With the expression "bone marrow hematopoietic stem cell transplant" we intend a complex procedure used especially, but not only, in the treatment of leukimias and lymphomas. Stem cells can be obtained not only from bone marrow but also from peripheral blood after a specific preconditioning of the patient, or from umbilical-cord blood.. Indications for hematopoietic stem cell transplant are acute leukimias, chronic leukimias, different forms of bone marrow insufficiency, thalassemias, Hodgkin lymphoma, non Hodgkin lymphomas, myelomas, other chronic myeloproliferative diseases, numerous genetic disorders and, as a recent indication, some autoimmune illnesses.. ...
TY - JOUR. T1 - CD34 expression on long-term repopulating hematopoietic stem cells changes during developmental stages. AU - Matsuoka, Sahoko. AU - Ebihara, Yasuhiro. AU - Xu, Ming Jiang. AU - Ishii, Takefumi. AU - Sugiyama, Daisuke. AU - Yoshino, Hiroshi. AU - Ueda, Takahiro. AU - Manabe, Atsushi. AU - Tanaka, Ryuhei. AU - Ikeda, Yasuo. AU - Nakahata, Tatsutoshi. AU - Tsuji, Kohichiro. PY - 2001/1/15. Y1 - 2001/1/15. N2 - The CD34 antigen serves as an important marker for primitive hematopoietic cells in therapeutic transplantation of hematopoietic stem cells (HSC) and gene therapy, but it has remained an open question as to whether or not most HSC express CD34. Using a competitive long-term reconstitution assay, the results of this study confirm developmental changes in CD34 expression on murine HSC. In fetuses and neonates, CD34 was expressed on Lin-c-Kit+ long-term repopulating HSC of bone marrow (BM), liver, and spleen. However, CD34 expression on HSC decreased with aging, and in mice older ...
HemoGenyx is a preclinical-stage biotechnology company focused on the discovery, development and commercialisation of novel therapies and treatments for blood diseases, like leukemia and lymphoma. The companys leading technologies aim to change the way in which bone marrow/hematopoietic stem cell (BM/HSC) transplants are performed and improve their efficacy.
TY - JOUR. T1 - Runx1 expression marks long-term repopulating hematopoietic stem cells in the midgestation mouse embryo. AU - North, Trista E.. AU - De Bruijn, Marella F T R. AU - Stacy, Terryl. AU - Talebian, Laleh. AU - Lind, Evan. AU - Robin, Catherine. AU - Binder, Michael. AU - Dzierzak, Elaine. AU - Speck, Nancy A.. PY - 2002. Y1 - 2002. N2 - Hematopoietic stem cells (HSCs) are first found in the aorta-gonad-mesonephros region and vitelline and umbilical arteries of the midgestation mouse embryo. Runx1 (AML1), the DNA binding subunit of a core binding factor, is required for the emergence and/or subsequent function of HSCs. We show that all HSCs in the embryo express Runx1. Furthermore, HSCs in Runx1+/- embryos are heterogeneous and include CD45+ cells, endothelial cells, and mesenchymal cells. Comparison with wild-type embryos showed that the distribution of HSCs among these various cell populations is sensitive to Runx1 dosage. These data provide the first morphological description of ...
TY - JOUR. T1 - The repopulation potential of fetal liver hematopoietic stem cells in mice exceeds that of their adult bone marrow counterparts. AU - Rebel, Vivienne I.. AU - Miller, Cindy L.. AU - Eaves, Connie J.. AU - Lansdorp, Peter M.. PY - 1996/4/15. Y1 - 1996/4/15. N2 - Varying, limiting numbers of unseparated or purified cells (Ly-5.1), either from 14.5-day-old fetal liver (FL) or from adult bone marrow (BM) were coinjected with 105 unseparated BM cells (Ly-5.2) into lethally irradiated adult C57B1/6 recipients (Ly-5.2). The kinetics of donor cell repopulation of the lymphoid and myeloid compartments by Ly-5.1+ donor hematopoietic stem cells (ie, competitive repopulation units [CRU]) were monitored at various time points after the transplantation by Ly-5 analysis of the peripheral white blood cells (WBC). Recipients that had received on average less than 2 adult BM or FL CRU did not show a significant difference in the level of donor-reconstitution when analyzed 4 weeks after the ...
TY - JOUR. T1 - Self-renewal of a purified Tie2+ hematopoietic stem cell population relies on mitochondrial clearance. AU - Ito, Kyoko. AU - Turcotte, Raphaël. AU - Cui, Jinhua. AU - Zimmerman, Samuel E.. AU - Pinho, Sandra. AU - Mizoguchi, Toshihide. AU - Arai, Fumio. AU - Runnels, Judith M.. AU - Alt, Clemens. AU - Teruya-Feldstein, Julie. AU - Mar, Jessica C.. AU - Singh, Rajat. AU - Suda, Toshio. AU - Lin, Charles P.. AU - Frenette, Paul S.. AU - Ito, Keisuke. PY - 2016/12/2. Y1 - 2016/12/2. N2 - A single hematopoietic stem cell (HSC) is capable of reconstituting hematopoiesis and maintaining homeostasis by balancing self-renewal and cell differentiation. The mechanisms of HSC division balance, however, are not yet defined. Here we demonstrate, by characterizing at the single-cell level a purified and minimally heterogeneous murine Tie2+ HSC population, that these top hierarchical HSCs preferentially undergo symmetric divisions. The induction of mitophagy, a quality control process in ...
TY - JOUR. T1 - Functional association between expression of adhesion molecules and marrow repopulating potential of primitive murine hematopoietic progenitor cells (hpc). AU - Travcpff, C. M.. AU - Voder, M. C.. AU - Hiatt, K.. AU - Srour, Edward. PY - 1997. Y1 - 1997. N2 - A number of adhesion molecules have been implicated in the ability of transplanted hematopoietic stem cells (HSC) to engraft. We investigated whether the expression, or lack thereof, of CD11 a, CD43, CD44, CD49d, CD49e, and CD62L on Sca-1 + lin- cells augments or diminishes the bone marrow (BM) repoputatlng potential of these cells. A total of 103 Sca-l+ lin X+ or Sca-1+ lin X- cells (where X is any of the 6 molecules mentioned above) from B6.Hbbd congenic mice were competitively transplanted along with 3 x 104 C57/BI6 low density BM cells into fethally irradiated C57/BI6 recipients. In the event where all analyzed Sca-1+ Ifrr cells were positive for the expression of a particular adhesion molecule (CD44 and CD49d), Sca-1 ...
TY - JOUR. T1 - Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and proliferation. AU - Hoggatt, Jonathan. AU - Singh, Pratibha. AU - Sampath, Janardhan. AU - Pelus, Louis M.. PY - 2009. Y1 - 2009. N2 - Adult hematopoietic stem cells (HSCs) are routinely used to reconstitute hematopoiesis after myeloablation; however, transplantation efficacy and multilineage reconstitution can be limited by inadequate HSC number, or poor homing, engraftment, or self-renewal. Here we report that mouse and human HSCs express prostaglandin E2 (PGE2) receptors, and that short-term ex vivo exposure of HSCs to PGE2 enhances their homing, survival, and proliferation, resulting in increased long-term repopulating cell (LTRC) and competitive repopulating unit (CRU) frequency. HSCs pulsed with PGE2 are more competitive, as determined by head-to-head comparison in a competitive transplantation model. Enhanced HSC frequency and competitive advantage is stable and maintained upon serial transplantation, ...
Hematopoietic Stem Cell Biology is the newest installment in the Stem Cell Biology and Regenerative Medicine series, to which it adeptly contributes as it offers a selection of carefully chosen topics so that the readers can understand recent advances in the field of the hematopoietic stem cells and hemato/lymphopoiesis. Each chapter is not a simple review of the topic, but rather an in-depth insight, which allows the reader to attain a multifaceted knowledgebase on hematopoietic stem cells. The chapters, which are authored by the leading experts in the field, cover characteristics of the hematopoietic stem cells at the cellular and molecular levels, offers details in regulatory mechanisms of differentiation mechanisms of hematopoietic stem cells to more mature blood cell, and discusses abnormal hematopoiesis that leads to leukemia. Hematopoietic Stem Cell Biology serves the inquiring minds of researchers, graduate students and post doctorate fellows as it expertly addresses the ever-growing ...
Hematopoietic Stem Cell Biology is the newest installment in the Stem Cell Biology and Regenerative Medicine series, to which it adeptly contributes as it offers a selection of carefully chosen topics so that the readers can understand recent advances in the field of the hematopoietic stem cells and hemato/lymphopoiesis. Each chapter is not a simple review of the topic, but rather an in-depth insight, which allows the reader to attain a multifaceted knowledgebase on hematopoietic stem cells. The chapters, which are authored by the leading experts in the field, cover characteristics of the hematopoietic stem cells at the cellular and molecular levels, offers details in regulatory mechanisms of differentiation mechanisms of hematopoietic stem cells to more mature blood cell, and discusses abnormal hematopoiesis that leads to leukemia. Hematopoietic Stem Cell Biology serves the inquiring minds of researchers, graduate students and post doctorate fellows as it expertly addresses the ever-growing ...
Quiescent long-term hematopoietic stem cells (LT-HSCs) are efficiently activated by type I interferon (IFN-I). However, this effect remains poorly investigated in the context of IFN-I-inducing virus infections. Here we report that both vesicular stomatitis virus (VSV) and murine cytomegalovirus (MCMV) infection induce LT-HSC activation that substantially differs from the effects triggered upon injection of synthetic IFN-I-inducing agents. In both infections, inflammatory responses had to exceed local thresholds within the bone marrow to confer LT-HSC cell cycle entry, and IFN-I receptor triggering was not critical for this activation. After resolution of acute MCMV infection, LT-HSCs returned to phenotypic quiescence. However, non-acute MCMV infection induced a sustained inflammatory milieu within the bone marrow that was associated with long-lasting impairment of LT-HSC function. In conclusion, our results show that systemic virus infections fundamentally affect LT-HSCs and that also non-acute ...
Background Many biological processes are characterized by allometric relations of the type Y = Y0Mb between an observable Y and body mass M, which pervade at multiple levels of organization. In what regards the hematopoietic stem cell pool, there is experimental evidence that the size of the hematopoietic stem cell pool is conserved in mammals. However, demands for blood cell formation vary across mammals and thus the size of the active stem cell compartment could vary across species. Methodology/Principle Findings Here we investigate the allometric scaling of the hematopoietic system in a large group of mammalian species using reticulocyte counts as a marker of the active stem cell pool. Our model predicts that the total number of active stem cells, in an adult mammal, scales with body mass with the exponent ¾. Conclusion/Significance The scaling predicted here provides an intuitive justification of the Hayflick hypothesis and supports the current view of a small active stem cell pool supported by a
TY - JOUR. T1 - Endothelial cells provide a niche for placental hematopoietic stem/progenitor cell expansion through broad transcriptomic modification. AU - Raynaud, Christophe M.. AU - Butler, Jason M.. AU - Halabi, Najeeb M.. AU - Ahmad, Faizzan S.. AU - Ahmed, Badereldeen. AU - Rafii, Shahin. AU - Rafii, Arash. PY - 2013/11/1. Y1 - 2013/11/1. N2 - Umbilical cord blood (UCB) is an attractive source of hematopoietic stem cells (HSCs). However, the number of HSCs in UCB is limited, and attempts to amplify them in vitro remain inefficient. Several publications have documented amplification of hematopoietic stem/progenitor cells (HSPCs) on endothelial or mesenchymal cells, but the lack of homogeneity in culture conditions and HSC definition impairs direct comparison of these results. We investigated the ability of different feeder layers, mesenchymal progenitors (MPs) and endothelial cells (ECs), to amplify hematopoietic stem/progenitor cells. Placental derived HSPCs (defined as ...
TY - JOUR. T1 - The Paf oncogene is essential for hematopoietic stem cell function and development. AU - Amrani, Yacine M.. AU - Gill, Jonathan. AU - Matevossian, Armine. AU - Alonzo, Eric S.. AU - Yang, Chingwen. AU - Shieh, Jae Hung. AU - Moore, Malcolm A.. AU - Park, Christopher Y.. AU - SantAngelo, Derek B.. AU - Denzin, Lisa K.. PY - 2011/8/29. Y1 - 2011/8/29. N2 - Hematopoietic stem cells (HSCs) self-renew to maintain the lifelong production of all blood populations. Here, we show that the proliferating cell nuclear antigen-associated factor (Paf) is highly expressed in cycling bone marrow HSCs and plays a critical role in hematopoiesis. Mice lacking Paf exhibited reduced bone marrow cellularity; reduced numbers of HSCs and committed progenitors; and leukopenia. These phenotypes are caused by a cellintrinsic blockage in the development of long-term (LT)-HSCs into multipotent progenitors and preferential loss of lymphoid progenitors caused by markedly increased p53-mediated apoptosis. In ...
TY - JOUR. T1 - Primitive adult hematopoietic stem cells can function as osteoblast precursors. AU - Olmsted-Davis, Elizabeth A.. AU - Gugala, Zbigniew. AU - Camargo, Fernando. AU - Gannon, Francis H.. AU - Jackson, KathyJo. AU - Kienstra, Kirsten Anderson. AU - Shine, H. David. AU - Lindsey, Ronald. AU - Hirschi, Karen K.. AU - Goodell, Margaret A.. AU - Brenner, Malcolm K.. AU - Davis, Alan R.. PY - 2003/12/23. Y1 - 2003/12/23. N2 - Osteoblasts are continually recruited from stem cell pools to maintain bone. Although their immediate precursor is a plastic-adherent mesenchymal stem cell able to generate tissues other than bone, increasing evidence suggests the existence of a more primitive cell that can differentiate to both hematopoietic and mesenchymal cells. We show here that the "side population" (SP) of marrow stem cells, defined by their ability to rapidly expel a DNA-binding dye and to regenerate the hematopoietic compartment, can differentiate to osteoblasts through a mesenchymal ...
Whereas the cellular basis of the hematopoietic stem cell (HSC) niche in the bone marrow has been characterized, the nature of the fetal liver niche is not yet elucidated. We show that Nestin+NG2+ pericytes associate with portal vessels, forming a niche promoting HSC expansion. Nestin+NG2+ cells and HSCs scale during development with the fractal branching patterns of portal vessels, tributaries of the umbilical vein. After closure of the umbilical inlet at birth, portal vessels undergo a transition from Neuropilin-1+Ephrin-B2+ artery to EphB4+ vein phenotype, associated with a loss of periportal Nestin+NG2+ cells and emigration of HSCs away from portal vessels. These data support a model in which HSCs are titrated against a periportal vascular niche with a fractal-like organization enabled by placental circulation. ...
Although previous studies suggested that the expression of FMS-like tyrosine kinase 3 (Flt3) initiates downstream of mouse hematopoietic stem cells (HSCs),FLT3internal tandem duplications (FLT3ITDs) have recently been suggested to intrinsically suppress HSCs. Herein, single-cell interrogation foundFlt3mRNA expression to be absent in the large majority of phenotypic HSCs, with a strong negative correlation betweenFlt3and HSC-associated gene expression. Flt3-ITD knock-in mice showed reduced numbers of phenotypic HSCs, with an even more severe loss of long-term repopulating HSCs, likely reflecting the presence of non-HSCs within the phenotypic HSC compartment. Competitive transplantation experiments established that Flt3-ITD compromises HSCs through an extrinsically mediated mechanism of disrupting HSC-supporting bone marrow stromal cells, with reduced numbers of endothelial and mesenchymal stromal cells showing increased inflammation-associated gene expression. Tumor necrosis factor (TNF), a cell
The CD105 MultiSort Kit (PE), mouse has been developed for the isolation of CD105+ cells or cell subsets, including vascular endothelial cells from mouse tissue or cell cultures long-term repopulating hematopoietic stem cells (LTR-HSCs) from mouse bone marrow when used in combination with the Anti-Sca-1 MicroBead Kit (FITC). - USA
TY - JOUR. T1 - Osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization. AU - Miyamoto, Kana. AU - Yoshida, Shigeyuki. AU - Kawasumi, Miyuri. AU - Hashimoto, Kazuaki. AU - Kimura, Tokuhiro. AU - Sato, Yuiko. AU - Kobayashi, Tami. AU - Miyauchi, Yoshiteru. AU - Hoshi, Hiroko. AU - Iwasaki, Ryotaro. AU - Miyamoto, Hiroya. AU - Hao, Wu. AU - Morioka, Hideo. AU - Chiba, Kazuhiro. AU - Kobayashi, Takashi. AU - Yasuda, Hisataka. AU - Penninger, Josef M.. AU - Toyama, Yoshiaki. AU - Suda, Toshio. AU - Miyamoto, Takeshi. PY - 2011/12/19. Y1 - 2011/12/19. UR - http://www.scopus.com/inward/record.url?scp=84862936378&partnerID=8YFLogxK. UR - http://www.scopus.com/inward/citedby.url?scp=84862936378&partnerID=8YFLogxK. U2 - 10.1084/jem.2010189020813c. DO - 10.1084/jem.2010189020813c. M3 - Article. AN - SCOPUS:84862936378. VL - 208. SP - 2761. JO - Journal of Experimental Medicine. JF - Journal of Experimental Medicine. SN - 0022-1007. IS - 13. ER - ...
There are comments on PubPeer for publication: Ezh1 is required for hematopoietic stem cell maintenance and prevents senescence-like cell cycle arrest (2012)
The only curative therapy for sickle cell disease (SCD) is allogeneic hematopoietic stem cell (HSC) transplantation. Gene therapy approaches for autologous HSC transplantation are being developed. Although earlier engraftment is seen when cells from GCSF-mobilized blood are transplanted than when bone marrow is transplanted, administration of GCSF to patients with SCD can cause significant morbidity. We tested whether primitive hematopoietic progenitors are spontaneously mobilized in the blood of patients with SCD during acute crisis (AC-SCD patients). The frequency of myeloid-lymphoid-initiating cells (ML-ICs) and SCID-repopulating cells (SRCs) was significantly higher in blood from AC-SCD patients than in blood from patients with steady-state SCD or from normal donors. The presence of SRCs in peripheral blood was not associated with detection of long-term culture-initiating cells, consistent with the notion that SRCs are more primitive than long-term culture-initiating cells. As ML-ICs and ...
Maintenance of blood homeostasis depends on the balance between self-renewal of hematopoietic stem cells (HSCs) and their differentiation into blood cell progenitors. A variety of different intrinsic or extrinsic regulators, including multiple microRNA (miRNA) species, have been described to play a role in the regulation of these processes. Disruption of any of these regulators could lead to stem cell exhaustion or increased risk of leukemogenesis. Given recent reports of the role of miR-146a in malignant hematopoiesis, we evaluated its role in hematopoietic stem progenitor cell (HSPC) function. We show that miR-146a is highly expressed in HSCs and its expression decreases in committed progenitors. miR-146a- deficient HSCs had dramatically reduced self-renewal capacity as measured by serial competitive bone marrow transplantation assays. The lower self-renewal capacity was accompanied by decreased quiescence in miR-146a-deficient cells, as revealed by decreased proportion of miR-146a-/- HSPCs ...
Holmes, T., Yan, F., Ko, K.-H., Nordon, R., Song, E., OBrien, T. A. and Dolnikov, A. (2012), Ex vivo expansion of cord blood progenitors impairs their short-term and long-term repopulating activity associated with transcriptional dysregulation of signalling networks. Cell Proliferation, 45: 266-278. doi: 10.1111/j.1365-2184.2012.00813.x ...
Adult hematopoietic stem cells (HSCs) are maintained in a microenvironment, known as niche in the endosteal regions of the bone marrow. This stem cell niche with low oxygen tension requires HSCs to adopt a unique metabolic profile. We have recently demonstrated that mouse long-term hematopoietic stem cells (LT-HSCs) utilize glycolysis instead of mitochondrial oxidative phosphorylation as their main energy source. However, the metabolic phenotype of human hematopoietic progenitor and stem cells (HPSCs) remains unknown. We show that HPSCs have a similar metabolic phenotype, as shown by high rates of glycolysis, and low rates of oxygen consumption. Fractionation of human mobilized peripheral blood cells based on their metabolic footprint shows that cells with a low mitochondrial potential are highly enriched for HPSCs. Remarkably, low MP cells had much better repopulation ability as compared to high MP cells. Moreover, similar to their murine counterparts, we show that Hif-1α is upregulated in human HPSCs
PRIME-XV® Mouse Hematopoietic Cell Basal Medium was developed in a collaboration program with a leading stem-cell research facility in the USA to fulfill the need for a serum-free, cost-effective medium for in vitro culture and expansion and self-renewal of murine hematopoietic progenitor cells (mHPCs).. PRIME-XV Mouse Hematopoietic Cell Basal Medium is:. ...
During embryonic development a variety of tissues and organs such as the lung, eye, and kidney are being formed. The generation of functional organs is regulated by reciprocal cell-cell interactions. Via the secretion of soluble molecules one type of cells affect the fate of their neighboring cells. A central issue in organogenesis is how a cell interprets such extrinsic signals and adopts a specific fate, and how the cell in response to this signal establishes reciprocal signaling. Transcription factors play a critical role in this process and my thesis focuses on the role of the LIM-homeodomain transcription factor, Lhx2, in the development of three different organ systems, the liver, the hematopoietic system and the olfactory system.. The liver is formed from endoderm of the ventral foregut and mesenchyme of the septum transversum (st) and its development depends upon signaling interactions between these two tissues. As the liver becomes a distinct organ it is colonized by hematopoietic cells ...
Wnt signaling increases hematopoietic stem cell self-renewal and is activated in both myeloid and lymphoid malignancies, indicating involvement in both normal and malignant hematopoiesis. We report here activated canonical Wnt signaling in the hematopoietic system through conditional expression of a stable form of beta-catenin. This enforced expression led to hematopoietic failure associated with loss of myeloid lineage commitment at the granulocyte-macrophage progenitor stage; blocked erythrocyte differentiation; disruption of lymphoid development; and loss of repopulating stem cell activity. Loss of hematopoietic stem cell function was associated with decreased expression of Cdkn1a ( encoding the cell cycle inhibitor p21(cdk)), Sfpi1, Hoxb4 and Bmi1 ( encoding the transcription factors PU.1, HoxB4 and Bmi-1, respectively) and altered integrin expression in Lin(-)Sca-1(+)c-Kit(+) cells, whereas PU.1 was upregulated in erythroid progenitors. Constitutive activation of canonical Wnt signaling ...
Hematopoiesis is a complex process through which hematopoietic stem cells (HSCs) generate all the cell types found in the blood. This originates during the early stages of embryonic development and continues in the bone marrow (BM) throughout adulthood to preserve homeostasis in the blood system. The interest in the expansion and production of HSCs has increased in recent years. After the derivation of human embryonic stem cells (ESCs) and the discovery of cellular reprogramming, much effort has been devoted to obtain HSCs and mature blood cells from human pluripotent stem cells (PSCs). In addition to their unlimited, yet-to-be realized, therapeutic potential, human PSCs make a very useful tool that can be utilized to understand the signaling pathways involved in hematopoiesis. Recently, long term engraftment and multi-lineage differentiation of hPSCs-derived hematopoietic progenitor cells was achieved after screening large numbers of potential transcription factors that were activated in vivo ...
Bennett, M and Cudkowicz, G, "Hemopoietic precursor cells of the mouse spleen incapable of self- -replication. Abstr." (1967). Subject Strain Bibliography 1967. 1376 ...
TY - JOUR. T1 - Rapid 1-hour transduction of whole bone marrow leads to long-term repopulation of murine recipients with lentivirus-modified hematopoietic stem cells. AU - Kurre, Peter. AU - Anandakumar, P.. AU - Kiem, H. P.. PY - 2006/2. Y1 - 2006/2. N2 - Efficient gene transfer to hematopoietic stem cells by Moloney murine leukemia virus-derived retroviral vectors benefits from ex vivo culture and cytokine support. Both also increase the risks of apoptosis and differentiation among cells targeted for transduction. In an effort to maximize the retention of stem cell properties in target cells, we developed a transduction protocol with a focus on minimizing graft manipulation, cytokine stimulation, and ex vivo exposure duration. Based on their wide host range and ability to transduce quiescent cells, human immunodeficiency virus (HIV)-derived lentivirus vectors are ideally suited for this purpose. Our present studies in a murine model show that whole bone marrow cells are readily transduced ...
Gpr56, one of the top hits in our HSC versus HEC comparison (30-fold increase) and bound by all heptad TFs, is indeed a novel regulator for emerging HSCs in the embryonic vasculature. Contrary to expectations raised by the lack of HSC defects in mouse Gpr56 KO embryos (generated by deletion of the first two exons [Saito et al. 2013]), our RNAseq data suggested a strong role for Gpr56 in emergence of HSCs. In the E10.5 mouse aorta, we localized Gpr56 expression to a few HCs/HSCs (Ly6aGFP+). Upon gpr56 knockdown, zebrafish embryos showed severe reduction in HSCs (cmyb) and CD41+ hematopoietic stem/progenitor cells, revealing a requirement for Gpr56 in HSC generation. Our rescue experiments in gpr56 morphants show that both zebrafish and mouse Gpr56 RNA can restore aortic hematopoietic stem/progenitor generation. Moreover, Gpr56 overexpression resulted in ectopic hematopoietic progenitor/stem cell formation in the axial vein, suggesting that the Gpr56 signaling axis may be useful for inducing new ...
Abstract. We show here for the first time that pluripotent hematopoietic stem cells express the CD4 antigen. CD4+ cells isolated from mouse marrow repopulated
Receptor tyrosine kinase (RTK) c-Kit signalling is crucial for the proliferation, survival and differentiation of haematopoietic stem cells (HSCs). To further understand the mechanisms underlying these events we explored how the downstream mediators interact. The present study investigated the function of conventional protein kinase Cs (c-PKC) in c-Kit mediated signalling pathways in HSC-like cell lines. This analysis supported earlier findings, that steel factor (SF) activates c-PKC, extracellular signal-regulated kinase (Erk) and protein kinase B (PKB). The present results were consistent with an important role of c-PKC in the positive activation of Erk and for proliferation. Further, it was observed that c-PKC negatively regulated PKB activity upon SF stimulation, indicating that c-PKC acts as a suppressor of c-Kit signalling. Finally, these observations were extended to show that c-PKC mediated the phosphorylation of the endogenous c-Kit receptor on serine 746, resulting in decreased overall ...
Two categories of blood-forming stem cells exist in adult bone marrow. One population can provide permanent long-term reconstitution of the entire hematopoietic system. These cells, referred to as hematopoietic stem cells (HSCs), are rare, perhaps as few as 1:10 000 bone marrow cells.28 However, utilizing the specificity of monoclonal antibodies, HSCs can be enriched by flow cytometry to near purity on the basis of surface markers. As few as 20 to 100 highly purified mouse bone marrow HSCs can reconstitute the entire lymphohematopoietic system in myeloablated adult mice.29-31 They can self-renew and can differentiate into the more mature progenitor cells in bone marrow.. The progenitor cells of bone marrow have a limited capacity for self-renewal and differentiation. They can only sustain hematopoiesis for 1 to 2 months and therefore are considered to be short-term repopulating stem cells. It is proposed that one subclass of mouse progenitor cells, the common lymphocytic progenitors (CLP), ...
The current study identifies a potential interaction between the FA pathway and Notch signaling in HSC differentiation and establishes a role of FA proteins in the control of balance between renewal and lineage commitment. There are several findings that highlight the significance of our study: 1) loss of murine FA proteins results in enhanced Notch signaling in MPPs, which is correlated with decreased phenotypic and functional LT-HSCs and increased formation of MPP1 progenitors; 2) deletion of the Fanca or Fancc gene deregulates genes in the Notch signaling and the NF-κB pathway; 3) TNF-α stimulation enhances Notch signaling in Fanca−/− and Fancc−/− LSK cells, leading to decreased HSC quiescence and compromised HSC self-renewal; 4) inflammation-activated Notch target gene expression in Fanca−/− and Fancc−/− MPP cells requires NF-κB; 5) genetic ablation or pharmacologic inhibition of NF-κB reduces Notch signaling in FA MPPs to near WT levels and significantly increases ...
TY - JOUR. T1 - Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. AU - Ding, Lei. AU - Morrison, Sean J.. PY - 2013/3/14. Y1 - 2013/3/14. N2 - Although haematopoietic stem cells (HSCs) are commonly assumed to reside within a specialized microenvironment, or niche, most published experimental manipulations of the HSC niche have affected the function of diverse restricted progenitors. This raises the fundamental question of whether HSCs and restricted progenitors reside within distinct, specialized niches or whether they share a common niche. Here we assess the physiological sources of the chemokine CXCL12 for HSC and restricted progenitor maintenance. Cxcl12DsRed knock-in mice (DsRed-Express2 recombined into the Cxcl12 locus) showed that Cxcl12 was primarily expressed by perivascular stromal cells and, at lower levels, by endothelial cells, osteoblasts and some haematopoietic cells. Conditional deletion of Cxcl12 from haematopoietic cells or ...
To clarify the molecular pathways governing hematopoietic stem cell (HSC) development, we screened a fetal liver (FL) HSC cDNA library and identified a unique gene, hematopoietic expressed mammalian polycomb (hemp), encoding a protein with a zinc-finger domain and four malignant brain tumor (mbt) repeats. To investigate its biological role, we generated mice lacking Hemp (hemp−/−). Hemp−/− mice exhibited a variety of skeletal malformations and died soon after birth. In the FL, hemp was preferentially expressed in the HSC and early progenitor cell fractions, and analyses of fetal hematopoiesis revealed that the number of FL mononuclear cells, including HSCs, was reduced markedly in hemp−/− embryos, especially during early development. In addition, colony-forming and competitive repopulation assays demonstrated that the proliferative and reconstitution abilities of hemp−/− FL HSCs were significantly impaired. Microarray analysis revealed alterations in the expression levels of ...
Background Cdx4 is a homeobox gene essential for normal blood formation during embryonic development in the zebrafish, through activation of posterior hox genes. However, its role in adult mammalian hematopoiesis has not been extensively studied and its requirement in leukemia associated with Hox gene expression alteration is unclear. Design and Methods We inactivated Cdx4 in mice through either a germline or conditional knockout approach and analyzed requirement for Cdx4 in both normal adult hematopoiesis and leukemogenesis initiated by the MLL-AF9 fusion oncogene. Results Here, we report that loss of Cdx4 had minimal effect on adult hematopoiesis. Indeed, although an increase in white blood cell counts was observed, no significant difference in the distribution of mature blood cells, progenitors or stem cells were observed in Cdx4-deficient animals. In addition, long-term repopulating activity in competitive transplantation assays was not significantly altered. In vitro, B-cell progenitor ...
Since monocytes and macrophages that arise during the culture of bone marrow progenitor cells are potential sources of interleukin 6 (IL-6), we investigated whether auto- or paracrine production of this factor is involved in colony formation by normal hematopoietic progenitor cells. We added a polyclonal anti-IL-6 antiserum and a monoclonal anti-IL-6 antibody to cultures of monocyte- and T cell-depleted bone marrow cells. Colony formation was stimulated with granulocyte/monocyte-colony-stimulating factor (GM-CSF), monocyte-CSF, or IL-3. Addition of anti-IL-6 antibody resulted in decreased numbers of monocytic colonies to 40-50% of control values, whereas the numbers of granulocytic colonies were not altered. The inhibitory effect was preserved in cultures of CD34(+)-enriched bone marrow cells. As a second approach, we added a monoclonal antibody directed against the IL-6 receptor to cultures of monocyte- and T cell-depleted bone marrow cells. This antibody almost completely inhibited the growth ...
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DOI: 10.11607/jomi.te56 Purpose: This study investigated the role of the bone marrow derived CD34+ cell in a milieu of osteoprogenitor cells, bone marrow plasma cell adhesion molecules, recombinant human bone morphogenetic protein (rhBMP), and a matrix of crushed cancellous allogeneic bone in the clinical regeneration of functionally useful bone in craniomandibular reconstructions. The history and current concepts of bone marrow hematopoietic stem cells and mesenchymal stem cells are reviewed as they relate to bone regeneration in large continuity defects of the mandible. Materials and Methods: Patients with 6- to 8-cm continuity defects of the mandible with retained proximal and distal segments were randomized into two groups. Group A received an in situ tissue-engineered graft containing 54 38 CD34+ cells/mL along with 54 38 CD44+, CD90+, and CD105+ cells/mL together with rhBMP-2 in an absorbable collagen sponge (1 mg/cm of defect) and crushed cancellous allogeneic bone. Group B received the ...
Hematopoietic stem cells (HSC) are defined by their ability to renew and differentiate into all blood cell lineages. Hematopoietic stem cells are characterized by the expression of Lin-CD34+CD38-CD90+CD45RA-. Under normal conditions, the majority of HSCs are found in the bone marrow (BM) and only limited numbers are found in the peripheral blood. However, in response to certain stress conditions or mobilizing agents, their number in the circulating peripheral blood rises.. In clinical practice, HSCs are identified by positive expression of CD34.. ...
Loss of immune function and an increased incidence of myeloid leukemia are two of the most clinically significant consequences of aging of the hematopoietic system. To better understand the mechanisms underlying hematopoietic aging, we evaluated the cell intrinsic functional and molecular properties of highly purified long-term hematopoietic stem cells (LT-HSCs) from young and old mice. We found that LT-HSC aging was accompanied by cell autonomous changes, including increased stem cell self-renewal, differential capacity to generate committed myeloid and lymphoid progenitors, and diminished lymphoid potential. Expression profiling revealed that LT-HSC aging was accompanied by the systemic down-regulation of genes mediating lymphoid specification and function and up-regulation of genes involved in specifying myeloid fate and function. Moreover, LT-HSCs from old mice expressed elevated levels of many genes involved in leukemic transformation. These data support a model in which age-dependent alterations
Hellman, S and Grate, H E., "Effect of cyclophosphamide on the murine hematopoietic stem cell compartment as measured by different assay techniques." (1971). Subject Strain Bibliography 1971. 1381 ...
Strategies for expanding hematopoietic stem cells (HSCs) include coculture with cells that recapitulate their natural microenvironment, such as bone marrow stromal stem/progenitor cells (BMSCs). Plastic-adherent BMSCs may be insufficient to preserve primitive HSCs. Here, we describe a method of isolating and culturing human BMSCs as nonadherent mesenchymal spheres. Human mesenspheres were derived from CD45(-) CD31(-) CD71(-) CD146(+) CD105(+) nestin(+) cells but could also be simply grown from fetal and adult BM CD45(-)-enriched cells. Human mesenspheres robustly differentiated into mesenchymal lineages. In culture conditions where they displayed a relatively undifferentiated phenotype, with decreased adherence to plastic and increased self-renewal, they promoted enhanced expansion of cord blood CD34(+) cells through secreted soluble factors. Expanded HSCs were serially transplantable in immunodeficient mice and significantly increased long-term human hematopoietic engraftment. These results ...
TY - JOUR. T1 - Intrinsic Hematopoietic Stem Cell/Progenitor Plasticity. T2 - Inversions. AU - Colvin, Gerald A.. AU - Lambert, Jean François. AU - Moore, Brian E.. AU - Carlson, Jane E.. AU - Dooner, Mark S.. AU - Abedi, Mehrdad. AU - Cerny, Jan. AU - Quesenberry, Peter J.. PY - 2004/4. Y1 - 2004/4. N2 - Traditional concepts indicate that stem cells give rise to progenitor cells in a hierarchical system. We studied murine engraftable stem cells (ESCs) and progenitors in in vitro and found that ESC and progenitors exist in a reversible continuum, rather then a hierarchy. B6.SJL and BALB/c marrow cells were serially cultured with thrombopoietin (TPO), FLT-3 ligand (FLT-3L), and steel factor through cell cycle. Progenitors (high-proliferative potential colony-forming cells (HPP-CFC) and colony-forming unit culture (CFU-c)) and ESC capacity was determined. The cell cycle status of purified lineage negativerhodaminelowHoechstlow stem cells was determined under the same conditions using tritiated ...
Hematopoietic homeostasis depends on the maintenance of hematopoietic stem cells (HSCs), which are regulated within a specialized bone marrow (BM) niche. When HSC sense external stimuli, their adhesion status may be critical for determining HSC cell fate. The cell surface molecule, integrin αvβ3, is activated through HSC adhesion to extracellular matrix and niche cells. Integrin β3 signaling maintains HSCs within the niche. Here, we showed the synergistic negative regulation of the pro‐inflammatory cytokine interferon‐γ (IFNγ) and β3 integrin signaling in murine HSC function by a novel definitive phenotyping of HSCs. Integrin αvβ3 suppressed HSC function in the presence of IFNγ and impaired integrin β3 signaling mitigated IFNγ‐dependent negative action on HSCs. During IFNγ stimulation, integrin β3 signaling enhanced STAT1‐mediated gene expression via serine phosphorylation. These findings show that integrin β3 signaling intensifies the suppressive effect of IFNγ on HSCs, ...
This unit describes a protocol for the isolation of cells from murine embryonic stem cells with hematopoietic stem cell activity, defined by the ability to reconstitute, long term, multiple lineages of the hematopoietic system of lethally irradiated mice. The protocol subjects hematopoietic progenitors specified in differentiating embryoid bodies to ectopic HoxB4 expression (delivered via retroviral infection), followed by coculture and expansion on OP9 stromal cells in the presence of hematopoietic cytokines for 10 days. The protocol results in the generation of hundreds of millions of cells that can rescue mice from lethal irradiation. Although little is known about the phenotype and frequency of the actual hematopoietic stem cell-like cell within the population of cells generated by this protocol, the protocol establishes a system in which these cells can be further studied and the results ultimately translated to the human system. McKinney-Freeman, Shannon L.; Naveiras, Olaia; Daley, George Q.
We have identified a population of cells in murine bone marrow that has many of the phenotypic characteristics attributed to resting hematopoietic stem cells but does not reconstitute irradiated mice. These cells express high levels of Sca-1, H-2K and CD38 and low levels of Thy-1.1, but do not express CD34 nor any of the lineage markers including CD3, CD4, CD5, CD8 NK1.1, I-A, B220, Ig(MGA), CD40, kappa, Mac-1, Gr-1 or Ter119. In addition, this population can be found at normal frequency in nu/nu as well as rag-1(- /-) mice. These cells incorporate only low levels of Rh123, are resistant to the cytotoxic effects of 5-fluorouracil and, consistent with their resting phenotype, less than 2% of these cells are in the S/G2/M phases of the cell cycle. The only phenotypic characteristic that distinguishes these cells from the lineage- Sca-1+, Thy-1.1(low) long-term reconstituting hematopoietic stem cell population is their lack of c-kit expression. Here we have explored the possibility that these cells ...
The canonical Wnt signaling pathway plays key roles in stem-cell maintenance, progenitor cell expansion, and lineage decisions. Transcriptional responses induced by Wnt depend on the association of either beta-catenin or gamma-catenin with lymphoid enhancer factor/T cell factor transcription factors. Here we show that hematopoiesis, including thymopoiesis, is normal in the combined absence of beta- and gamma-catenin. Double-deficient hematopoietic stem cells maintain long-term repopulation capacity and multilineage differentiation potential. Unexpectedly, 2 independent ex vivo reporter gene assays show that Wnt signal transmission is maintained in double-deficient hematopoietic stem cells, thymocytes, or peripheral T cells. In contrast, Wnt signaling is strongly reduced in thymocytes lacking TCF-1 or in nonhematopoietic cells devoid of beta-catenin. These data provide the first evidence that hematopoietic cells can transduce canonical Wnt signals in the combined absence of beta- and gamma-catenin.