pro-regenerative effects and render HSCs immune privileged. The transfer of BM niche Tregs exhibits high therapeutic effects against BM transplantation and injury(Hirata et al., 2018; Kakiuchi et al., 2021b10, 14). Yet, the treatment effects of transferred BM niche Tregs in non-BM disease settings remain unknown.

We investigated the therapeutic effects of transfer of BM niche Tregs for IBD using mouse models of experimental colitis. To identify the key effector molecule of niche Tregs, we further examined the roles of cell-surface ectoenzyme CD39 expressed at high levels by BM niche Tregs.

Mouse colitis was induced by administering dextran sulfate sodium salt. Subsequently, the mice received intravenous injections of BM niche Tregs, BM non-niche Tregs, lymph node Tregs, or vehicle alone. We compared these treatment effects on clinical scores, histopathological features and profiles of immune cells. We also tested how targeted deletion of CD39 in the adoptively transferred Tregs impacted experimental outcomes.

The transfer of as few as 1.5 × 104 BM niche Tregs per mouse ameliorated clinical and histopathological features of the mouse colitis far better than the transfer of other Tregs. The transfer of BM niche Tregs inhibited the generation of Th17 cells and promoted the regeneration and recovery of the colon tissue. Targeted deletion of CD39 in Tregs abrogated therapeutic effects of transferred BM niche Tregs.

We show robust therapeutic effects of the transfer of BM niche Tregs in the experimental model of colitis. Donor niche Tregs mediate anti-inflammatory and pro-regenerative effects via Treg CD39. Our work suggests the transfer of BM niche Tregs is a promising approach to treat colitic disorders and boost tissue regeneration.

Energy metabolism of immune cells, such as glycolysis and mitochondrial activity, requires strict regulation. This is especially critical in the complex environment of the bone marrow (BM), where there is a need to both preserve the quiescence of hematopoietic stem cells (HSCs) and guarantee timed and effective lineage differentiation of the HSCs. Recent advances highlight the critical roles played by bioactive metabolites in regulating hematopoiesis. In particular, secreted immune metabolites (SIMets), such as γ-aminobutyric acid (GABA) and acetylcholine, secreted by B-lineage cells, act as potent modulators of hematopoietic processes, influencing HSC differentiation and emergency hematopoiesis. In this review, we provide an overview and discuss mechanisms by which energy metabolism and SIMets regulate hematopoiesis. We propose that biochemical communication facilitated by these metabolites is essential for maintaining the BM niche and suggest potential therapeutic strategies using SIMets in hematological disorders.

Uncovering early gene network changes of human hematopoietic stem cells (HSCs) leading to differentiation induction is of utmost importance for therapeutic manipulation. We employed single cell proteo-transcriptomic sequencing to FACS-enriched bone marrow hematopoietic stem and progenitor cells (HSPCs) from 15 healthy donors. Pseudotime analysis reveals four major differentiation trajectories, which remain consistent upon aging, with an early branching point into megakaryocyte-erythroid progenitors. However, young donors suggest a more productive differentiation from HSPCs to committed progenitors of all lineages. tradeSeq analysis depicts continuous changes in gene expression of HSPC-related genes (DLK1, ADGRG6), and provides a roadmap of gene expression at the earliest branching points. We identify CD273/PD-L2 to be highly expressed in a subfraction of immature multipotent HSPCs with enhanced quiescence. Functional experiments confirm the immune-modulatory function of CD273/PD-L2 on HSPCs in regulating T-cell activation and cytokine release. Here, we present a molecular map of early HSPC differentiation across human life.

Interactions between acute myeloid leukemia (AML) and the bone marrow microenvironment (BMME) are critical to leukemia progression and chemoresistance. In the solid tumor microenvironment, altered metabolite levels contribute to cancer progression. We performed a metabolomic analysis of AML patient bone marrow serum, revealing increased metabolites compared to age- and sex-matched controls. The most highly elevated metabolite in the AML BMME was lactate. Lactate signaling in solid tumors induces immunosuppressive tumor-associated macrophages and correlates with poor prognosis. This has not yet been studied in the leukemic BMME. Herein, we describe the role of lactate in the polarization of leukemia-associated macrophages (LAMs). Using a murine AML model of blast crisis chronic myelogenous leukemia (bcCML), we characterize the suppressive phenotype of LAMs by surface markers, transcriptomics, and cytokine profiling. Then, mice genetically lacking GPR81, the extracellular lactate receptor, were used to demonstrate GPR81 signaling as a mechanism of both the polarization of LAMs and the direct support of leukemia cells. Furthermore, elevated lactate diminished the function of hematopoietic progenitors and reduced stromal support for normal hematopoiesis. We report microenvironmental lactate as a mechanism of AML-induced immunosuppression and leukemic progression, thus identifying GPR81 signaling as an exciting and novel therapeutic target for treating this devastating disease.

Lineage tracing is a valuable technique that has greatly facilitated the exploration of cell origins and behavior. With the continuous development of single-cell sequencing technology, lineage tracing technology based on the single-cell level has become an important method to study biological development. Single-cell Lineage tracing technology plays an important role in the hematological system. It can help to answer many important questions, such as the heterogeneity of hematopoietic stem cell function and structure, and the heterogeneity of malignant tumor cells in the hematological system. Many studies have been conducted to explore the field of hematology by applying this technology. This review focuses on the superiority of the emerging single-cell lineage tracing technologies of Integration barcodes, CRISPR barcoding, and base editors, and summarizes their applications in the hematology system. These studies have suggested the vast potential in unraveling complex cellular behaviors and lineage dynamics in both normal and pathological contexts.

Stem cells reside in specialized microenvironments, termed niches, at several different locations in tissues1-3. The differential functions of heterogeneous stem cells and niches are important given the increasing clinical applications of stem-cell transplantation and immunotherapy. Whether hierarchical structures among stem cells at distinct niches exist and further control aspects of immune tolerance is unknown. Here we describe previously unknown new hierarchical arrangements in haematopoietic stem cells (HSCs) and bone marrow niches that dictate both regenerative potential and immune privilege. High-level nitric oxide-generating (NOhi) HSCs are refractory to immune attack and exhibit delayed albeit robust long-term reconstitution. Such highly immune-privileged, primitive NOhi HSCs co-localize with distinctive capillaries characterized by primary ciliated endothelium and high levels of the immune-checkpoint molecule CD200. These capillaries regulate the regenerative functions of NOhi HSCs through the ciliary protein IFT20 together with CD200, endothelial nitric oxide synthase and autophagy signals, which further mediate immunoprotection. Notably, previously described niche constituents, sinusoidal cells and type-H vessels2-10 co-localize with less immune-privileged and less potent NOlow HSCs. Together, we identify highly immune-privileged, late-rising primitive HSCs and characterize their immunoprotective niches comprising specialized vascular domains. Our results indicate that the niche orchestrates hierarchy in stem cells and immune tolerance, and highlight future immunotherapeutic targets.

Bone marrow hematopoietic injury encompasses a range of pathological conditions that disrupt the normal function of the hematopoietic system, primarily through the impaired production and differentiation of bone marrow hematopoietic cells. Key pathogenic mechanisms include aging, radiation damage, chemical induction, infection and inflammation, and cross-talk with non-hematopoietic diseases. These pathological factors often lead to myelosuppression and myeloid skewing. Furthermore, we explored the potential and application prospects of natural products in the treatment of bone marrow hematopoietic injury. Natural products, particularly those derived from Chinese herbal medicines and other natural sources, have emerged as promising therapeutic options due to their distinctive mechanisms and minimal side effects. A deeper understanding of the underlying mechanisms of bone marrow hematopoietic injury could illuminate how natural products exert their effects, thereby optimizing treatment strategies and offering safer, more effective options for patients. Future research should leverage emerging technologies to further elucidate the composition and interactions within the bone marrow microenvironment, as well as the specific pathways through which natural products modulate hematopoietic dysfunction.

Knowledge of the complex interplay between gut microbiota and human health is gradually increasing as it has just recently been a field of such great interest.

Recent studies have reported that communities of microorganisms inhabiting the gut influence the immune system through cellular responses and shape many physiological and pathophysiological aspects of the body, including muscle and bone metabolism (formation and resorption). Specifically, the gut microbiota affects skeletal homeostasis through changes in host metabolism, the immune system, hormone secretion, and the gut-brain axis. The major role on gut-bone axis is due to short-chain fatty acids (SCFAs). They have the ability to influence regulatory T-cell (Tregs) development and activate bone metabolism through the action of Wnt10. SCFA production may be a mechanism by which the microbial community, by increasing the serum level of insulin-like growth factor 1 (IGF-1), leads to the growth and regulation of bone homeostasis. A specific SCFA, butyrate, diffuses into the bone marrow where it expands Tregs. The Tregs induce production of the Wnt ligand Wnt10b by CD8+ T cells, leading to activation of Wnt signaling and stimulation of bone formation. At the hormonal level, the effect of the gut microbiota on bone homeostasis is expressed through the biphasic action of serotonin. Some microbiota, such as spore-forming microbes, regulate the level of serotonin in the gut, serum, and feces. Another group of bacterial species (Lactococcus, Mucispirillum, Lactobacillus, and Bifidobacterium) can increase the level of peripheral/vascular leptin, which in turn manages bone homeostasis through the action of brain serotonin.

Immunotherapy has become a key new pillar of cancer treatment, and this has sparked interest in understanding mechanisms of cancer immune evasion. It has long been appreciated that cancers are constituted by heterogeneous populations of tumour cells. This feature is often fuelled by specialized cells that have molecular programs resembling tissue stem cells. Although these cancer stem cells (CSCs) have capacity for unlimited self-renewal and differentiation, it is increasingly evident that some CSCs are capable of achieving remarkable immune resistance. Given that most immunotherapy regiments have overlooked CSC-specific immune-evasive mechanisms, many current treatment strategies often lead to cancer relapse. This Review focuses on advancements in understanding how CSCs in solid tumours achieve their unique immune-evasive properties, enabling them to drive tumour regrowth. Moreover, as cancers often arise from tissue stem cells that acquired oncogenic mutations, we discuss how tissue stem cells undergoing malignant transformation activate intrinsic immune-evasive mechanisms and establish close interactions with suppressive immune cells to escape immune surveillance. In addition, we summarize how in advanced disease stages, CSCs often hijack features of normal stem cells to resist antitumour immunity. Finally, we provide insights in how to design a new generation of cancer immunotherapies to ensure elimination of CSCs.

Hematopoietic stem cells (HSCs) reside in a milieu that supports their functions, differentiation, and survival. This niche consists of several types of cells, including mesenchymal stem/stromal cells, endothelial cells, osteoblasts, megakaryocytes, macrophages, adipocytes, lymphoid cells, and nerve fibers. The interactions between these cells and HSCs have a role in HSC fate. Several studies have focused on identification of the biological and cellular mechanisms contributing to the establishment of this niche. However, the exact mechanisms of the interaction between HSCs and the bone marrow niche have not been elucidated yet. Unraveling these mechanisms would help in the design of effective methods for maintenance and multiplication of HSCs in clinical settings, in addition to establishment of novel therapies for hematopoietic diseases. The current review summarizes the effects of the niche cells on HSC function and underlying mechanisms of interplay between HSCs and their niche.

The bone marrow niche is a special microenvironment that comprises elements, including hematopoietic stem cells, osteoblasts, and endothelial cells, and helps maintain their characteristic functions. Here, we elaborate on the crosstalk between various cellular components, hematopoietic stem cells, and other cells in the bone marrow niche. We further explain the mechanism of preserving equilibrium in the bone marrow niche, which is crucial for the directional regulation of bone reconstruction and repair. Additionally, we elucidate the intercommunication among osteocytes, the regulation of osteoblast maturation and activation by lymphocytes, the deficiency of megakaryocytes that can markedly impair osteoblast formation, and the mechanism of interaction between macrophages and mesenchymal stem cells in the bone marrow niche. Finally, we discussed the new immunotherapies for bone tumors in the BM niche. In this review, we aimed to provide a candid overview of the crosstalk among bone marrow niche cells and to highlight new concepts underlying the unknown mechanisms of hematopoiesis and bone reconstruction. Thus, this review may provide a more comprehensive understanding of the role of these niche cells in improving hematopoietic function and help identify their therapeutic potential for different diseases in the future.

In this study we investigated the presence of resident Foxp3+ regulatory T cells (Tregs) within the cornea and assessed the role of resident Tregs in corneal epithelial wound healing. Using a mouse model, we showed that in the steady state Foxp3+Tregs are either in close proximity or co-localize with ABCG2+ limbal stem cells. We also showed that these Tregs reside within the epithelial layer and not the corneal stroma. In addition, using a mouse model of mechanical injury, we demonstrated that depletion of Tregs from the cornea prior to corneal mechanical injury, using subconjunctival injection of anti-CD25, was associated with delayed epithelial healing. These results suggest a role for cornea resident Tregs in corneal epithelial cell function and wound healing and opens doors for further exploration of the role of Tregs in limbal stem cell function and survival.

Intervertebral disk degeneration (IDD) is a common clinical spinal disease and one of the main causes of low back pain (LBP). Generally speaking, IDD is considered a natural degenerative process with age. However, with the deepening of research, people have discovered that IDD is not only related to age, but also has many factors that can induce and accelerate its progression. In addition, the pathogenesis of IDD remains unclear, resulting in limited traditional treatment methods that cannot effectively prevent and treat IDD. Conservative treatment may lead to patients' dependence on drugs, and the pain relief effect is not obvious. Similarly, surgical treatment is highly invasive, with a longer recovery time and a higher recurrence rate. With the deepening of exploration, people have discovered that intestinal microorganisms are an important symbiotic microbial community in the human body and are closely related to the occurrence and development of various diseases. Changes in intestinal microorganisms and their metabolites may affect the body's inflammatory response, immune regulation, and metabolic processes, thereby affecting the health of the intervertebral disk. In this context, the gut microbiota has received considerable attention as a potential target for delaying or treating IDD. This article first introduces the impact of gut microbes on common distal organs, and then focuses on three potential mechanisms by which gut microbes and their metabolites influence IDD. Finally, we also summarized the methods of delaying or treating IDD by interfering with intestinal microorganisms and their metabolites. Further understanding of the potential mechanisms between intestinal microorganisms and IDD will help to formulate reasonable IDD treatment strategies to achieve ideal therapeutic effects.

Leukocyte immunoglobulin-like receptor (LILR) B4 (also known as ILT3/CD85k) is an immune checkpoint protein that is highly expressed in solid tumors and hematological malignancies and plays a significant role in the pathophysiology of cancer. LILRB4 is highly expressed in acute myeloid leukemia (AML), and this phenotype is associated with adverse patient outcomes. Its differential expression in tumors compared to normal tissues, its presence in tumor stem cells, and its multifaceted roles in tumorigenesis position it as a promising therapeutic target in AML. Currently, several immunotherapies targeting LILRB4 are undergoing clinical trials. This review summarizes advancements made in the study of LILRB4 in AML, focusing on its structure, ligands, expression, and significance in normal tissues and AML; its protumorigenic effects and mechanisms in AML; and the application of LILRB4-targeted therapies in AML. These insights highlight the potential advantages of LILRB4 as an immunotherapeutic target in the context of AML.

This study investigates the role of Annexin A1 (ANXA1) in regulating T cell function and its implications in bone marrow adiposity in aplastic anaemia (AA). Utilizing single-cell sequencing analysis, we compared bone marrow tissues from AA patients and healthy individuals, focusing on T cell subgroups and their impact on bone marrow pathology. Our findings reveal a significant activation of CD8+ T cells in AA, driven by reduced ANXA1 expression. This heightened T cell activity promotes adipogenesis in bone marrow-derived mesenchymal stem cells via IFN-γ secretion. Overexpression of ANXA1 was found to suppress this process, suggesting its therapeutic potential in AA treatment. The study highlights ANXA1 as a crucial regulator in the AA-associated immune microenvironment and bone marrow adiposity. KEY POINTS: This study found that ANXA1 is significantly downregulated in AA and provides detailed insights into its critical role in the disease. The study demonstrates the excessive activation of CD8+ T cells in the progression of AA. The research shows that the overexpression of ANXA1 can effectively inhibit the activation of CD8+ T cells. The study confirms that overexpression of ANXA1 reduces the secretion of the cytokine IFN-γ, decreases adipogenesis in bone marrow-derived mesenchymal stem cells and may improve AA symptoms. This research provides new molecular targets for the treatment of AA.

The gut microbiota is a key regulator of bone metabolism. Investigating the relationship between the gut microbiota and bone remodeling has revealed new avenues for the treatment of bone-related disorders. Despite significant progress in understanding gut microbiota-bone interactions in mammals, research on avian species remains limited. Birds have unique bone anatomy and physiology to support egg-laying. However, whether and how the gut microbiota affects bone physiology in birds is still unknown. In this study, we utilized laying hens as a research model to analyze bone development patterns, elucidate the relationships between bone and the gut microbiota, and mine probiotics with osteomodulatory effects.

Aging led to a continuous increase in bone mineral density in the femur of laying hens. The continuous deposition of medullary bone in the bone marrow cavity of aged laying hens led to significant trabecular bone loss and weakened bone metabolism. The cecal microbial composition significantly shifted before and after sexual maturity, with some genera within the class Clostridia potentially linked to postnatal bone development in laying hens. Four bacterial strains associated with bone development, namely Blautia coccoides CML164, Fournierella sp002159185 CML151, Anaerostipes caccae CML199 (ANA), and Romboutsia lituseburensis CML137, were identified and assessed in chicks with low bacterial loads and chicken primary osteoblasts. Among these, ANA demonstrated the most significant promotion of bone formation both in vivo and in vitro, primarily attributed to butyrate in its fermentation products. A long-term feeding experiment of up to 72 weeks confirmed that ANA enhanced bone development during sexual maturity by improving the immune microenvironment of the bone marrow in laying hens. Dietary supplementation of ANA for 50 weeks prevented excessive medullary bone deposition and mitigated aging-induced trabecular bone loss.

These findings highlight the beneficial effects of ANA on bone physiology, offering new perspectives for microbial-based interventions for bone-related disorders in both poultry and possibly extending to human health. Video Abstract.

Certain immune cells, including neutrophils, macrophages, dendritic cells, B cells, Breg cells, CD4+ T cells, CD8+ T cells, and Treg cells, establish enduring residency within the bone marrow. Their distinctive interactions with hematopoiesis and the bone marrow microenvironment are becoming increasingly recognized alongside their multifaceted immune functions. These cells play a dual role in shaping hematopoiesis. They directly influence the quiescence, self-renewal, and multi-lineage differentiation of hematopoietic stem and progenitor cells through either direct cell-to-cell interactions or the secretion of various factors known for their immunological functions. Additionally, they actively engage with the cellular constituents of the bone marrow niche, particularly mesenchymal stem cells, endothelial cells, osteoblasts, and osteoclasts, to promote their survival and contribute to tissue repair, thereby fostering a supportive environment for hematopoietic stem and progenitor cells. Importantly, these bone marrow immune cells function synergistically, both locally and functionally, rather than in isolation. In summary, immune cells residing in the bone marrow are pivotal components of a sophisticated network of regulating hematopoiesis.

Mammalian hematopoietic stem cells (HSCs) emerge from the hemogenic endothelium in the major embryonic arteries. HSCs undergo a complex journey first migrating to the fetal liver (FL) and from there to the fetal bone marrow (FBM), where they mostly remain during adult life. In this process, a pool of adult HSCs is produced, which sustains lifelong hematopoiesis. Multiple cellular components support HSC maturation and expansion and modulate their response to environmental and developmental cues. While the adult HSC niche has been extensively studied over the last two decades, the niches present in the major embryonic arteries, FL, FBM and perinatal bone marrow (BM) are poorly described. Recent investigations highlight important differences among FL, FBM and adult BM niches and emphasize the important role that inflammation, microbiota and hormonal factors play regulating HSCs and their niches. We provide a review on our current understanding of these important cellular microenvironments across ontogeny. We mainly focused on mice, as the most widely used research model, and, when possible, include relevant insights from other vertebrates including birds, zebrafish, and human. Developing a comprehensive picture on these processes is critical to understand the earliest origins of childhood leukemia and to achieve multiple goals in regenerative medicine, such as mimicking HSC development in vitro to produce HSCs for broad transplantation purposes in leukemia, following chemotherapy, bone marrow failure, and in HSC-based gene therapy.

In this review, the authors outlined concepts and strategies to achieve immune tolerance through inducing hematopoietic chimerism after solid organ transplantation and introduced challenges and opportunities in harnessing two-way alloresponses to improve outcomes after intestinal transplantation (ITx). Next, the authors discussed the dynamics and phenotypes of peripheral blood and intestinal graft T-cell subset chimerism and their association with outcomes. The authors also summarized studies on other types of immune cells after ITx and their potential participation in chimerism-mediated tolerance. The authors further discussed strategies and future directions to promote chimerism-associated tolerance after ITx to overcome rejection and minimize immunosuppression.

The bone marrow microenvironment (BMM) has highly specialized anatomical characteristics that provide a sanctuary place for hematopoietic stem cells (HSCs) that allow appropriate proliferation, maintenance, and self-renewal capacity. Several cell types contribute to the constitution and function of the bone marrow niche. Interestingly, uncovering the secrets of BMM and its interaction with HSCs in health paved the road for research aiming at better understanding the concept of leukemic stem cells (LSCs) and their altered niche. In fact, they share many signals that are responsible for interactions between LSCs and the bone marrow niche, due to several biological similarities between LSCs and HSCs. On the other hand, LSCs differ from HSCs in their abnormal activation of important signaling pathways that regulate survival, proliferation, drug resistance, invasion, and spread. Targeting these altered niches can help in better treatment choices for hematological malignancies and bone marrow disorders in general and acute myeloid leukemia (AML) in particular. Moreover, targeting those niches may help in decreasing the emergence of drug resistance and lower the relapse rate. In this article, the authors reviewed the most recent literature on bone marrow niches and their relations with either normal HSCs and AML cells/LSC, by focusing on pathogenetic and therapeutic implications.

Luminescent technology based on the luciferin-luciferase reaction has been extensively employed across various disciplines as a quantitative imaging modality. Owing to its non-invasive imaging capacity, it has evolved as a valuable in vivo bioimaging tool, particularly in small animal models in fields such as gene and cell therapies. We have previously successfully generated rats with a systemic expression of the luciferase gene at the Rosa26 locus. In this study, we transplanted bone marrow from these rats into micro-mini pigs and used in vivo imaging to non-invasively analyze the dynamics of the transplanted cells. In addition, we established that the rat-to-pig transplantation system is a discordant system, similar to the pig-to-human transplantation system. Thus, rat-to-pig transplantation may provide a clinically appropriate large animal model for pig-to-human xenotransplantation.

Hematopoietic stem cells (HSCs) are the cornerstone of the hematopoietic system. HSCs sustain the continuous generation of mature blood derivatives while self-renewing to preserve a relatively constant pool of progenitors throughout life. Yet, long-term maintenance of functional HSCs exclusively takes place in association with their native tissue microenvironment of the bone marrow (BM). HSCs have been long proposed to reside in fixed and identifiable anatomical units found in the complex BM tissue landscape, which control their identity and fate in a deterministic manner. In the last decades, tremendous progress has been made in the dissection of the cellular and molecular fabric of the BM, the structural organization governing tissue function, and the plethora of interactions established by HSCs. Nonetheless, a holistic model of the mechanisms controlling HSC regulation in their niche is lacking to date. Here, we provide an overview of our current understanding of BM anatomy, HSC localization, and crosstalk within local cellular neighborhoods in murine and human tissues, and highlight fundamental open questions on how HSCs functionally integrate in the BM microenvironment.

With the widespread application of nuclear technology across various fields, ionizing radiation-induced injuries are becoming increasingly common. The bone marrow (BM) hematopoietic tissue is a primary target organ of radiation injury. Recent researches have confirmed that ionizing radiation-induced hematopoietic dysfunction mainly results from BM hematopoietic stem cells (HSCs) injury. Additionally, disrupting and reshaping BM microenvironment is a critical factor impacting both the injury and regeneration of HSCs post radiation. However, the regulatory mechanisms of ionizing radiation injury to BM HSCs and their microenvironment remain poorly understood, and prevention and treatment of radiation injury remain the focus and difficulty in radiation medicine research. In this review, we aim to summarize the effects and mechanisms of ionizing radiation-induced injury to BM HSCs and microenvironment, thereby enhancing our understanding of ionizing radiation-induced hematopoietic injury and providing insights for its prevention and treatment in the future.

The human gut microbiome accompanies us from birth, and it is developed and matured by diet, lifestyle, and environmental factors. During aging, the bacterial composition evolves in reciprocal communication with the host's physiological properties. Many diseases are closely related to the gut microbiome, which means the modulation of the gut microbiome can promote the disease targeting remote organs. This review explores the intricate interaction between the gut microbiome and other organs, and their improvement from disease by prebiotics, probiotics, synbiotics, and postbiotics. Each section of the review is supported by clinical trials that substantiate the benefits of modulation the gut microbiome through dietary intervention for improving primary health outcomes across various axes with the gut. In conclusion, the review underscores the significant potential of targeting the gut microbiome for therapeutic and preventative interventions in a wide range of diseases, calling for further research to fully unlock the microbiome's capabilities in enhancing human health.

Hematopoiesis occurs in the bone marrow (BM), within a specialized microenvironment referred to as the stem cell niche, where the hematopoietic stem cells (HSCs) reside and are regulated for quiescence, self-renewal and differentiation through intrinsic and extrinsic mechanisms. The BM contains at least two distinctive HSC-supportive niches: an endosteal osteoblastic niche that supports quiescence and self-renewal and a more vascular/perisinusoidal niche that promotes proliferation and differentiation. Both associate with supporting mesenchymal stromal cells. Within the more hypoxic osteoblastic niche, HSCs specifically interact with the osteoblasts that line the endosteal surface, which secrete several important HSC quiescence and maintenance regulatory factors. In vivo imaging indicates that the HSCs and progenitors located further away, in the vicinity of sinusoidal endothelial cells, are more proliferative. Here, HSCs interact with endothelial cells via specific cell adhesion molecules. Endothelial cells also secrete several factors important for HSC homeostasis and proliferation. In addition, HSCs and mesenchymal stromal cells are embedded within the extracellular matrix (ECM), an important network of proteins such as collagen, elastin, laminin, proteoglycans, vitronectin, and fibronectin. The ECM provides mechanical characteristics such as stiffness and elasticity important for cell behavior regulation. ECM proteins are also able to bind, sequester, display, and distribute growth factors across the BM, thus directly affecting stem cell fate and regulation of hematopoiesis. These important physical and chemical features of the BM require careful consideration when creating three-dimensional models of the BM.

Since the first published case study of human intestinal transplantation in 1967, there have been significant studies of intestinal transplant immunology in both animal models and humans. An improved understanding of the profiles of different immune cell subsets is critical for understanding their contributions to graft outcomes. While different studies have focused on the contribution of one or a few subsets to intestinal transplant, no study has integrated these data for a comprehensive overview of immune dynamics after intestinal transplant. Here, we provide a systematic review of the literature on different immune subsets and discuss their roles in intestinal transplant outcomes on multiple levels, focusing on chimerism and graft immune reconstitution, clonal alloreactivity, and cell phenotype. In Sections 1, 2 and 3, we lay out a shared framework for understanding intestinal transplant, focusing on the mechanisms of rejection or tolerance in the context of mucosal immunology and illustrate the unique role of the bidirectional graft-versus-host (GvH) and host-versus-graft (HvG) alloresponse. In Sections 4, 5 and 6, we further expand upon these concepts as we discuss the contribution of different cell subsets to intestinal transplant. An improved understanding of intestinal transplantation immunology will bring us closer to maximizing the potential of this important treatment.

Regulatory T (Treg) cells are classically known for their critical immunosuppressive functions that support peripheral tolerance. More recent work has demonstrated that Treg cells produce pro-repair mediators independent of their immunosuppressive function, a process that is critical to repair and regeneration in response to numerous tissue insults. These factors act on resident parenchymal and structural cells to initiate repair in a tissue-specific context. This review examines interactions between Treg cells and tissue-resident non-immune cells-in the context of tissue repair, fibrosis, and cancer-and discusses areas for future exploration.

Conventionally, it was thought that innate immunity operated through a simple system of nonspecific responses to an insult. However, this perspective now seems overly simplistic. It has become evident that intricate cooperation and networking among various cells, receptors, signaling pathways, and protein complexes are essential for regulating and defining the overall activation status of the immune response, where the distinction between innate and adaptive immunity becomes ambiguous. Given the evolutionary timeline of vertebrates and the success of plants and invertebrates which depend solely on innate immunity, immune memory cannot be considered an innovation of only the lymphoid lineage. Indeed, the evolutionary innate immune memory program is a conserved mechanism whereby innate immune cells can induce a heightened response to a secondary stimulus due to metabolic and epigenetic reprogramming. Importantly, the longevity of this memory phenotype can be attributed to the reprogramming of self-renewing hematopoietic stem cells (HSCs) in the bone marrow, which is subsequently transmitted to lineage-committed innate immune cells. HSCs reside within a complex regulated network of immune and stromal cells that govern their two primary functions: self-renewal and differentiation. In this review, we delve into the emerging cellular and molecular mechanisms as well as metabolic pathways of innate memory in HSCs, which harbor substantial therapeutic promise.

Donor-specific tolerance remains a goal in transplantation because it could improve graft survival and reduce morbidity. Cotransplantation of donor hematopoietic cells to achieve chimerism is a promising approach for tolerance induction, which was successfully tested in clinical trials. However, current protocols are associated with side effects related to the myelosuppressive recipient conditioning, which makes it difficult to introduce them as standard therapy. More recently, adoptive cell therapy with polyclonal or donor-specific regulatory T cells (Treg) proved safe and feasible in several transplant trials, but it is unclear whether it can induce tolerance on its own. The combination of both approaches-Treg therapy and hematopoietic cell transplantation-leads to chimerism and tolerance without myelosuppressive treatment in murine models. Treg therapy promotes engraftment of allogeneic hematopoietic cells, reducing conditioning requirements and enhancing regulatory mechanisms maintaining tolerance. This review discusses possible modes of action of transferred Treg in experimental chimerism models and describes translational efforts investigating the potent synergy of Treg and chimerism.

Acute myeloid leukemia (AML) is a common hematological cancer. Cancer cells exchange information with the surrounding microenvironment, which can be transmitted by extracellular vesicles (EVs). In recent years, the genetic materials transported by EVs have attracted attention due to their important roles in different pathological processes. EV-derived ncRNAs (EV-ncRNAs) regulate physiological functions and maintain homeostasis, mainly including microRNAs, long noncoding RNAs, and circular RNAs. However, the mechanism of involvement and potential clinical application of EV-ncRNAs in AML have not been reported. Given the unique importance of the bone marrow microenvironment (BMME) for AML, a greater understanding of the communication between leukemic cells and the BMME is needed to improve the prognosis of patients and reduce the incidence of recurrence. Additionally, studies on leukemic EV-ncRNA transport guide the design of new diagnostic and therapeutic tools for AML. This review systematically describes intercellular communication in the BMME of AML and emphasizes the role of EVs. More importantly, we focus on the information transmission of EV-ncRNAs in the BMME to explore their clinical application as potential biomarkers and therapeutic targets.

Epithelial cells form a resilient barrier and orchestrate defensive and reparative mechanisms to maintain tissue stability. This review focuses on gut and airway epithelia, which are positioned where the body interfaces with the outside world. We review the many signaling pathways and mechanisms by which epithelial cells at the interface respond to invading pathogens to mount an innate immune response and initiate adaptive immunity and communicate with other cells, including resident microbiota, to heal damaged tissue and maintain homeostasis. We compare and contrast how airway and gut epithelial cells detect pathogens, release antimicrobial effectors, collaborate with macrophages, Tregs and epithelial stem cells to mount an immune response and orchestrate tissue repair. We also describe advanced research models for studying epithelial communication and behaviors during inflammation, tissue injury and disease.

Both alopecia areata (AA) and vitiligo are distinct, heterogenous, and complex disease entities, characterized by nonscarring scalp terminal hair loss and skin pigment loss, respectively. In AA, inflammatory cell infiltrates are in the deep reticular dermis close to the hair bulb (swarm of bees), whereas in vitiligo the inflammatory infiltrates are in the epidermis and papillary dermis. Immune privilege collapse has been extensively investigated in AA pathogenesis, including the suppression of immunomodulatory factors (e.g., transforming growth factor-β (TGF-β), programmed death-ligand 1 (PDL1), interleukin-10 (IL-10), α-melanocyte-stimulating hormone (α-MSH), and macrophage migration inhibitory factor (MIF)) and enhanced expression of the major histocompatibility complex (MHC) throughout hair follicles. However, immune privilege collapse in vitiligo remains less explored. Both AA and vitiligo are autoimmune diseases that share commonalities in pathogenesis, including the involvement of plasmacytoid dendritic cells (and interferon-α (IFN- α) signaling pathways) and cytotoxic CD8+ T lymphocytes (and activated IFN-γ signaling pathways). Blood chemokine C-X-C motif ligand 9 (CXCL9) and CXCL10 are elevated in both diseases. Common factors that contribute to AA and vitiligo include oxidative stress, autophagy, type 2 cytokines, and the Wnt/β-catenin pathway (e.g., dickkopf 1 (DKK1)). Here, we summarize the commonalities and differences between AA and vitiligo, focusing on their pathogenesis.

The immune system is traditionally classified as a defense system that can discriminate between self and non-self or dangerous and non-dangerous situations, unleashing a tolerogenic reaction or immune response. These activities are mainly coordinated by the interaction between innate and adaptive cells that act together to eliminate harmful stimuli and keep tissue healthy. However, healthy tissue is not always the end point of an immune response. Much evidence has been accumulated over the years, showing that the immune system has complex, diversified, and integrated functions that converge to maintaining tissue homeostasis, even in the absence of aggression, interacting with the tissue cells and allowing the functional maintenance of that tissue. One of the main cells known for their function in helping the immune response through the production of cytokines is CD4+ T lymphocytes. The cytokines produced by the different subtypes act not only on immune cells but also on tissue cells. Considering that tissues have specific mediators in their architecture, it is plausible that the presence and frequency of CD4+ T lymphocytes of specific subtypes (Th1, Th2, Th17, and others) maintain tissue homeostasis. In situations where homeostasis is disrupted, such as infections, allergies, inflammatory processes, and cancer, local CD4+ T lymphocytes respond to this disruption and, as in the healthy tissue, towards the equilibrium of tissue dynamics. CD4+ T lymphocytes can be manipulated by tumor cells to promote tumor development and metastasis, making them a prognostic factor in various types of cancer. Therefore, understanding the function of tissue-specific CD4+ T lymphocytes is essential in developing new strategies for treating tissue-specific diseases, as occurs in cancer. In this context, this article reviews the evidence for this hypothesis regarding the phenotypes and functions of CD4+ T lymphocytes and compares their contribution to maintaining tissue homeostasis in different organs in a steady state and during tumor progression.

Tissue inflammation is a hallmark of tumour microenvironments. In the bone marrow, tumour-associated inflammation impacts normal niches for haematopoietic progenitor cells and mature immune cells and supports the outgrowth and survival of malignant cells residing in these niche compartments. This Review provides an overview of our current understanding of inflammatory changes in the bone marrow microenvironment of myeloid and lymphoid malignancies, using acute myeloid leukaemia and multiple myeloma as examples and highlights unique and shared features of inflammation in niches for progenitor cells and plasma cells. Importantly, inflammation exerts profoundly different effects on normal bone marrow niches in these malignancies, and we provide context for possible drivers of these divergent effects. We explore the role of tumour cells in inflammatory changes, as well as the role of cellular constituents of normal bone marrow niches, including myeloid cells and stromal cells. Integrating knowledge of disease-specific dynamics of malignancy-associated bone marrow inflammation will provide a necessary framework for future targeting of these processes to improve patient outcome.

Bone is a common organ for solid tumor metastasis. Malignant bone tumor becomes insensitive to systemic therapy after colonization, followed by poor prognosis and high relapse rate. Immune and bone cells in situ constitute a unique immune microenvironment, which plays a crucial role in the context of bone metastasis. This review firstly focuses on lymphatic cells in bone metastatic cancer, including their function in tumor dissemination, invasion, growth and possible cytotoxicity-induced eradication. Subsequently, we examine myeloid cells, namely macrophages, myeloid-derived suppressor cells, dendritic cells, and megakaryocytes, evaluating their interaction with cytotoxic T lymphocytes and contribution to bone metastasis. As important components of skeletal tissue, osteoclasts and osteoblasts derived from bone marrow stromal cells, engaging in 'vicious cycle' accelerate osteolytic bone metastasis. We also explain the concept tumor dormancy and investigate underlying role of immune microenvironment on it. Additionally, a thorough review of emerging treatments for bone metastatic malignancy in clinical research, especially immunotherapy, is presented, indicating current challenges and opportunities in research and development of bone metastasis therapies.

Hematopoietic stem cells (HSCs) rely on specialized microenvironments known as niches to maintain their self-renewal and multilineage potential to generate diverse types of blood cells continuously. Over the last two decades, substantial advancements have been made in unraveling the niche cell components and HSC localizations under homeostatic and stressed circumstances. Advances in imaging, combined with the discovery of phenotypic surface markers combinations and single cell sequencing, have greatly facilitated the systematic examination of HSC localizations. This review aims to present a summary of HSC localizations, highlighting potential distinctions between phenotypically and functionally defined HSCs, and explore the functionality of niches in ensuring the integrity and long-term maintenance of HSCs.

Plasma cells produce large quantities of antibodies and so play essential roles in immune protection1. Plasma cells, including a long-lived subset, reside in the bone marrow where they depend on poorly defined microenvironment-linked survival signals1. We show that bone marrow plasma cells use the ligand-gated purinergic ion channel P2RX4 to sense extracellular ATP released by bone marrow osteoblasts through the gap-junction protein pannexin 3 (PANX3). Mutation of Panx3 or P2rx4 each caused decreased serum antibodies and selective loss of bone marrow plasma cells. Compared to their wild-type counterparts, PANX3-null osteoblasts secreted less extracellular ATP and failed to support plasma cells in vitro. The P2RX4-specific inhibitor 5-BDBD abrogated the impact of extracellular ATP on bone marrow plasma cells in vitro, depleted bone marrow plasma cells in vivo and reduced pre-induced antigen-specific serum antibody titre with little posttreatment rebound. P2RX4 blockade also reduced autoantibody titre and kidney disease in two mouse models of humoral autoimmunity. P2RX4 promotes plasma cell survival by regulating endoplasmic reticulum homeostasis, as short-term P2RX4 blockade caused accumulation of endoplasmic reticulum stress-associated regulatory proteins including ATF4 and B-lineage mutation of the pro-apoptotic ATF4 target Chop prevented bone marrow plasma cell demise on P2RX4 inhibition. Thus, generating mature protective and pathogenic plasma cells requires P2RX4 signalling controlled by PANX3-regulated extracellular ATP release from bone marrow niche cells.

The bone marrow (BM) niche is a microenvironment where both immune and non-immune cells functionally interact with hematopoietic stem cells (HSC) and more differentiated progenitors, contributing to the regulation of hematopoiesis. It is regulated by various signaling molecules such as cytokines, chemokines, and adhesion molecules in its microenvironment. However, despite the strict regulation of BM signals to maintain their steady state, accumulating evidence in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) indicates that leukemic cells can disrupt the physiological hematopoietic niche in the BM, creating a new leukemia-supportive microenvironment. This environment favors immunological evasion mechanisms and the interaction of these cells with the development and progression of BCP-ALL. With a growing understanding of the tumor immune microenvironment (TIME) in the development and progression of BCP-ALL, current strategies focused on "re-editing" TIME to promote antitumor immunity have been developed. In this review, we summarize how TIME cells are disrupted by the presence of leukemic cells, evading immunosurveillance mechanisms in the BCP-ALL model. We also explore the crosstalk between TIME and leukemic cells that leads to treatment resistance, along with the most promising immuno-therapy strategies. Understanding and further research into the role of the BM microenvironment in leukemia progression and relapse are crucial for developing more effective treatments and reducing patient mortality.

Regenerative medicine harnesses the body's innate capacity for self-repair to restore malfunctioning tissues and organs. Stem cell therapies represent a key regenerative strategy, but to effectively harness their potential necessitates a nuanced understanding of the stem cell niche. This specialized microenvironment regulates critical stem cell behaviors including quiescence, activation, differentiation, and homing. Emerging research reveals that dysfunction within endogenous neural stem cell niches contributes to neurodegenerative pathologies and impedes regeneration. Strategies such as modifying signaling pathways, or epigenetic interventions to restore niche homeostasis and signaling, hold promise for revitalizing neurogenesis and neural repair in diseases like Alzheimer's and Parkinson's. Comparative studies of highly regenerative species provide evolutionary clues into niche-mediated renewal mechanisms. Leveraging endogenous bioelectric cues and crosstalk between gut, brain, and vascular niches further illuminates promising therapeutic opportunities. Emerging techniques like single-cell transcriptomics, organoids, microfluidics, artificial intelligence, in silico modeling, and transdifferentiation will continue to unravel niche complexity. By providing a comprehensive synthesis integrating diverse views on niche components, developmental transitions, and dynamics, this review unveils new layers of complexity integral to niche behavior and function, which unveil novel prospects to modulate niche function and provide revolutionary treatments for neurodegenerative diseases.

Although chemotherapeutic regimens can eliminate blasts in leukaemia patients, such therapies are associated with toxicity and often fail to eliminate all malignant cells resulting in disease relapse. Disease relapse has been attributed to the persistence of leukaemia cells in the bone marrow (BM) with the capacity to recapitulate disease; these cells are often referred to as leukaemia stem cells (LSCs). Although LSCs have distinct characteristics in terms of pathobiology and immunophenotype, they are still regulated by their interactions with the surrounding microenvironment. Thus, understanding the interaction between LSCs and their microenvironment is critical to identify effective therapies. To this end, there are numerous efforts to develop models to study such interactions. In this review, we will focus on the reciprocal interactions between LSCs and their milieu in the BM. Furthermore, we will highlight relevant therapies targeting these interactions and discuss some of the promising in vitro models designed to mimic such relationship. LINKED ARTICLES: This article is part of a themed issue on Cancer Microenvironment and Pharmacological Interventions. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.2/issuetoc.