Blood-forming Stem Cells Research Articles

Regulation of the hematopoietic stem cell pool by C-Kit-associated trogocytosis.

Hematopoietic stem cells (HSCs) are routinely mobilized from the bone marrow (BM) to the blood circulation for clinical transplantation. However, the precise mechanisms by which individual stem cells exit the marrow are not understood. This study identified cell-extrinsic and molecular determinants of a mobilizable pool of blood-forming stem cells. We found that a subset of HSCs displays macrophage-associated markers on their cell surface. Although fully functional, these HSCs are selectively niche-retained as opposed to stem cells lacking macrophage markers, which exit the BM upon forced mobilization. Macrophage markers on HSCs could be acquired through direct transfer by trogocytosis, regulated by receptor tyrosine-protein kinase C-Kit (CD117), from BM-resident macrophages in mouse and human settings. Our study provides proof of concept that adult stem cells utilize trogocytosis to rapidly establish and activate function-modulating molecular mechanisms.

Systematic identification of regulatory elements in Leukemia.

Background: Leukemia is a type of cancer that originates from the bone marrow's blood-forming stem cells. Cancer cells don't follow the usual cellular differentiation and function pathway, so they supersede the healthy cells. Depending on the population and maturity level of abnormal cells, leukemia can be classified as Acute or Chronic. Methodology: We mapped defined leukemia mutations from the COSMIC- The Catalogue of Somatic Mutations to perspective regulatory elements. GeneCards - Human Genes Database and Factorbook were utilized in this work to extract data to analyze gene-centric data related to AML and CML. The chromosomal location, Ensembl version, GRCh37 coordinates, and detailed examination of exons, introns, promoter binding regions, and enhancers were used to investigate co-expressed and differentially expressed genes. Downloaded from Factorbook, the expression levels of healthy and sick genes were compared to known transcription factor binding patterns. Results: When translational control genes become mutated, they begin performing their function excessively, leading to uncontrolled cell proliferation and an accumulation of immature cells in the blood that are unable to perform any function on the one hand and interfering with healthy cells' ability to function optimally due to overpopulation and growth on the other. There is a group of genes whose expression level declines as they are affected by the gene, suggesting that these genes should function as insulators or silencers under normal circumstances. The data for Myc and Max genes were extracted from the Human Genome database and sorted using different techniques to find the common regulatory regions (CRRs). These CRRs were then divided into distinct categories based on the degree to which they co-expressed or their level of expression. Conclusion: Regulatory elements have been identified depending on the values of their expression level and how they are changing concerning the control group. This work will help in understanding the guidelines of blood malignancy at the cellular level by recognizing administrative destinations and are, in this manner, possible focuses for the treatment plans and precession accuracy medication.

Stem cell-based therapy for corals

Stem cell-based therapy for corals The laboratory at Ben Gurion University of the Negev in Israel is concerned with immunology and focuses on transplantation immunology, mainly at the immune cell level. We focus on stem cell transplantation, specifically on the blood-forming stem cells, termed "bone marrow transplantation". Could medical approaches of stem cell-based therapy be a tool for corals' resilience to heat stress? Benyamin Rosental, Principal Investigator, Assistant Professor at the Ben Gurion University of the Negev in Israel answers the compelling question here.

Specification of hematopoietic stem cells in mammalian embryos: a rare or frequent event?

AbstractHematopoietic stem cells (HSCs) are the blood-forming stem cells thought to be responsible for supporting the blood system throughout life. Transplantability has long been the flagship assay used to define and characterize HSCs throughout ontogeny. However, it has recently become clear that many cells emerge during ontogeny that lack transplantability yet nevertheless are fated to ultimately contribute to the adult HSC pool. Here, we explore recent advances in understanding the numbers and kinetics of cells that emerge during development to support lifelong hematopoiesis; these advances are made possible by new technologies allowing interrogation of lifelong blood potential without embryo perturbation or transplantation. Illuminating the dynamics of these cells during normal development informs efforts to better understand the origins of hematologic disease and engineer HSCs from differentiating pluripotent stem cells.

Exploring the Current Trends of Artificial Intelligence in Stem Cell Therapy: A Systematic Review.

The concept of healing in medicine has been taking a new form where scientists and researchers are in pursuance of regenerative medicine. Until now, doctors have "reacted" to disease by treating the symptoms; however, modern medicine is transforming toward regeneration rather than reactive treatment, which is where stem cell therapy comes into the play-the concept of replacing damaged cells with brand new cells that perform the same function better. Stem cell treatment is currently being used to treat autoimmune, inflammatory, neurological, orthopedic, and traumatic disorders, with various research being undertaken for a wide range of diseases. It could also be the answer to anti-aging and a disease-free state. Despite the benefits, numerous errors could prevail in treating patients with stem cells. With the advancement of technology and research in the modern period, medicine is beginning to turn to artificial intelligence (AI) to address the complicated errors that could occur in regenerative medicine. For successful treatment, one must achieve precision and accuracy when analyzing healthy and productive stem cells that possess all the properties of a native cell. This review intends to discuss and study the application of AI in stem cell therapy and how it influences how medicine is practiced, thus creating a path to a regenerative future with negligible adverse effects.The following databases were used for a literature search: PubMed, Google Scholar, PubMed Central, and Institute of Electrical and Electronics Engineers (IEEE) Xplore. After a thorough analysis, studies were chosen, keeping in mind the inclusion and exclusion criteria set by the authors of this review, which comprised reports published within the last six years in the English language. The authors also made sure to include studies that sufficed the quality of each report assessed using appropriate quality appraisal tools, after which eight reports were found to be eligible and were included in this review. This research mainly revolves around machine learning, deep neural networks (DNN), and other subclasses of AI encompassed in these categories.While there are concerns and limitations in implementing various mediums of AI in stem cell therapy, the analysis of the eligible studies concluded that artificial intelligence provides significant benefits to the global healthcare ecosystem in numerous ways, such as determining the viability, functionality, biosafety, and bioefficacy of stem cells, as well as appropriate patient selection. Applying AI to this novelty brings out the precision, accuracy, and a revolution in regenerative medicine. In addition, stem cell therapy is not currently FDA approved (except for the blood-forming stem cells) and, to date, is considered experimental with no clear outline of risks and benefits. Given this limitation, studies are conducted regularly around the world in hopes for a concrete conclusion where technological advances such as AI could help in shaping the future of regenerative medicine.

Bone Vasculature and Bone Marrow Vascular Niches in Health and Disease.

Bone vasculature and bone marrow vascular niches supply oxygen, nutrients, and secrete angiocrine factors required for the survival, maintenance, and self-renewal of stem and progenitor cells. In the skeletal system, vasculature creates nurturing niches for bone and blood-forming stem cells. Blood vessels regulate hematopoiesis and drive bone formation during development, repair, and regeneration. Dysfunctional vascular niches induce skeletal aging, bone diseases, and hematological disorders. Recent cellular and molecular characterization of the bone marrow microenvironment has provided unprecedented insights into the complexity, heterogeneity, and functions of the bone vasculature and vascular niches. The bone vasculature is composed of distinct vessel subtypes that differentially regulate osteogenesis, hematopoiesis, and disease conditions in bones. Further, bone marrow vascular niches supporting stem cells are often complex microenvironments involving multiple different cell populations and vessel subtypes. This review provides an overview of the emerging vascular cell heterogeneity in bone and the new roles of the bone vasculature and associated vascular niches in health and disease. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Hematopoietic stem cell transplantation for people with sickle cell disease.

Sickle cell disease is a genetic disorder involving a defect in the red blood cells due to its sickled hemoglobin. The main therapeutic interventions include preventive and supportive measures. Hematopoietic stem cell transplantations are carried out with the aim of replacing the defective cells and their progenitors (hematopoietic (i.e. blood forming) stem cells) in order to correct the disorder. This is an update of a previously published review. To determine whether stem cell transplantation can improve survival and prevent symptoms and complications associated with sickle cell disease. To examine the risks of stem cell transplantation against the potential long-term gain for people with sickle cell disease. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Group's Haemoglobinopathies Trials Register complied from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of the Cochrane Library) and quarterly searches of MEDLINE. We also searched trial registries for ongoing trials up to April 2020. Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 09 December 2019. Randomized controlled and quasi-randomized trials that compared any method of stem cell transplantation with either each other or with any of the preventive or supportive interventions (e.g. periodic blood transfusion, use of hydroxyurea, antibiotics, pain relievers, supplemental oxygen) in people with sickle cell disease irrespective of the type of sickle cell disease, gender and setting. No trials were eligible for inclusion in the review. We identified 12 potentially-eligible trials by the searches; we excluded 11 of these and the remaining trial is an ongoing trial that may be eligible for inclusion in a future version of the review. Reports on the use of hematopoietic stem cell transplantation improving survival and preventing symptoms and complications associated with sickle cell disease are currently limited to observational and other less robust studies. We did not find any eligible randomized controlled trials assessing the benefit or risk of hematopoietic stem cell transplantations. However, there is an ongoing quasi-randomized trial comparing hematopoietic stem cell transplantation with standard care, Thus, this systematic review identifies the need for a multicentre randomized controlled trial assessing the benefits and possible risks of hematopoietic stem cell transplantations comparing sickle status and severity of disease in people with sickle cell disease.

Do haematopoietic stem cells age?

Genetic defects that accumulate in haematopoietic stem cells (HSCs) are thought to be responsible for age-related changes in haematopoiesis that include a decline in lymphopoiesis and skewing towards the myeloid lineage. This HSC-centric view is based largely on studies showing that HSCs from aged mice exhibit these lineage biases following transplantation into irradiated young recipient mice. In this Opinion article, we make the case that the reliance on this approach has led to inaccurate conclusions regarding the effects of ageing on blood-forming stem cells; we suggest instead that changes in the environment contribute to haematopoietic system ageing. We propose that a complete understanding of how ageing affects haematopoiesis depends on the analysis of blood cell production in unperturbed mice. We describe how this can be achieved using in situ fate mapping. This approach indicates that changes in downstream progenitors, in addition to any HSC defects, may explain the reduced lymphopoiesis and sustained myelopoiesis that occur during ageing.

Steady-state and regenerative hematopoiesis occurs normally in mice in the absence of GDF11

AbstractTightly regulated production of mature blood cells is essential for health and survival in vertebrates and dependent on discrete populations of blood-forming (hematopoietic) stem and progenitor cells. Prior studies suggested that inhibition of growth differentiation factor 11 (GDF11) through soluble activin receptor type II (ActRII) ligand traps or neutralizing antibodies promotes erythroid precursor cell maturation and red blood cell formation in contexts of homeostasis and anemia. As Gdf11 is expressed by mature hematopoietic cells, and erythroid precursor cell expression of Gdf11 has been implicated in regulating erythropoiesis, we hypothesized that genetic disruption of Gdf11 in blood cells might perturb normal hematopoiesis or recovery from hematopoietic insult. Contrary to these predictions, we found that deletion of Gdf11 in the hematopoietic lineage in mice does not alter erythropoiesis or erythroid precursor cell frequency under normal conditions or during hematopoietic recovery after irradiation and transplantation. In addition, although hematopoietic cell-derived Gdf11 may contribute to the pool of circulating GDF11 protein during adult homeostasis, loss of Gdf11 specifically in the blood system does not impair hematopoietic stem cell function or induce overt pathological consequences. Taken together, these results reveal that hematopoietic cell–derived Gdf11 is largely dispensable for native and transplant-induced blood formation.

Concise Review: Regulation of Self-Renewal in Normal and Malignant Hematopoietic Stem Cells by Krüppel-Like Factor 4.

Pluripotent and tissue‐specific stem cells, such as blood‐forming stem cells, are maintained through a balance of quiescence, self‐renewal, and differentiation. Self‐renewal is a specialized cell division that generates daughter cells with the same features as the parental stem cell. Although many factors are involved in the regulation of self‐renewal, perhaps the most well‐known factors are members of the Krüppel‐like factor (KLF) family, especially KLF4, because of the landmark discovery that this protein is required to reprogram somatic cells into induced pluripotent stem cells. Because KLF4 regulates gene expression through transcriptional activation or repression via either DNA binding or protein‐to‐protein interactions, the outcome of KLF4‐mediated regulation largely depends on the cellular context, cell cycle regulation, chromatin structure, and the presence of oncogenic drivers. This study first summarizes the current understanding of the regulation of self‐renewal by KLF proteins in embryonic stem cells through a KLF circuitry and then delves into the potential function of KLF4 in normal hematopoietic stem cells and its emerging role in leukemia‐initiating cells from pediatric patients with T‐cell acute lymphoblastic leukemia via repression of the mitogen‐activated protein kinase 7 pathway. stem cells translational medicine 2019;8:568–574

Nocturnal Melatonin Renews Bone and Blood Forming Stem Cells Reservoir By Metabolic Reprograming

Bone marrow (BM) residing hematopoietic stem and progenitor cells (HSPC) replenish the blood with mature cells with a finite life span on a daily basis while maintaining the reservoir of undifferentiated stem cells. We recently showed that light/darkness onset induce two different BM HSPC peaks. Morning-induced norepinephrine and TNF secretion metabolically facilitate HSPC differentiation and egress to replenish the circulation with new mature leukocytes. Night augmented BM melatonin renews BM CD150+ hematopoietic stem cell (HSC) reservoir and their long-term repopulation potential (Golan et al, Cell Stem Cell, In Press). How melatonin primes BM HSPC to change their phenotype and function to re-acquire an undifferentiated and primitive state, is poorly understood. The hormone melatonin is an important mediator of bone formation and mineralization, and ultimately regulates the balance of bone remodeling (Cardinali DP et al, J. Pineal Res., 2003). The cross talk between HSPC and their BM stromal microenvironment is tightly regulated and determines HSPC fate. Therefore, we examined whether melatonin plays a role in regulation of murine BM mesenchymal stem and progenitor cells (MSPC, CD45-/Sca-1+/PDGFRα+), known to support HSPC maintenance in their BM niches. Mice treated with melatonin for 5h during the morning had increased levels of BM MSPC endowed with higher colony-forming unit fibroblast (CFU-F) potential in vitro. Interestingly, the metabolic state of these progenitor cells was altered by melatonin demonstrating reduced glucose uptake ability and lower mitochondria content. To test if differences in stromal cells content exist between day and night, we examined BM MSPC and found increased levels at 11PM, the time of melatonin BM peak, with higher Sca-1high surface expression levels, as compared to daylight 11AM. These changes were associated with augmented CFU-F levels by MSPC harvested at 11PM and accompanied by reduced glucose uptake levels and mitochondria content. Our preliminary results suggest that melatonin at night increases BM MSPC levels and reduces their metabolic activity to maintain them in a primitive and undifferentiated state. Moreover, we found that melatonin-elevated HSPC at 11PM also share lower glucose uptake ability with reduced mitochondria content and lower mitochondrial membrane potential (evaluated by TMRE). We hypothesize that melatonin reprograms the metabolic state of both HSPC and their stromal MSPC microenvironment to renew and maintain a primitive state of both populations at night. One of the factors inhibited by melatonin is the bioactive lipid Sphingosine 1-Phosphate (S1P), which in turn inhibits melatonin production. We found that mice with low S1P levels (S1Plow) due to lack of the SPHK1 enzyme have high BM melatonin levels also during the day in contrast to wild type (WT) mice. S1Plow mice had higher levels of primitive stromal progenitor cells including CFU-F and lower levels of differentiating osteoblast precursors compared to WT mice. In addition, these mice had less BM Reactive Oxygen Species (ROS)high committed hematopoietic progenitor cells, but more primitive ROSlow EPCR+ HSC endowed with higher long-term repopulation capacity in both primary and serially transplanted recipients. Next, we examined how light/dark cues affect the homing of transplanted BM HSPC into the BM of irradiated hosts 18h after transplantation. We found that donor HSPC harvested at 11PM have elevated homing ability compared to 11AM harvested cells. Importantly, MSPC also better homed to the BM of irradiated recipients when we transplanted donor BM cells obtained at 11PM compared with 11AM. As a result, accelerated BM repopulation kinetics was documented one week post transplantation in mice transplanted with BM cells harvested at 11 PM.Taken together, our results reveal that in vivo melatonin renews and maintains the BM reservoir and function of primitive MSPC and HSPC by metabolically reprogramming these cells during the night on a daily basis. Since the primed HSPC and MSPC at night showed improved function and BM homing potential, these features might be mimicked by human BM cells in order to harness them for improved clinical transplantation protocols. DisclosuresNo relevant conflicts of interest to declare.

Evidence of a Dose Threshold for Radiation-Induced Leukemia.

In 1958, Neil Wald presented data on the incidence of leukemia among the Hiroshima atomic bomb survivors. These data, which suggested a dose–response threshold for radiation-induced leukemia, were included in the first UNSCEAR report (1958). However, this evidence of a threshold was not recognized. It was obfuscated and concealed. In 2010, Zbigniew Jaworowski identified these data as evidence of radiation hormesis. A letter to the editor in 2014 and 2 articles in 2014 and 2015 presented a graph of these UNSCEAR 1958 data, which revealed a threshold at about 500 mSv. Since the blood-forming stem cells of bone marrow are more radiosensitive than most other cell types, it is reasonable to expect thresholds for inducing other types of cancer by ionizing radiation—their thresholds are likely higher than 500 mSv. A careful examination of the Wald data reveals the suprisingly low incidence of radiogenic leukemia, only 0.5% of the survivors who were in the high radiation zone. Many articles on radiation risk have been published since 2015 by other authors, but none makes reference to this evidence of a threshold, either to challenge or endorse it. In this commentary, the author addresses the comments from a colleague.

Induced Pluripotent Stem Cells: The Most Versatile Source for Stem Cell Therapy

Cell therapy has existed since the first bone marrow transplant in the 1950s involving identical twins. The blood-forming stem cells were used to restore healthy blood cells for the twin with leukemia. It was not until 1968 that genetic matching (known as human leukocyte antigen matching) was known to be important, and not until 1973 that bone marrow transplants were performed from non–twin-related and nonrelated donors. The most important application of human stem cells is for the generation of cells and tissues for cell-based therapies. Currently, donated organs and tissues are often the only option to replace diseased, injured, or destroyed tissue. The availability for these transplantable tissues and organs is very limited, however. To satisfy the demand for a source for these cells and tissues, induced pluripotent stem cells that have been differentiated into specific cell types can serve as a renewable source of replacement cells and tissues. A bank of suitable human leukocyte antigen–matched cells will be an important source providing immediate availability of cells that are readily scalable, economical, and well characterized. Areas of active pursuit with stem cell therapy is being investigated for treating diseases such as macular degeneration, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis, rheumatoid arthritis, and neurodegenerative diseases. This article describes the advantages and hurdles for the use of induced pluripotent cells as the starting material for a source of replacement cells for regenerative medicine.

Leukaemia: Vitamin C regulates stem cells and cancer.

It emerges that high levels of vitamin C in blood-forming stem cells influence the number and function of the cells and affect the development of leukaemia, through binding to a tumour-suppressor protein, Tet2. See Article p.476 The effect of changes in metabolite levels on stem-cell fate in vivo has been unclear. Sean Morrison and colleagues survey the metabolites of haematopoietic stem cells (HSCs) and progenitors. They show that each type of blood cell has a specific signature and that human and mouse HSCs have high levels of ascorbate, which drop during differentiation. Depletion of ascorbate in mice increases the number and function of HSCs and cooperates with a mutation associated with leukaemia to accelerate tumorigenesis. Analysis of the phenotypes indicates that ascorbate can act in a non-cell-autonomous fashion, partly by modulating the function of the tumour suppressor Tet2.

Is Stem Cell a Curer or an Obstruction?

Introduction: Each cell in human body is assigned with a specialized function to perform. Before a cell becomes specialized, it is a stem cell. Stem cell research and therapy is progressing dramatically these days. Stem cell therapy holds enormous treatment potential for many diseases which currently have no or limited therapeutic options. Unfortunately, this potential also comes with side-effects. In this review, the positive and negative effects of regulation of stem cells will be explained.Content: Stem cells are undifferentiated cells that have potential to develop into many different cell types in the body during early life and growth. The type of stem cells are embryonic stem cells, induced pluripotent stem cells, somatic stem cells, foetal stem cells and mesenchymal stem cells. Stem cell transplantation is one form of stem cell therapy, it comes with different sources, and those are autologous and allogenic transplantation stem cells. In an autologous transplant, a patient’s own blood-forming stem cells are collected, meanwhile in an allogeneic transplant, a person’s stem cells are replaced with new stem cells obtained from a donor or from donated umbilical cord blood.Summary: Its abilities to maintain undifferentiated phenotype, self-renewing and differentiate itself into specialized cells, give rise to stem cell as a new innovation for the treatment of various diseases. In the clinical setting, stem cells are being explored in various conditions, such as in tissue repair and regeneration and autoimmune diseases therapy. But along with its benefit, stem cell therapy also holds some harm. It is known that the treatment using stem cell for curing and rehabilitation has the risk in tumor formation.

BRCA1 Gene Key for Blood Forming Stem Cells

BRCA1 Gene Key for Blood Forming Stem Cells

Hematopoietic stem cell transplantation for people with sickle cell disease.

Sickle cell disease is a genetic disorder involving a defect in the red blood cells due to its sickled hemoglobin. The main therapeutic interventions include preventive and supportive measures. Hematopoietic stem cell transplantations are carried out with the aim of replacing the defective cells and their progenitors (hematopoietic (i.e. blood forming) stem cells) in order to correct the disorder. This is an update of a previously published review. To determine whether stem cell transplantation can improve survival and prevent symptoms and complications associated with sickle cell disease. To examine the risks of stem cell transplantation against the potential long-term gain for people with sickle cell disease. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Group's Haemoglobinopathies Trials Register complied from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of The Cochrane Library) and quarterly searches of MEDLINE.Unpublished work was identified by searching the abstract books of major conference proceedings and we conducted a search of the website: www.ClinicalTrials.gov.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 06 October 2015. Randomized controlled and quasi-randomized studies that compared any method of stem cell transplantation with either each other or with any of the preventive or supportive interventions (e.g. periodic blood transfusion, use of hydroxyurea, antibiotics, pain relievers, supplemental oxygen) in people with sickle cell disease irrespective of the type of sickle cell disease, gender and setting. No relevant trials were identified. Ten trials were identified by the initial search and none for the update. None of these trials were suitable for inclusion in this review. Reports on the use of hematopoietic stem cell transplantation improving survival and preventing symptoms and complications associated with sickle cell disease are currently limited to observational and other less robust studies. No randomized controlled trial assessing the benefit or risk of hematopoietic stem cell transplantations was found. Thus, this systematic review identifies the need for a multicentre randomized controlled trial assessing the benefits and possible risks of hematopoietic stem cell transplantations comparing sickle status and severity of disease in people with sickle cell disease.

Stem cells are units of natural selection for tissue formation, for germline development, and in cancer development

It is obvious that natural selection operates at the level of individuals and collections of individuals. Nearly two decades ago we showed that in multi-individual colonies of protochordate colonial tunicates sharing a blood circulation, there exists an exchange of somatic stem cells and germline stem cells, resulting in somatic chimeras and stem cell competitions for gonadal niches. Stem cells are unlike other cells in the body in that they alone self-renew, so that they form clones that are perpetuated for the life of the organism. Stem cell competitions have allowed the emergence of competitive somatic and germline stem cell clones. Highly successful germline stem cells usually outcompete less successful competitors both in the gonads of the genotype partner from which they arise and in the gonads of the natural parabiotic partners. Therefore, natural selection also operates at the level of germline stem cell clones. In the colonial tunicate Botryllus schlosseri the formation of natural parabionts is prevented by a single-locus highly polymorphic histocompatibility gene called Botryllus histocompatibility factor. This limits germline stem cell predation to kin, as the locus has hundreds of alleles. We show that in mice germline stem cells compete for gonad niches, and in mice and humans, blood-forming stem cells also compete for bone marrow niches. We show that the clonal progression from blood-forming stem cells to acute leukemias by successive genetic and epigenetic events in blood stem cells also involves competition and selection between clones and propose that this is a general theme in cancer.

Understanding multiple myeloma

Understanding multiple myeloma

Macrophages and Bone Marrow Stem Cell Niches: The Roles of PGE2 and Coagulation

Blood-forming hematopoietic stem cells (HSC) functionally express the chemokine receptor CXCR4, which is required to control their directional motility, cell cycle, adhesion, and bone marrow (BM) repopulation. HSC are mostly BM-retained in a quiescent, non-motile mode via CXCR4-induced adhesion interactions with BM niche cells, which functionally express surface CXCL12. Surface CXCL12-mediated adhesion interactions with BM stromal cells protect quiescent CXCR4+ stem cells from DNA damaging agents while preserving their developmental potential. On the other hand, CXCL12 secretion by BM stromal cells and its release to the blood increase CXCR4 expression and signaling in hematopoietic stem and progenitor cells (HSPC), inducing their egress and clinical mobilization. Finally, CXCR4+ HSC also follow CXCL12 gradients to the BM when they home back from the blood. Intriguingly, dynamic CXCR4/CXCL12 signaling cascades control not only HSC retention in the BM, but also their homing to the BM and their release and mobilization to the blood. In addition to their central role in host defense, myeloid cells participate in organ homeostasis, including HSC localization. Monocyte-derived bone resorbing osteoclasts cleave and release endosteal membrane-bound CXCL12, stem cell factor, and osteopontin, factors needed for HSC adhesion and BM retention, leading to CXCL12/CXCR4-mediated HSPC mobilization. Recently, we identified a rare population of BM αSMA+ macrophages that highly express, which protects HSC from inflammatory insults via COX-2-mediated PGE2 secretion and reactive oxygen species inhibition. In vitro PGE2 upregulates CXCR4 on enriched human cord blood CD34+ and murine HSC via cAMP activation, leading to enhanced CXCL12-induced migration, homing and BM repopulation. However, preliminary results reveal that in vivo PGE2 treatment reduced CXCR4 expression on BM HSC by increasing surface CXCL12 expression by stromal cells. Surface CXCL12 upregulation is due to PGE2-mediated secretion and autocrine signaling of lactate, which is followed by cAMP inhibition in BM stromal cells. Indeed, antagonizing COX-2 or activating cAMP induced HSPC mobilization via BM CXCL12 secretion and increased CXCR4 expression and signaling in HSPC. Coagulation cascades also navigate HSC localization. We revealed that anticoagulant microenvironments in the BM mediate HSC adhesion and retention via inhibition of nitric oxide (NO) production and HSC migration. Physiologic stress induced extensive production of the pro-coagulant factor thrombin, which activates NO generation, CXCL12 secretion and enhanced CXCR4+ stem cell motility and mobilization. We found multinucleated pre-osteoclast cell clusters in femoral metaphysis expressing Tissue Factor (TF) a potent initiator of coagulation leading to thrombin generation. Osteoclast maturation and stress signals also activate TF induced pro-coagulation cascades, mediating HSPC egress and recruitment to the circulation. Daily light and darkness cues regulate many physiological processes, including osteoclast/osteoblast bone remodeling, BM CXCL12 production and secretion and CXCR4+ HSC egress. In addition to the previously identified morning peak of HSC egress to the blood, we identified two peaks of BM HSC proliferation: a morning peak in conjunction with stem cell egress and an evening peak of HSC expansion without egress. Higher BM levels of the HSC-protecting aSMA+ monocyte/macrophages documented in the evening and their associate “low-CXCR4/high CXCL12” BM microenvironment provide the mechanism for these fluctuating patterns. Finally, we found higher PGD2 levels and reduced PGE2 levels in monocyte/macrophages in the morning, whereas at night we documented the opposite patterns. PGD2 induced CXCL12 secretion and HSC egress, while PGE2 induced their retention. Our studies attribute central roles for BM myeloid cells in HSC regulation. Disclosures No relevant conflicts of interest to declare.