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At least 19 recordsLinked to original sources
PubMed1977

Patterns of exogenous and endogenous hematopoietic repopulation following radiation injury.

Patterns of hematopoietic recovery in mice given an LD50/30 radiation exposure were different from those in animals given an LD100/30 exposure and a marrow transplant sufficient to effect 50 per cent 30-day survival. Death occurred later, and recovery of some peripheral blood elements was delayed in the LD50/30 mice. Over the period of study, splenic hematopoiesis and stem cell renewal were insignificant in the LD50/30 mice yet were active in the marrow-transplanted animals. The slow recovery of erythropoiesis in the LD30/30 mice is explained in part by the lack of early splenic hematopoiesis. This effect appeared to be attributable to the splenic microenvironment which, although being suitable for growth of unirradiated hematopoietic cells, was not conducive to repair of radiated splenic hematopoietic cells.

Animals↗
PubMed2025

Histone modifications in the regulation of erythropoiesis.

INTRODUCTION: The pathogenesis of anemia and other erythroid dysphasia are mains poorly understood, primarily due to limited knowledge about the differentiation processes and regulatory mechanisms governing erythropoiesis. Erythropoiesis is a highly complex and precise biological process, that can be categorized into three distinct stages: early erythropoiesis, terminal erythroid differentiation, and reticulocyte maturation, and this complex process is tightly controlled by multiple regulatory factors. Emerging evidence highlights the crucial role of epigenetic modifications, particularly histone modifications, in regulating erythropoiesis. Methylation and acetylation are two common modification forms that affect genome accessibility by altering the state of chromatin, thereby regulating gene expression during erythropoiesis. DISCUSSION: This review systematically examines the roles of histone methylation and acetylation, along with their respective regulatory enzymes, in regulating the development and differentiation of hematopoietic stem/progenitor cells (HSPCs) and erythroid progenitors. Furthermore, we discuss the involvement of these histone modifications in erythroid-specific developmental processes, including hemoglobin switching, chromatin condensation, and enucleation.Conclusions This review summarizes the current understanding of the role of histone modifications in erythropoiesis based on existing research, as a foundation for further research the mechanisms of epigenetic regulatory in erythropoiesis.

Erythropoiesis↗
PubMed1978

The cyclic hematopoietic dog: a model for spontaneous secondary amyloidosis. A morphologic study.

Spontaneous amyloidosis was found in dogs affected with hereditary cyclic hematopoiesis (CH dogs). Early perifollicular deposits of amyloid were observed in the spleens of 15-week-old CH dogs. By the 24th week, amyloid deposits were also found in the liver, kidneys, pancreas, adrenals, and small intestine; the incidence of the condition rose to more than 90%. The visceral involvement and the histologic characteristics of amyloid deposition closely resemble those of the secondary form in humans. A transient lymphoid hypoplasia was noted in the spleens of neonates and pups. This abnormality did not appear to be related to exogenous conditions. In young adult dogs, the initial hypoplastic characteristics were replaced by enlarged marginal zones in the follicles of the spleen, composed of pyroninophilic cells and, in a later stage, of PAS-positive cells. These cellular changes preceded the amyloid deposition. Due to the characteristic cyclic neutropenia of the hereditarily transmitted hematologic syndrome, most CH dogs experience episodes of infectious diseases, although the episodes of infection may be separated by long periods of relatively good health. This may provide the underlying antigenic stimulation which triggers the process of amyloid deposition. However, the lag period for the onset of amyloidosis is extremely short and the type of infections is not considered a predisposing factor for amyloid deposition. It is possible that a peculiar sensitivity of the lymphoid system in the CH dog would facilitate the development of widespread amyloidosis. Since the sequence of splenic lymphoid hypoplasia, follicular activation, and amyloid deposition associated with age are consistently repeated, the CH dog may be a suitable animal model for the study of the pathogenesis of secondary form of amyloidosis in humans.

Age Factors↗
PubMed2025

Arginine methylation-dependent METTL14-SMN interaction regulates RNA m6A homeostasis.

N6-methyladenosine (m6A) homeostasis is essential for development, and its dysregulation is linked to cancers and neurological disorders. However, the mechanisms regulating m6A remain unclear. Here, we identify the survival of motoneuron (SMN) protein as a novel interaction partner of METTL14, a key component of the m6A methyltransferase complex. SMN binds METTL14 via its Tudor domain in an arginine methylation-dependent manner. Mutations in the SMN Tudor domain identified in spinal muscular atrophy (SMA) disrupt its interaction with METTL14 and reduce m6A levels in patient-derived fibroblasts, linking m6A dysregulation to SMA pathology. Both SMN knockdown and SMA mutations impair m6A deposition on the mRNAs of DNA repair genes, mirroring the effects of METTL14 hypomethylation. Consequently, SMA patient fibroblasts are hypersensitive to DNA-damaging agents due to reduced levels of DNA repair gene expression. To explore the function of METTL14 arginine methylation in vivo, we generated a Mettl14 methylation-deficient mouse model (Mettl14RK). Although this model does not show SMA-like phenotypes, the mutants are partially embryonic lethal and show abnormal hematopoiesis, underscoring a role for methylated METTL14 in early development.

Methyltransferases↗
PubMed2026

Spatial profiling of the spleen in mouse and human myelofibrosis reveals complement-driven immune-stromal interactions as a therapeutic target.

Splenomegaly is a defining feature of myelofibrosis, yet the contribution of splenic mesenchymal stroma to disease progression remains unclear. We combined spatial and single-nucleus transcriptomics of patient spleens with spatial and single-cell transcriptomics, as well as imaging analyses, of murine spleens to map extramedullary hematopoiesis niches. Activated red pulp reticular cells localize near hematopoietic stem and progenitor cells, and early disease is characterized by marginal zone disruption with lymphoid depletion preceding stromal remodeling. Trajectory analyses reveal a shift in reticular cells from hematopoiesis-supportive to inflammatory and pro-fibrotic states, driven by macrophage- and megakaryocyte-derived signals that activate complement and induce tumor necrosis factor α (TNF-α), transforming growth factor β (TGF-β), extracellular matrix, and Thbs1 programs. Non-hematopoietic complement component C3 deficiency or pharmacological C3 inhibition suppresses these pathways, restores splenic architecture, and reduces splenomegaly and bone marrow fibrosis. These findings identify complement-dependent stromal reprogramming as a mechanism governing hematopoietic niches and as a targetable axis in myelofibrosis.

Animals↗
PubMed1978

Lack of correlation between splenic and marrow hematopoiesis following irradiation or irradiation and transplantation in mice.

Differences were seen in the relative importance of spleen and marrow in early erythroid regeneration of lethally irradiated mice given spleen or marrow cell transplants compared with that in sublethally irradiated mice with surviving endogenous hematopoietic cells. Radioactive iron uptake was predominantly in the spleen of mice with transplants and in the marrow of endogenously recovering mice. Visable spleen colony counts increased from day 4 to day 7 and plateaued through day 10 in the transplant system, but shoed a small abortive rise with a 5-day peak, followed by a steady increase from days 6 to 10 in the endogenous system. Comparisons of peroxidase-positive cells (granulocytes) in the marrow of femurs and humeri and iron uptake in marrow and spleen suggested that repopulation of the marrow and spleen were independent, while that of different areas of the marrow was interrelated. The interrelationship of the rate of marrow regeneration was closer in the endogenous than in the transplant system.

Animals↗
PubMed1978

Cellular maturation in human preleukemia.

Bone marrow cells from three preleukemic patients with prominent marrow karyotypic abnormalities were studied in liquid culture to determine if the neoplastic clones were capable of maturation. Parallel cytogenetic and cytologic studies were performed in sequentially harvested bone marrow cultures. Maturation, albeit delayed, occurred in cultures from all three patients. By 14 days of culture in vitro, morphologic, cytochemical, and functional evidence of maturation was observed in about 70% of the cells. By day 21, 85% of the cells were mature by these criteria. All but 2 of 249 metaphases from the cultured cells contained the cytogenetic abnormality of the neoplastic clone. We conclude that some preleukemic cells identified by a chromosomal abnormality can mature in vitro. Preleukemia may be viewed as a syndrome of "early leukemia" in which the neoplastic clone is established and manifested functionally as ineffective hematopoiesis. Hematopoietic cell differentiation becomes progressively abnormal with termination in the nearly complete maturational block characteristic of acute myelogenous leukemia.

Adult↗
PubMed2026

How advances in chromosome conformation capture (3C) methods are reshaping our understanding of gene regulation in hematopoiesis.

The three-dimensional organization of the DNA within the nucleus plays a key role in regulating gene expression. Over the past two decades, advances in chromosome conformation capture (3C) technologies, in tandem with other methods, have shown that the genome forms a complex structure at multiple scales. Early studies identified large-scale structures such as chromosome territories, compartments and topologically associating domains (TADs). As the resolution of 3C techniques has improved, it has become possible to identify contacts between regulatory elements in detail and more recently, it has become possible to define intricate structures within cis-regulatory elements. In this chapter, we review the development of 3C-based methodologies and discuss the strengths and limitations of the different approaches. We examine how these technologies have refined our understanding of genome organization and gene regulation. Recent high-resolution studies reveal that chromatin architecture extends beyond classical domain structures to include nanoscale organization. Integration of 3C data with super-resolution imaging and molecular dynamics simulations supports a model in which genome folding is governed by the biophysical properties of chromatin.

Animals↗
PubMed1979

Erythroid stem cell regeneration in normal and plethoric mice treated with hydroxyurea.

Hydroxyurea (4 x 500 mg/kg at 6 hour intervals) was used to study hemopoietic regeneration in normal and in hypertransfused mice. All recognizable granuloid and erythroid cells, most granulopoietic (CFU-C) and all erythroid (CFU-E) precursors and about 80% of the pluripotent stem cells were eliminated after this treatment. Regeneration started between days 2 and 3 in the marrow and 1 day later in the spleen. An overshoot in CFU-C and CFU-E per femur was seen at day 4. In parallel to their committed precursors granulopoietic cells reappeared between days 2 and 4, erythroblasts between days 3 and 5. In the spleen a maximum CFU-S and CFU-C concentration was seen at day 7. The early increase of CFU-E in the marrow was followed by a fall to low levels, then the CFU-E concentration in the spleen increased. The regeneration was further studied in hypertransfused mice. CFU-S and also CFU-E in the marrow regenerated in exactly the same way as in normal mice and erythroblasts were found in marrow smears. The further maturation of erythroblasts to reticulocytes was impaired in hypertransfused mice, but not in normal mice. The role of erythropoietin (Ep) in the regulation of the CFU-E regeneration is discussed; early differentiation steps seem to be possible without Ep.

Animals↗
PubMed1978

Effect of glucan, a macrophage activator, on murine hemopoietic cell proliferation in diffusion chambers in mice.

Pretreatment of mice with glucan, a potent macrophage activator, resulted in enhanced myeloid cluster and colony formation by bone marrow cells in diffusion chambers implanted into the peritoneal cavity. Simultaneously, erythroid colony formation was also augmented. In some experiments the plasma clots formed inside the chambers were dissolved, and the number of hematopoietic cells was determined. An increased yield of early proliferative cells, granulocytes, and macrophages was found in glucan-treated hosts. Concomitantly, higher leukocyte counts were noted in the peripheral blood of treated animals. These results suggest that glucan has a strong stimulatory effect on hematopoiesis. This stimulation is probably mediated by humoral factors of host animal origin rather than by direct interaction with proliferating hematopoietic precursors enclosed within the chambers.

Animals↗
PubMed1978

Growth of diffusion chamber hematopoietic colonies derived from spleen cells of rats administered hydroxyurea.

Donor rats of the Hebrew University strain were administered a single intraperitoneal injection of hydroxyurea (400 mg/kg body weight). 1--3 h following the administration of the drug, a suspension of spleen cells, the majority of which consisted of lymphocytes, was prepared. Spleen cells were placed in diffusion chambers and these were implanted in the peritoneal cavity of preirradiated mice. 5--8 days following implantation, erythroid and granulocytic colonies developed in 30.3% of the diffusion chambers studied. However, in most chambers, macrophages were observed. In control experiments with implantation of spleen cells of normal rats, granulocytic colonies did not grow and in only 3.1% of the chambers erythroid colonies were noted. Macrophage colonies, however, developed in all 32 control cultures. Our previous studies showed that administration of a single dose of hydroxyurea strips the rat bone marrow of approximately 50% of replicating cells within 9--10 h. The results of the present study indicate that such a severe depletion of rat marrow cells results in early committment of spleen stem cells to various blood cell lines.

Animals↗
PubMed1977

[Bone-marrow biopsy in Hodgkin's disease].

In 349 subjects with Hodgkin's disease 520 bone marrow biopsies were carried out: 454 did not lead to the discovery of any tumour (87.5%), 66 permitted us to discover a tumour (12.5%). Among the bone marrows without Hodgkin tissue, the hematopoietic tissue was normal in 233 bone marrows (51.2%), hyperplastic in 157 bone marrows (34.7%), hypoplastic or aplastic in 64 bone marrows (14%). Eosinophilia was noted in 13% of cases, marked plasmacytosis was noted in 24%. Among the cases with a tumour, 89.2% showed a massive lesion; 10.7% showed partial lesions. The frequency of involvement was 5.4% for clinical stages I. 6.2% for stage II. 17.1% for stage III. 47.6% for stageIV. Bone marrow involvement at the start of the disease was found in 3% of cases, even in stages I and II. The involvements were especially frequent in the histological forms, stage III (19.4%) and IV (30.4%). In splenectomised patients, bone marrow involvement was 5 times more common when the spleen was also involved. 50 times more common when the liver was involved. The bone marrow which may be used to detect hematogenic spread of Hodgkin's disease is an investigation which should be carried out as a routine in the early stages of the disease and whenever a relapse is suspected.

Adult↗
PubMed1977

Histogenesis of myeloid metaplasia in the spleen.

Hemopoietic activity in the spleen is caused by the proliferation of the RE cells of the red pulp, lining the sinusoids and the endothelial cells lining the venous channels and their vasa vasora. The RE cells of the marginal zone do not contribute. As the cells involved line blood spaces, and the immature cells are washed into the circulation hemopoiesis appears to be intravascular. Different agents produce different effect: copper sulphate an early proliferation of both the red pulp and venous cells, phenylhydrazine a red pulp proliferation and antiserum a high venous endothelial activity.

Animals↗
PubMed1978

Effect of myleran on murine hemopoiesis. I. Granulocytic cell line specificity of action on progenitor cells.

Time- and dose-dependent patterns of depletion and regeneration of hemopoietic progenitor cells in mouse femora and spleens following treatment with the antileukemic agent Myleran (Busulphan, MY) were studied using the murine spleen colony system and the agar gel in vitro colony system. MY was found to depress granulopoiesis selectively, as manifested by the development of marked prolonged neutropenia, hypoplasia of the bone marrow and (to a lesser degree) of the spleen, reduction of the incidence of multipotential hemopoietic progenitor cells (CFU-S) and of granulocytic progenitor cells (CFU-C) in both femora and spleens, and impairment of the capacity of CFU-S from either tissue to generate granulocytic colonies in the spleens of irradiated hosts. The severity and duration was greatest at high dose levels of MY (800 microgram). The action of MY on CFU-S was more pronounced than that on CFU-C, suggesting that MY is a cycle-independent agent. Repopulation of the CFU-C pool preceded that of the CFU-S pool. Development of neutropenia and maximal marrow hypoplasia followed the onset of depression of CFU-S and CFU-C incidence, while recovery of normal nucleated cellularity in the blood, femur and spleen preceded repopulation of the CFU-S and CFU-C pools. MY treatment resulted in transitory stimulation of colony stimulating factor (CSF) generation by the femur but had no effect on serum CSF levels. The peak of femoral CSF generation coincided with the nadir of CFU-C depression. These findings indicated that the prolonged neutropenia following MY treatment was secondary to depletion of the progenitor cell pools, that during recovery granulopoietic repopulation took precedence over self-maintenance of the hemopoietic progenitor cell pools, and that increased generation of CSF may play a role in the early phase of granulopoietic recovery.

Animals↗
PubMed1979

Cellular interactions in haematopoiesis.

In vitro culture of haematopoietic cells has provided some surprising insights into critical interactions of blood-forming cells. Subpopulations of lymphoid cells have been shown to produce colony-stimulating activity, to interact with macrophages, and to have important effects on the very early stages of erythropoiesis. Macrophages have multiple influences on the proliferation and differentiation of other haematopoietic cells.

Animals↗
PubMed1978

Sources and nature of granulocyte-macrophage colony stimulating factor in fetal mice.

At the earliest stages of fetal hepatic hemopoiesis in CBA mice (11-12 days gestation), colony stimulating activity could be found only in peripheral blood, yolk-sac fluid and media conditioned by yolk-sacs (YSCM). The colony stimulating factor (GM-CSF) from YSCM was able to be concentrated by absorption to DEAE-cellulose and subsequent elution. Titration of this material produced a sigmoid dose-response curve in agar cultures of adult CBA bone marrow cells. Unlike the high proportion of granulocyte colonies stimulated by the GM-CSF from mouse lung conditioned medium, all concentrations of YSCM produced a high proportion of macrophage colonies after 7 days of incubation. Mixing experiments eliminated the possibility that a specific inhibitor preventing granulocyte differentiation was present in YSCM. Fetal liver cells were relatively unresponsive to YSCM, but their ability to respond increased with gestational age. When stimulated by YSCM, fetal liver colony forming cells from mice of all gestational ages produced more than 90% macrophage colonies after 7 days of incubation. The experimental data suggest that the proliferation and differentiation of granulocyte and macrophage precursors in the early fetal liver could be controlled by a fetal type of GM-CSF favoring macrophage production.

Animals↗