Bone marrow is the main site for hematopoiesis in adults. It acts as a niche for hematopoietic stem cells (HSCs) and contains non‐hematopoietic cells that contribute to stem cell dormancy, quiescence, self‐renewal, and differentiation. HSC also exist in resting spleen of several species, although their contribution to hematopoiesis under steady‐state conditions is unknown. The spleen can however undergo extramedullary hematopoiesis (EMH) triggered by physiological stress or disease. With the loss of bone marrow niches in aging and disease, (...) the spleen as an alternative tissue site for hematopoiesis is an important consideration for future therapy, particularly during HSC transplantation. In terms of harnessing the spleen as a site for hematopoiesis, here the remarkable regenerative capacity of the spleen is considered with a view to forming additional or ectopic spleen tissue through cell engraftment. Studies in mice indicate the potential for such grafts to support the influx of hematopoietic cells leading to the development of normal spleen architecture. An important goal will be the formation of functional ectopic spleen tissue as an aid to hematopoietic recovery following clinical treatments that impact bone marrow. For example, expansion or replacement of niches could be considered where myeloablation ahead of HSC transplantation compromises treatment outcomes. (shrink)

Various cell types cooperate to create a highly organized and dynamic micro-environmental niche in the bone marrow. Over the past several years, the field has increasingly recognized the critical roles of the interplay between bone marrow environment and hematopoietic cells in normal and deranged hematopoiesis. These advances rely on several new technologies that have allowed us to characterize the identity and roles of these niches in great detail. Here, we review the progress of the last several years, list some (...) of the outstanding questions in the field and propose ways to target the diseased environment to better treat hematologic diseases. Understanding the extrinsic regulation by the niche will help boost hematopoiesis for regenerative medicine. Based on natural development of hematologic malignancies, we propose that combinatory targeting the niche and hematopoietic intrinsic mechanisms in early stages of hematopoietic malignancies may help eliminate minimal residual disease and have the highest efficacy. The bone marrow is the home for blood-forming hematopoietic stem and progenitor cells. Normal generation of blood and immune cells depends on highly regulated interactions between these stem and progenitor cells with their surrounding environment. Emerging evidence suggests that therapeutic interventions directed at these cellular interdependencies can help boost hematopoiesis and eradicate malignant hematopoietic cells. (shrink)

The evolutionarily conserved Notch signaling pathway regulates a broad spectrum of cell fate decisions and differentiation processes during fetal and postnatal life. It is involved in embryonic organogenesis as well as in the maintenance of homeostasis of self‐renewing systems. In this article, we review the role of Notch signaling in the hematopoietic system with particular emphasis on lymphocyte development and highlight the similarities in Notch function between Drosophila and mammalian differentiation processes. Recent studies indicating that aberrant NOTCH signaling is frequently (...) linked to the induction of T leukemia in humans will also be discussed. BioEssays 27:1117–1128, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Interleukin 5 (IL‐5) is a kind of peptide hormone released from T lymphocytes of mammals infected with microorganisms or parasites. It is an acidic glycoprotein with a molecular mass of 40 to 50 kDa that consists of a homodimer of polypeptides. It controls hematopoiesis so that it increases natural immunity. In the mouse, IL‐5 acts on committed B cells to induce differentiation into Ig‐producing cells and on common progenitors for CD5+ pre‐B cells and CD5+ macrophages to support their survival. (...) The antibodies secreted by CD5+ B cells seem to be responsible for the primary protection against the infection with microorganisms or parasites. It also supports the growth and/or differentiation of eosinophil precursor and mature eosinophils, which can be effective for the removal of parasites in combination with the antibodies against them. Murine IL‐5 receptor (IL‐5R) consists of two different polypeptide chains; αL chain and β chain. The IL‐5R α chain is 60 kDa protein that binds IL‐5 with low affinity. The IL‐5R β chain is a 130 kDa protein which does not bind IL‐5 by itself but is necessary to form the high affinity IL‐5R. The β chain was identified by using one of the anti‐IL‐5R mAb and anti‐IL‐3R mAb as the IL‐3R homologue. This β chain is also used as the β chain of GM‐CSF receptor. This fact suggests that there is a common signaling mechanism among these cytokines and efficient cooperation among them. At the same time, these findings may explain the overlapping role of these cytokines in the development of granulocytes. (shrink)

Clonal disease is often regarded as almost synonymous with cancer. However, it is becoming increasingly clear that our bodies harbor numerous mutant clones that are not tumors, and mostly give rise to no disease at all. Here we discuss three somatic mutations arising within the hematopoietic system: BCR‐ABL, characteristic of chronic myeloid leukemia; mutations of the PIG‐A gene, characteristic of paroxysmal nocturnal hemoglobinuria; the V617F mutation in the JAK2 gene, characteristic of myeloproliferative diseases. The population frequencies of these three blood (...) disorders fit well with a hierarchical model of hematopoiesis. The fate of any mutant clone will depend on the target cell and on the fitness advantage, if any, that the mutation confers on the cell. In general, we can expect that only a mutation in a hematopoietic stem cell will give long‐term disease; the same mutation taking place in a cell located more downstream may produce just a ripple in the hematopoietic ocean. (shrink)

The hematopoietic system consists of more than ten differentiated cell types, all of which are derived from a single type of hematopoietic stem cell. The accessibility and interest of this system have made it a model for understanding normal and abnormal differentiation of mammalian cells. Newer techniques have generated a mass of data that requires integrative approaches for analysis and interpretation. The traditional view of the differentiation program holds that a small number of regulators are involved in each stage of (...) cell specification. However, this may not be the case. Recent analyses have shown that almost all substantial subsets of genes, including the set of broadly expressed transcription factors, are expressed in patterns that are unique for each lineage. Further, much of this difference between lineages can be captured in two‐dimensional graphs. Understanding the biologic significance, mechanisms and constraints underlying these differences is a challenge for experimentalists and computational biologists alike. BioEssays 26:1276–1287, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Hematopoiesis unfolds within the bone marrow niche where hematopoietic stem cells (HSCs) play a central role in continually replenishing blood cells. The hypoxic bone marrow environment imparts peculiar metabolic characteristics to hematopoietic processes. Here, we discuss the internal metabolism of HSCs and describe external influences exerted on HSC metabolism by the bone marrow niche environment. Importantly, we suggest that the metabolic environment and metabolic cues are intertwined with HSC cell fate, and are crucial for hematopoietic processes. Metabolic dysregulation within (...) the bone marrow niche during acute stress, inflammation, and chronic inflammatory conditions can lead to reduced HSC vitality. Additionally, we raise questions regarding metabolic stresses imposed on HSCs during implementation of stem cell protocols such as allo‐SCT and gene therapy, and the potential ramifications. Enhancing our comprehension of metabolic influences on HSCs will expand our understanding of pathophysiology in the bone marrow and improve the application of stem cell therapies. (shrink)

Recent research highlights that inflammatory signaling pathways such as pattern recognition receptor (PRR) signaling and inflammatory cytokine signaling play an important role in both on‐demand hematopoiesis as well as steady‐state hematopoiesis. Knockout studies have demonstrated the necessity of several distinct pathways in these processes, but often lack information about the contribution of specific cell types to the phenotypes in question. Transplantation studies have increased the resolution to the level of specific cell types by testing the necessity of inflammatory (...) pathways specifically in donor hematopoietic stem and progenitor cells (HSPCs) or in recipient niche cells. Here, we argue that for an integrated understanding of how these processes occur in vivo and to inform the development of therapies that modulate hematopoietic responses, we need studies that knockout inflammatory signaling receptors in a cell‐specific manner and compare the phenotypes caused by knockout in individual niche cells versus HSPCs. (shrink)

With decades of research seeking to generalize sterile alpha motif (SAM) biology, many outstanding questions remain regarding this multi‐tool protein module. Recent data from structural and molecular/cell biology has begun to reveal new SAM modes of action in cell signaling cascades and biomolecular condensation. SAM‐dependent mechanisms underlie blood‐related (hematologic) diseases, including myelodysplastic syndromes and leukemias, prompting our focus on hematopoiesis for this review. With the increasing coverage of SAM‐dependent interactomes, a hypothesis emerges that SAM interaction partners and binding affinities (...) work to fine tune cell signaling cascades in developmental and disease contexts, including hematopoiesis and hematologic disease. This review discusses what is known and remains unknown about the standard mechanisms and neoplastic properties of SAM domains and what the future might hold for developing SAM‐targeted therapies. (shrink)

Hematopoiesis is the complex developmental process through which undifferentiated, pluripotent, hematopoietic stem cells come to generate mature, functional blood cells. This process is regulated in large part by specific transcription factors that control expression of genes necessary for the developmental sequence. Leukemias represent one form of disruption of this normal developmental process, and studies over the past few years have shown that many of the genes that underlay leukemogenesis are also essential for normal hematopoiesis. In an interesting recent (...) example, Song et al.(1) demonstrate that haploinsufficiency of the AML1 gene is the genetic basis of a form of familial thrombocytopenia which predisposes the affected individuals to the development of acute myeloid leukemia. Here we summarize Song's paper and current information describing the interesting dosage effects of this gene and other members of its gene family. BioEssays 22:214–218, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Once hematopoiesis is established in the bone marrow, a continuous egress of hematopoietic stem cells (HSCs) to the periphery occurs at a low frequency. It has been proposed that this phenomenon is part of a regenerative homeostatic mechanism that ensures the maintenance of hematopoiesis through the life of the individual. The administration of certain cytotoxic drugs or cytokines can enhance the mobilization of hematopoietic progenitors to the periphery. During the past 15 years, granulocyte‐colony stimulating factor (G‐CSF) has been (...) used as a standard cytokine for mobilization protocols in experimental models and in humans. Despite extensive efforts by multiple groups, a definitive mechanism explaining its role in mobilization has not been provided. In a recent paper, Katayama et al.,1 through a series of clever associations supported by well‐defined experimental systems, proposed that signals through the sympathetic nervous system modify the activity of the hematopoietic niche, acting as regulators of the mobilization of hematopoietic progenitors. This surprising finding adds a new level of complexity to the cellular milieu responsible for generation and maintenance of the hematopoietic niche. BioEssays 28: 687–691, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Clinical success with human hematopoietic stem cell (HSC) transplantation establishes a paradigm for regenerative therapies with other types of stem cells. However, it remains generally challenging to therapeutically treat tissues after engineering of stem cells in vitro. Recent studies suggest that stem and progenitor cells sense physical features of their niches. Here, we review biophysical contributions to lineage decisions, maturation, and trafficking of blood and immune cells. Polarized cellular contractility and nuclear rheology are separately shown to be functional markers of (...) a hematopoietic hierarchy that predict the ability of a lineage to traffic in and out of the bone marrow niche. These biophysical determinants are regulated by a set of structural molecules, including cytoplasmic myosin‐II and nuclear lamins, which themselves are modulated by a diverse range of transcriptional and post‐translational mechanisms. Small molecules that target these mechanobiological circuits, along with novel bioengineering methods, could prove broadly useful in programming blood and immune cells for therapies ranging from blood transfusions to immune attack of tumors. (shrink)

Members of the CAR group of Ig‐like type I transmembrane proteins mediate homotypic cell adhesion, share a common overall extracellular domain structure and are closely related at the amino acid sequence level. CAR proteins are often found at tight junctions and interact with intracellular scaffolding proteins, suggesting that they might modulate tight junction assembly or function. However, impairment of tight junction integrity has not been reported in mouse knockout models or zebrafish mutants of CAR members. In contrast, in the same (...) knockout models deficits in gap junction communication were detected in several organ systems, including the atrioventricular node of the heart, smooth muscle cells of the intestine and the ureter and in Sertoli cells of the testes. Possible interactions between BT‐IgSF and connexin41.8 on the disturbed pattern of pigment stripes found in zebrafish mutants and between ESAM and connexin43 during hematopoiesis in the mouse are also discussed. On the basis of the combined data and phenotypic similarities between CAR member mutants and connexin mutants I hypothesize that they primarily play a role in the organization of gap junction communication. Also see the video abstract here: https://youtu.be/i0yq2KhuDAE. (shrink)

The cyclic opeptide Cyclosporinee A (CsA) is best known as the immunosuppressive drug which has revoulutionized organ transplantation. It selectively suppresses T cell activation by blocking the transcription of cytokine genes such as IL‐2 at the level of transxcription factor modulation. The structurally unrelated immuniusuppressant FK 506 acts on the same pathway and blocks cytokine gene expression. In contrast, rapamycin, a structural analoguwe of FK 506, interferes with the immune response at a different level, by blocking the response induced by (...) ctytokines such as IL‐2.Although these drugs have been most studied for their immunosuppressive activities, it is clear that their effects on cytokine pathways extend far beyond the scole IL‐2.‐mediated responses involved in the immune response. IFor instance, CsA and FK 506 inhibit the transcription of IL‐3, IL‐4, IFNγ, TNFα or GM‐CSF by activated T cells, and rapamycin has been shown to blcock the response to various growth factors such as IL‐3, IL‐4 or IL‐6.Here, we receap what is known about the effects of CsA, FK 506 and rapamycin on hematopoiesis in vitro and in vivo and extrapolate on what these drugs can teach us aboput the physiological role of cytokines for hematopoiesis. (shrink)

Development of gene transfer systems provides a key tool for understanding gene function. Exciting and often unexpected consequences from embryo manipulations are yielding insights into molecular mechanisms underlying development under normal and pathogenic states, and are providing animal models for diseases. Contributing to this progress is the elegant work on c‐fos(1), where Wagner and coworkers identify this proto‐oncogene as a primary factor which directs cell differentiation along the osteoclast/macrophage lineages, and thus regulates bone remodeling. Their studies support a link between (...) skeletogenesis, marrow formation and hematopoiesis, and may help to delineate mechanisms underlying the oncogenic transformation of skeletal and hematopoietic cells. (shrink)