Hematopoiesis

Hox genes are clearly implicated in leukemia; however, neither the specificity of the leukemogenic potential among Hox genes of different paralog groups nor the role of the homeodomain is clear. We tested the leukemogenic potential of various NUP98-Hox fusion genes alone and with MEIS1. All genes tested had a significant overlapping effect in bone marrow cells in vitro. However, not all formed strong leukemogenic NUP98 fusion genes; but together with overexpression of MEIS1, all induced myeloid leukemia. This phenomenon was also seen with NUP98 fusions containing only the homeodomain of the corresponding Hox protein. We then exploited the strong transforming potential of NUP98-HOXD13 and NUP98-HOXA10 to establish preleukemic myeloid lines composed of early myeloid progenitors with extensive in vitro self-renewal capacity, short-term myeloid repopulating activity, and low propensity for spontaneous leukemic conversion. We also showed that MEIS1 can efficiently induce their conversion to leukemic stem cells, thus providing a novel model for the study of leukemic progression. In contrast to the leukemogenic effect of most of the Hox genes tested, HOXB4 has the ability to increase the self-renewal of hematopoietic stem cells without disrupting normal differentiation. On the basis of the discovery that the leukemogenic gene HOXA9 can also expand hematopoietic stem cells, we compared the ability of NUP98-Hox fusions to that of HOXB4 to trigger HSC expansion in vitro. Our preliminary results indicate that the expanding potential of HOXB4 is retained and even augmented by fusion to NUP98. Moreover, even greater expansion may be possible using Abd-B-like Hox fusions genes.

Periodic chronic myelogenous leukemia (PCML) is an interesting dynamical disease of the hematopoietic system in which oscillating levels of circulating leukocytes, platelets and/or reticulocytes are observed. Typically all of these three differentiated cell types have the same oscillation period, but the relation of the oscillation mean and amplitude to the normal levels is variable. Given the appearance of the abnormal Philadelphia chromosome in all of the nucleated progeny of the hematopoietic stem cells (HSCs), the most parsimonious conclusion is that chronic myelogenous leukemia, and its periodic variant, arise from derangements partially involving the dynamics of the stem cells. Here, we have synthesized several previous mathematical models of HSC dynamics, and models for the regulation of neutrophils, platelets and erythrocytes into a comprehensive model for the regulation of the hematopoietic system. Based on estimates of parameters for a typical normal human, we have systematically explored the changes in some of these parameters necessary to account for the quantitative data on leukocyte, platelet and reticulocyte cycling in 11 patients with PCML. Our results indicate that the critical model parameter changes required to simulate the PCML patient data are an increase in the amplification in the leukocyte line, an increase in the differentiation rate from the stem cell compartment into the leukocyte line, and the rate of apoptosis in the stem cell compartment. Our model system is particularly sensitive to changes in stem cell apoptosis rates, suggesting that changes in the numbers of proliferating stem cells may be important in generating PCML. r

Hematopoietic transcription factors play a critical role in directing the commitment and differentiation of hematopoietic stem cells along a particular lineage. Y-box protein (YBX1) is a transcription factor which is widely expressed throughout development and is involved in erythroid cell development; however, its role in early hematopoietic differentiation is not known. This study aims to investigate the role of YBX1 expression in early hematopoietic differentiation and leukemia. Here, we show that YBX1 is highly expressed in mouse erythroid myeloid lymphoid-clone 1 (EML), a hematopoietic precursor cell line, but is down-regulated in myeloid progenitors and GM-CSF-treated EML cells during the course of myeloid differentiation. Moreover, we found that lineage − /IL-7R − / c-kit + /Sca1 + (LKS; enriched fraction of hematopoietic stem cells) and lineage − /IL-7R − /c-kit + /Sca1 − myeloid progenitor cells showed high level of YBX1 expression as compared to the differentiated cells like granulocytes in mouse bone marrow. Also, YBX1 protein was expressed at high levels in myeloid leukemic cell lines blocked at different stages of myeloid development. We further investigated the role of YBX1 in leukemic cells by knockdown studies and observed that down-regulation of YBX1 expression in K562 leukemic cells inhibited their proliferation ability, induced apoptosis, and differentiation towards megakaryocytic lineage upon arsenic trioxide treatments relative to untreated. Overall, our data indicates that YBX1 is down-regulated during myeloid differentiation and the aberrant YBX1 expression in leukemic cells could be a contributing factor in the development of leukemia by blocking their differentiation. Thus, YBX1 protein could be an excellent molecular target for therapy in myeloproliferative disorders and leukemia.

To specify the validity of bone marrow scanning using a monoclonal anti-granulocyte antibody labelled with 9 9 m T~ (BW 250/183) for the functional assessment of haemopoiesis, we compared this method with 52Fe scan in 16 patients with haematological disorders. The examinations were performed using a rectilinear whole-body scanner and the distribution of the two tracers was assessed visually and quantitatively in anatomical bone marrow segments, the spleen and liver. Qualitative comparison showed concordance in the bone marrow distribution of the two tracers in 83% of the segments. Discrepancies were found in six patients with hypoplastic or aplastic marrow. The spleen was visualized in all cases with the 99mTc-Moab, including nine patients without splenic haemopoiesis (i.e. without spleen uptake of 52Fe). The uptake of the two tracers, quantified in bone marrow segments and the spleen, correlated well (P<O.OOOl). but not in the liver (NS). The correlation between the uptake values for each patient was excellent, except in cases of aplastic bone marrow. In conclusion, bone marrow scanning using a 99mTc labelled anti-granulocyte monoclonal antibody enables functional evaluation of the distribution of haemopoiesis. Limitations include the evaluation of bone marrow aplasia and identification of splenic haemopoiesis, for which 52Fe remains the tracer of choice.

Abstract: There is strong evidence that non-immune chronic idiopathic neutropenia of adult is a cytokine-mediated syndrome characterized by (a) neutropenia of varying degree associated with a low number of lineage-specific CD34+ cells and increased production of inhibitors of hematopoiesis, including transforming growth factor-β1 and tumor necrosis factor-α; (b) lymphopenia due to selective loss of primed/memory T-cells and NK cells; (c) increased splenic volume on ultrasonography in 48.1% of patients; (d) osteopenia and/or osteoporosis in 60.0% of patients; (e) anemia, mostly of the type of anemia of chronic disease, in 15.6% of patients; (f) features of chronic antigenic stimulation, including increased proportion of bone marrow plasma cells, increased serum levels of IgG1 and/or IgA, increased frequency of monoclonal gammopathy of undetermined significance, increased frequency of antinuclear antibodies with specific reactivity, and increased serum levels of circulating immune complexes; and (g) increased concentrations of a variety of macrophage-derived pro-inflammatory cytokines and chemokines capable of affecting bone metabolism, bone marrow function, and leukocyte trafficking. All these findings are suggestive of the existence of an unrecognized low-grade chronic inflammatory process which may be involved in the pathogenesis of the disorder. Neutropenia in these patients is probably the result of a combination of at least three factors, reduced neutrophil production in bone marrow, enhanced neutrophil extravasation, and increased sequestration and/or extravasation of neutrophils into the spleen.

There is evidence that neutrophil production is a balance between the proliferative action of granulocyte–colony-stimulating factor (G-CSF) and a negative feedback from mature neutrophils (the chalone). Two neutrophil serine proteases have been implicated in granulopoietic regulation: pro–proteinase 3 inhibits granulocyte macrophage–colony-forming unit (CFU-GM) growth, and elastase mutations cause cyclic and congenital neutropenia. We further studied the action of the neutrophil serine proteases (proteinase 3, elastase, azurocidin, and cathepsin G) on granulopoiesis in vitro. Elastase inhibited CFU-GM in methylcellulose culture. In serum-free suspension cultures of CD34+ cells, elastase completely abrogated the proliferation induced by G-CSF but not that of GM-CSF or stem cell factor (SCF). The blocking effect of elastase was prevented by inhibition of its enzymatic activity with phenylmethylsulfonyl fluoride (PMSF) or heat treatment. When exposed to enzymatically active elastase, G...

A fluorescence stereomicroscope system was developed in order to observe in situ the distribution of nuclei in intravascular Bong-Han ducts and corpuscle tissues by injecting acridine orange, which stained specifically nuclei. Intravascular Bong-Han corpuscles, connected with Bong-Han ducts could be detected in the aortas of rats, mice, and rabbits.

Aplastic anemia, an unusual hematologic disease, is the paradigm of the human bone marrow failure syndromes. Almost universally fatal just a few decades ago, aplastic anemia can now be cured or ameliorated by stem-cell transplantation or immunosuppressive drug therapy. The pathophysiology is immune mediated in most cases, with activated type 1 cytotoxic T cells implicated. The molecular basis of the aberrant immune response and deficiencies in hematopoietic cells is now being defined genetically; examples are telomere repair gene mutations in the target cells and dysregulated T-cell activation pathways. Immunosuppression with antithymocyte globulins and cyclosporine is effective at restoring blood-cell production in the majority of patients, but relapse and especially evolution of clonal hematologic diseases remain problematic. Allogeneic stem-cell transplant from histocompatible sibling donors is curative in the great majority of young patients with severe aplastic anemia; the major challenges are extending the ben-efits of transplantation to patients who are older or who lack family donors. Recent results with alternative sources of stem cells and a variety of conditioning regimens to achieve their engraftment have been promising, with survival in small pediatric case series rivaling conventional transplantation results. (Blood.

Marsupials are a group of mammals that give birth to immature young lacking mature immune tissues at birth, and are unable to mount their own specific immune defence. Their immune tissues develop in a non-sterile ex-utero environment unlike that of eutherian mammals such as ourselves. Marsupials are therefore ideal models for studying the development of immune tissues, in particular haematopoiesis, yet relatively little has been investigated. Most studies have been restricted to histological or immu-nohistological studies, however some factors likely to be involved, based on eutherian studies in hae-matopoiesis, have been isolated and characterised, including a few key markers, and some cell signaling and regulation molecules, mostly involved in lymphocytopoiesis. However the role of many molecules in haematopoiesis is largely presumed. We currently lack much of the rudimentary information regarding time of appearance and expression levels of these molecules, and no functional studies have been conducted. This paper reviews our knowledge of marsupial haematopoiesis to date, and highlights the need for future research in marsupials to gain further insights into the evolution of haematopoiesis.

The liver plays an important role in the production of haemopoietic hormones. It acts as the primary site of synthesis of erythropoietin (EPO) in the fetal stage, and it is the predominant thrombopoietin (TPO)-producing organ for life. In contrast to that of EPO and other liver proteins, the hepatic synthesis of TPO is influenced little by external signals. Hepatocytes express the TPO gene in a constitutive way, i.e. irrespective of the level of platelets in blood. Megakaryocytes and platelets remove the hormone from blood by means of their high-affinity TPO receptors. Normally, the plasma level of TPO is relatively low ( approximately 10(-12) mol/l). However, in thrombocytopenic states due to marrow failure or bleeding, the concentration of circulating TPO may increase greatly. The simple feedback regulation by TPO and its target cells is efficient in maintaining constant platelet numbers in healthy people. Persisting thrombocytopenia develops only in severe liver or marrow failure...

Although it has been reported that fluoride ingestion has no influence on various indices of hematopoiesis, some research has been published that excessive fluoride developed anemia and eosinophilia of leukocytes. Isparta is situated on the lake region of Turkey where fluorosis is endemic. Our aim was to explore the hematological effects in rats induced by fluoride. In this study, Wistar-Albino rats were used, divided into two groups as control and fluorized. While the control group was administered commercial water (including 0.07 ppm fluoride), the fluorized group was administered 100 ppm fluoride in commercial drinking water for four months. At the end of four months, hematological indices (Hb, Hct, MCV, MCH, RDW, RBC, WBC, and platelet counts) were measured. In addition, bone marrow samples were investigated. Mean leukocyte counts (WBC) in the control group and fluorized group were 7.07 (2.62-12.25) and 2.76 (3.13-5.24)-/103/mm3, respectively. We observed displastic changes on g...

The CD34-positive cell: definition and morphology Cellular expression of the CD34 antigen identifies a morph o l ogi c a lly and immu n o l ogi c a lly heterogeneous cell population that is functiona lly ch a racteri zed by the in vi tro c a p a bi l i ty to gen era te cl onal aggrega tes derived from early and late progenitors and the in vivo capacity to reconstitute the myelo-lymphopoietic system in a supralethally irradiated host. 1-3 Im mu n o h i s toch emical studies have dem ons tra ted that the CD34 anti gen is stage but not l i n e a ge specific. In fact, indepen den t ly of the d i f feren ti a tive lineage, it is ex pre s s ed on ly by on togen eti c a lly early cell s. 4 For ye a rs a major ob s t acle to the morph o l ogical iden ti fic a ti on of p ut a tive hem a topoi etic stem cell has been the d i f f i c u l ty in sep a ra ting them from their direct progeny. The use of CD34 and other su i t a bl e cell surface markers (i.e. CD33, CD38, HLA-DR a n ti gens) in flu ore s cen ce-activa ted cells orti n g techniques or other cell separation methods has allowed considerable progress in this field. Positively selected, lineage committed CD34 + cells and more immatu re, lineage nega tive C D 3 4 + C D 3 3-H LAD R-cells are shown in F i g u re 1 and Figure 2, re s pectively. On May-Grünwald-Giemsa stained preparations, CD34 + cells are medium sized cells having large nuclei, eccen tri c a lly su rro u n ded by narrow rims of deep blue cytoplasm occ a s i on a lly con t a i n i n g cytoplasmic granules. Some normal CD34 + cell nu cl ei show one or more pale blue nu cl eo l i .

Hematopoiesis is the process in which all Blood lineages are produced from Hematopoietic Stem cells. Through series of Progenitor cells, Hematopoietic stem cells produce a large number of Adult Stem cells. Hematopoietic Stem cells have the ability of self-renewal and self-division This Divisional event results in the Differentiation of Hematopoietic Stem cells into-Lymphocytes, Granulocytes, Monocytes, etc. Progenitor cells also contain cells that act as our body's Defense mechanism. This Always active defense mechanism consists of T cells, B cells, and Natural Killer cells. These cells work together to fight against any viruses or any pathogen and destroy them or exclude them out of the body. By understanding the Hematopoietic process and Defense mechanism, development has been done in the formation of new therapies for curing specific diseases. The basic concept of Stem cell production and its classification are defined here. This paper includes the concept of the production of Progenitor cell lineages which are classified as Lymphoid Progenitor cells and Myeloid Progenitor cells. Here we discuss the Embryonic development and classification of each blood lineages.

In recent years, discovery of the in vitro and in vivo dierentiation of APL blasts by all-trans retinoic acid (ATRA) has modi®ed the therapeutic approach of APL and lead to important advances in understanding the biology of APL. Since it became apparent that dierentiation therapy of APL with ATRA was indeed a true model of targetted therapy, evidencing the molecular targets of retinoic acid ecacy became crucial. These molecular targets are closely related to the biological features of APL cells, some of which are well-known and have contributed to the morphological and cytogenetic de®nition of the leukemia, others have just been de®ned or re-discovered in the light of a better understanding of molecular controls of cell growth and dierentiation. The aims of characterizing the biological features of APL cells should allow a better management of APL therapy and the identi®cation of potential markers for dierentiation therapies in other leukemias or solid tumors. Oncogene (2001) 20, 7154 ± 7160.

Studies in athletes have shown that carnitine supplementation may foster exercise performance. As reported in the majority of studies, an increase in maximal oxygen consumption and a lowering of the respiratory quotient indicate that dietary carnitine has the potential to stimulate lipid metabolism. Treatment with L-carnitine also has been shown to induce a significant postexercise decrease in plasma lactate, which is formed and used continuously under fully aerobic conditions. Data from preliminary studies have indicated that L-carnitine supplementation can attenuate the deleterious effects of hypoxic training and speed up recovery from exercise stress. Recent data have indicated that L-carnitine plays a decisive role in the prevention of cellular damage and favorably affects recovery from exercise stress. Uptake of L-carnitine by blood cells may induce at least three mechanisms: 1) stimulation of hematopoiesis, 2) a dose-dependent inhibition of collagen-induced platelet aggregatio...

HEMATOPOIESIS Hematopoiesis merupakan proses produksi (mengganti sel yang mati) dan perkembangan sel darah dari sel induk / asal / stem sel, dimana terjadi proliferasi, maturasi dan diferensiasi sel yang terjadi secara serentak. Proliferasi sel menyebabkan peningkatan atau pelipat gandaan jumlah sel, dari satu sel hematopoietik pluripotent menghasilkan sejumlah sel darah. Maturasi merupakan proses pematangan sel darah, sedangkan diferensiasi menyebabkan beberapa sel darah yang terbentuk memiliki sifat khusus yang berbeda-beda (1) Tempat terjadinya hematopoiesis pada manusia : 1. Embrio dan Fetus a. Stadium Mesoblastik, Minggu ke 3-6 s/d 3-4 bulan kehamilan : Sel-sel mesenchym di yolk sac. Minggu ke 6 kehamilan produksi menurun diganti organ-organ lain. b. Stadium Hepatik, Minggu ke 6 s/d 5-10 bulan kehamilan : Menurun dalam waktu relatif singkat. Terjadi di Limpa, hati, kelenjar limfe c. Stadium Mieloid, Bulan ke 6 kehamilan sampai dengan lahir, pembentukan di sumsum tulang : Eritrosit, leukosit, megakariosit. (2) 2. Bayi sampai dengan dewasa Hematopoiesis terjadi pada sumsum tulang, normal tidak diproduksi di hepar dan limpa, keadaan abnormal dibantu organ lain. a. Hematopoiesis Meduler (N) Lahir sampai dengan 20 tahun : sel sel darah → sumsum tulang. Lebih dari 20 tahun : corpus tulang panjang berangsur-angsur diganti oleh jaringan lemak karena produksi menurun. (2) b. Hematopoiesis Ekstrameduler (AbN) Dapat terjadi pada keadaan tertentu,

Background: The abundance of monoclonal antibodies (mAb) and the routine use of quadruple stainings in flow cytometry allow stepwise analysis of bone marrow (BM) samples that are suspected for abnormal hematopoiesis. A screening phase that precedes lineage-specific classification phases should be sufficient to assess whether the BM has a normal or abnormal composition, as well as to identify the abnormal differentiation lineage.

This article describes the isolation of a novel cell population (B220 lo c-kit ؉ CD19 ؊ ) in the fetal liver that represents 70% of T-cell precursors in this organ. Interestingly, these precursors showed a bipotent T-cell and natural killer cell (NK)restricted reconstitution potential but completely lacked B and erythromyeloid differentiation capacity both in vivo and in vitro. Moreover, not only mature T-cell receptor (TCR)␣␤ ؉ peripheral T cells but also TCR␥␦ ؉ and TCR␣␤ ؉ CD8␣␣ ؉ intestinal epithelial cells of extrathymic origin were generated in reconstituted mice. The presence of this population in the fetal liver of athymic embryos indicates its prethymic origin. The comparison of the phenotype and differentiation potential of B220 lo c-kit ؉ CD19 ؊ fetal liver cells with those of thymic T/NK progenitors indi-cates that this is the most immature common T/NK cell progenitor so far identified. These fetal liver progenitors may represent the immediate developmental step before thymic immigration. (Blood. 2002; 99:463-471)

The effect of human recombinant granulocyte colony-stimulating factor (hrG-CSF) in rabbits with aortic endocarditis due to Pseudomonas aeruginosa was investigated. hrG-CSF significantly increased the number of polymorphonuclear neutrophils in blood and in cardiac vegetations and the expression of the adhesin molecule CD11b on the surface of polymorphonuclear neutrophils compared with those of animals that had not received hrG-CSF. When treatment was started 72 h after bacterial challenge, hrG-CSF alone had no antibacterial effect and did not enhance the efficacy of ciprofloxacin when used in combination, even with the higher dosing regimen used (50 g/kg of body weight subcutaneously every 12 h for 4 days), in terms of number of positive blood cultures, bacterial counts in vegetations, and survival. In contrast, when treatment was started 30 min prior to bacterial challenge, hrG-CSF (50 g/kg injected every 12 h) decreased bacterial titers in vegetations 72 h later (6.5 ؎ 0.9 versus 7.9 ؎ 0.9 log 10 CFU/g of vegetation for hrG-CSF and controls, respectively; P ‫؍‬ 0.0175). However, this antibacterial effect was no longer detected after a 7-day treatment with hrG-CSF, and prophylactic administration of hrG-CSF did not increase the antibacterial effect of ciprofloxacin. We concluded that the antibacterial effect of hrG-CSF in experimental endocarditis was related to the timing of its administration since hrG-CSF demonstrated a significant but transient antimicrobial effect only when treatment was initiated before bacterial challenge.

Granulocyte colony-stimulating factor (Gcsf) drives the proliferation and differentiation of granulocytes, monocytes, and macrophages (mφs) from hematopoietic stem and progenitor cells (HSPCs). Analysis of the zebrafish genome indicates the presence of 2 Gcsf ligands, likely resulting from a duplication event in teleost evolution. Although Gcsfa and Gcsfb share low sequence conservation, they share significant similarity in their predicted ligand/receptor interaction sites and structure. Each ligand displays differential temporal expression patterns during embryogenesis and spatial expression patterns in adult animals. To determine the functions of each ligand, we performed loss- and gain-of-function experiments. Both ligands signal through the Gcsf receptor to expand primitive neutrophils and mφs, as well as definitive granulocytes. To further address their functions, we generated recombinant versions and tested them in clonal progenitor assays. These sensitive in vitro techniques ...

Theuseof|(+)-l,2-bis(3,5-dioxopipera/inyl-l-yl)|propane(ICRF-187) as a protective agent against normal tissue toxicity caused by combined Adriamycin (ADR) and whole body hyperthermia (VVBH;2 h at 41.5°C) »asassessed in a rat model. The effect of ICRF-187 on the antitumor response induced by the combination of ADR and U HII was also investigated in order to assess alterations in the therapeutic index of this combined therapeutic

Mass cytometry addresses the analytical challenges of polychromatic flow cytometry by using metal atoms as tags rather than fluorophores and atomic mass spectrometry as the detector rather than photon optics. The many available enriched stable isotopes of the transition elements can provide up to 100 distinguishable reporting tags, which can be measured simultaneously because of the essential independence of detection provided by the mass spectrometer. We discuss the adaptation of traditional inductively coupled plasma mass spectrometry to cytometry applications. We focus on the generation of cytometrycompatible data and on approaches to unsupervised multivariate clustering analysis. Finally, we provide a highlevel review of some recent benchmark reports that highlight the potential for massively multi-parameter mass cytometry.

Key Points We observed that SMAD7, a negative regulator of TGF-β receptor-I kinase, is markedly reduced in MDS, and leads to ineffective hematopoiesis. Increased levels of microRNA-21 are seen in MDS and reduce SMAD7 levels, thus overactivating TGF-β signaling.

Hematopoiesis is a multistep process that results in the production of a variety of blood cells with different morphologies and diverse functions. All of these cells have their origin in hematopoietic stem cells (HSCs) that replicate slowly to selfrenew and give rise to progeny cells that proceed along the path of differentiation. The process is complex with the cells responding to a wide variety of cytokines and growth factors. We discuss a model of hematopoiesis based on stochastic cell behavior. Multiple compartments are introduced to keep track of each cell division process and increasing differentiation. Despite its simplicity, the model is able to account for the salient features of hematopoiesis and is compatible with considerable and independent experimental data. The model is applicable to hematopoiesis across mammals and can be used to understand the dynamics of various disorders both in humans and in animal models. 

Myelodysplastic syndromes and related disorders (myelodysplasia) are a heterogeneous group of myeloid neoplasms showing deregulated blood cell production with evidence of myeloid dysplasia and a predisposition to acute myeloid leukaemia, whose pathogenesis is only incompletely understood. Here we report whole-exome sequencing of 29 myelodysplasia specimens, which unexpectedly revealed novel pathway mutations involving multiple components of the RNA splicing machinery, including U2AF35, ZRSR2, SRSF2 and SF3B1. In a large series analysis, these splicing pathway mutations were frequent ( 45 to 85%) in, and highly specific to, myeloid neoplasms showing features of myelodysplasia. Conspicuously, most of the mutations, which occurred in a mutually exclusive manner, affected genes involved in the 39-splice site recognition during pre-mRNA processing, inducing abnormal RNA splicing and compromised haematopoiesis. Our results provide the first evidence indicating that genetic alterations of the major splicing components could be involved in human pathogenesis, also implicating a novel therapeutic possibility for myelodysplasia.

Impressive progress has been made since the turn of the century in the field of stem cells. Different types of stem cells have now been isolated from different types of tissues. Pluripotent stem cells are the most promising cell source for organ regeneration. One such cell type is the germline cell-derived pluripotent cell, which is derived from adult spermatogonial stem cells. The germline cell-derived pluripotent stem cells have been obtained from both human and mouse and, importantly, are adult stem cells with embryonic stem cell-like properties that do not require specific manipulations for pluripotency acquisition, hence bypassing problems related to induced pluripotent stem cells and embryonic stem cells. The germline cell-derived pluripotent stem cells have been induced to differentiate into cells deriving from the three germ layers and shown to be functional in vitro. This review will discuss the plasticity of the germline cell-derived pluripotent stem cells and their potent...

Lifelong blood cell production is governed through the poorly understood integration of cell-intrinsic and -extrinsic control of hematopoietic stem cell (HSC) quiescence and activation. MicroRNAs (miRNAs) coordinately regulate multiple targets within signaling networks, making them attractive candidate HSC regulators. We report that miR-126, a miRNA expressed in HSC and early progenitors, plays a pivotal role in restraining cell-cycle progression of HSC in vitro and in vivo. miR-126 knockdown by using lentiviral sponges increased HSC proliferation without inducing exhaustion, resulting in expansion of mouse and human long-term repopulating HSC. Conversely, enforced miR-126 expression impaired cell-cycle entry, leading to progressively reduced hematopoietic contribution. In HSC/early progenitors, miR-126 regulates multiple targets within the PI3K/AKT/GSK3β pathway, attenuating signal transduction in response to extrinsic signals. These data establish that miR-126 sets a threshold for HSC activation and thus governs HSC pool size, demonstrating the importance of miRNA in the control of HSC function.

Stem cell therapy is a potential method for the treatment of numerous diseases. The most frequent cellular source is bone-marrow-derived mesenchymal stromal cells (BM-MSCs). Human adipose-derived stromal cells (ADSCs) share similar properties with BM-MSCs as they support hematopoiesis, modulate ongoing immune responses, and differentiate into cells of mesodermal origin. On the other hand, ADSCs have higher frequency in situ, higher availability, and very few ethical issues compared with BM-MSCs, giving them an advantage over BM-MSCs for clinical use. Most of the methods used to isolate ADSCs contain a collagenase digestion step, but the type of collagenase and time of sample digestion vary among studies and these differences could have an impact on the cell properties and thus in result comparison. To overcome this obstacle, we propose a new method to isolate ADSCs from lipoaspirate without collagenase digestion step. We compared ADSCs obtained with our method versus classical protocol using collagenase digestion. Cells obtained with our method are equivalent but they have a better long-term hematopoietic support than those obtained with classical method. Moreover, our method has an advantage over the classical one as it is easier, safer, faster, less expensive, and more consistent with good manufacturing practices to obtain large number of ADSCs ex vivo.

SMOC2 is a member of the BM-40 (SPARC) family of matricellular proteins, reported to influence signaling in the extracellular compartment. In mice, Smoc2 is expressed in many different tissues and was shown to enhance the response to angiogenic growth factors, mediate cell adhesion, keratinocyte migration, and metastasis. Additionally, SMOC2 is associated with vitiligo and craniofacial and dental defects. The function of Smoc2 during early zebrafish development has not been determined to date. In pregastrula zebrafish embryos, smoc2 is expressed ubiquitously. As development progresses, the expression pattern becomes more anteriorly restricted. At the onset of blood cell circulation, smoc2 morphants presented a mild ventralization of posterior structures. Molecular analysis of the smoc2 morphants indicated myelopoietic defects in the rostral blood islands during segmentation stages. Hemangioblast development and further specification of the myeloid progenitor cells were shown to be i...

Microglia are the resident macrophages of the central nervous system and are associated with the pathogenesis of many neurodegenerative and brain inflammatory diseases; however, the origin of adult microglia remains controversial. We show that postnatal hematopoietic progenitors do not significantly contribute to microglia homeostasis in the adult brain. In contrast to many macrophage populations, we show that microglia develop in mice that lack colony stimulating factor-1 (CSF-1) but are absent in CSF-1 receptor–deficient mice. In vivo lineage tracing studies established that adult microglia derive from primitive myeloid progenitors that arise before embryonic day 8. These results identify microglia as an ontogenically distinct population in the mononuclear phagocyte system and have implications for the use of embryonically derived microglial progenitors for the treatment of various brain disorders.

Background: Many methods for dimensionality reduction of large data sets such as those generated in microarray studies boil down to the Singular Value Decomposition (SVD). Although singular vectors associated with the largest singular values have strong optimality properties and can often be quite useful as a tool to summarize the data, they are linear combinations of up to all of the data points, and thus it is typically quite hard to interpret those vectors in terms of the application domain from which the data are drawn. Recently, an alternative dimensionality reduction paradigm, CUR matrix decompositions, has been proposed to address this problem and has been applied to genetic and internet data. CUR decompositions are low-rank matrix decompositions that are explicitly expressed in terms of a small number of actual columns and/or actual rows of the data matrix. Since they are constructed from actual data elements, CUR decompositions are interpretable by practitioners of the field from which the data are drawn. Results: We present an implementation to perform CUR matrix decompositions, in the form of a freely available, open source R-package called rCUR. This package will help users to perform CUR-based analysis on large-scale data, such as those obtained from different high-throughput technologies, in an interactive and exploratory manner. We show two examples that illustrate how CUR-based techniques make it possible to reduce significantly the number of probes, while at the same time maintaining major trends in data and keeping the same classification accuracy.

This review describes the current knowledge about cell subsets involved in vasculogenesis (i.e., differentiation of endothelial cells from mesodermal precursors) and angiogenesis (i.e., blood vessel generation from pre-existing vessels), together with recent findings about angiogenesis and antiangiogenic therapies in hematopoietic malignancies such as leukemia, lymphoma, myeloma, and myelodysplastic syndromes.