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[Acquired mutation of JAK2 tyrosine kinase and polycythaemia vera].
Polycythaemia vera is an acquired myeloproliferative disorder characterised by a polycythaemia resulting of a clonal disorder arising in a multipotent hematopoietic stem cell. The increase of red cell mass exposes to a high risk of arterial or venous thrombosis and thus requires a cytoreductive treatment. An acquired genetic mutation in exon 12 of the JAK2 tyrosine kinase gene, leading to a substitution of a valine to a phenylalanine (V617F), has been described in most polycythaemia vera patients. This mutation increases the phosphorylation activity of JAK2, promotes the spontaneous cellular growth and induces erythrocytosis in a mouse model. Prevalence studies of V617F JAK2 mutation in different myeloproliferative disorders have found this genetic alteration in half of idiopathic myelofibrosis and in one third of essential thrombocythaemia. This finding is a huge progress in the understanding of polycythaemia vera physiopathology, it will be also an useful tool for the diagnosis of myeloproliferative disorders and it opens a new field for the development of targeted therapeutic approaches in these disorders.
Amino Acid Sequence↗
Predominance of granulocytopoiesis in bone marrow grafts in the omenta of mice treated with erythropoietin.
The effects of erythropoietin on the differentiation of murine bone marrow injected into the omenta of x-irradiated mice were investigated. Experimental hosts were injected with 2.5 units of erythropoietin on days 0-7 and sacrificed on day 10. Control hosts were injected with saline or sheep serum. After 10 days the grafts were greater than 95% granulocytic regardless of host treatment. Since these grafts contain multipotent hematopoietic stem cells and the experimental hosts were exposed to large doses of erythropoietin, the results of this experiment indicate that a specialized microenvironment is required for murine erythropoiesis in vivo.
Animals↗
Mechanisms of compensation of hemolytic anemia in a lactate dehydrogenase mouse mutant.
Hemopoiesis was studied in homozygous lactate dehydrogenase (LDH) mutant mice not showing noticeable impairment in viability and fertility but afflicted with a severe hemolytic anemia. In order to investigate the mechanisms of erythropoietic compensation, the numbers of multipotent hemopoietic stem cells (CFU-S), myeloid (GM-CFC), and early and late erythroid progenitors (BFU-E and CFU-E) in femur and spleen were determined, and the total body content of each cell type was computed. While the total CFU-S and GM-CFC numbers showed only slight deviations from normal, the total BFU-E pool was 1.4 and the CFU-E pool 18 times enlarged. No difference in cell cycle status could be detected in these compartments by means of tritiated thymidine (3H-TdR) suicide in vitro. However, splenic erythroblasts of homozygous LDH mutants had a shorter DNA synthesis time and a higher labeling index compared to the wild type mice. It is concluded that the hemolysis is compensated at a lower level of red blood cell count primarily by an increase in the total number of late erythroid progenitors resulting from roughly four extra divisions, and secondarily by an increase in the flux through the recognizable erythroblast compartments, predominantly a space-saving mechanism.
Anemia, Hemolytic↗
Myelodysplastic syndromes: the pediatric point of view.
Myelodysplastic syndromes (MDS) are clonal disorders of the multipotent hematopoietic stem cell characterized by ineffective hematopoiesis and associated with marrow hypercellularity, increased intramedullary cell death and peripheral cytopenias of varying severity. Patients with myelodysplasia have a propensity (20% to 30% of cases) to undergo transformation into acute myeloid leukemia (AML), and a large body of evidence indicates that MDS represent steps in the multiphasic evolution of AML. Progression of the disease is characterized by expansion of the abnormal clone and inhibition of normal hematopoiesis leading to deterioration of the blood cell count and/or development of AML. MDS are relatively unusual in childhood, representing only 3% of pediatric hematological malignancies, although it has been reported that up to 17% of pediatric AML cases may have a previous myelodysplastic phase. The first systematic attempt at morphological classification of MDS was provided by the French-American-British (FAB) group. However, the FAB classification of MDS is only partially applicable in children. Some variants are extremely rare or absent (refractory anemia with ring sideroblasts and chronic myelomonocytic leukemia), and other peculiar pediatric disorders, represented by juvenile chronic myelogenous leukemia (JCML) and the monosomy 7 syndrome, are not included. Moreover, since there is a partial overlap between pediatric MDS and myeloproliferative disorders and the variants occurring in young children have rather specific features, some confusion still surrounds the nosographical definition of childhood MDS, so that none of the proposed classifications are widely accepted and used. Characteristically, some genetic conditions such as Fanconi's anemia, Shwachman's and Down's syndromes predispose to the development of MDS in childhood. The most common variants of childhood MDS are represented by JCML and the monosomy 7 syndrome, both disorders typically occurring in young children. JCML is characterized by a spontaneous growth of granulocyte-macrophage progenitors that show a striking hypersensitivity to granulocyte-macrophage colony-stimulating factor. Clinical presentation resembles that of some myeloproliferative disorders, with massive organomegaly usually not observed in the classically reported variants of MDS. Clinical features of the monosomy 7 syndrome resemble those observed in JCML and a differential diagnosis between these two entities relies upon the higher percentage of fetal hemoglobin, the more pronounced decrease in platelet count and, in some cases, the lack of the peculiar cytogenetic abnormality in the latter. With the number of children being cured of cancer constantly rising, a significant increase in secondary or chemotherapy-related myelodysplasia is being observed, and these disorders represent a formidable challenge for pediatric hematologists due to their poor response to chemotherapy.(ABSTRACT TRUNCATED AT 400 WORDS)
Child↗
Effects of treatment with 5-azacytidine on the in vivo and in vitro hematopoiesis in patients with myelodysplastic syndromes.
The myelodysplastic syndrome (MDS) comprises a group of clonal hematopoietic disorders derived from an abnormality affecting a multipotent hematopoietic stem cell. Despite trials testing numerous agents in patients with MDS, no single drug has yet emerged as the accepted standard of treatment. Observation and supportive care with blood products and antibiotics, when necessary, continue to be the mainstays of therapy. We administered 5-azacytidine, a cell-cycle specific ring analog of the pyrimidine nucleoside cytosine, as a continuous intravenous infusion, 75 mg/m2 per day for 7 days every 4 weeks. Patients had refractory anemia with excess blasts (RAEB) or refractory anemia with excess blasts in transformation (RAEB-T). Responses were seen in 21 (49%) of 43 evaluable patients: five (12%) in complete remission (CR, complete normalization of bone marrow and peripheral blood counts); 11 (25%) in partial remission (PR, > or = 50% restoration of the deficit from normal of all three peripheral blood cell lines, elimination of transfusion requirements, and a decrease in percentage bone marrow blasts by > or = 50% from prestudy values); five (12%) improved (> or = 50% restoration in the deficit from normal of one or more peripheral blood cell lines and/or a > or = 50% decrease in transfusion requirements). A trilineage improvement (CR and PR) occurred in 37% of the patients. The median survival for all patients was 13.3 months and the median duration of remission for those with CR and PR was 14.7 months. Mild to moderate nausea and/or vomiting was the most common side effect (63%). Myelosuppression, either bone marrow hypoplasia or drug related cytopenias requiring a reduction in the dose of azacitidine, occurred in only 33% of the patients. Prior to treatment, bone marrow erythroid progenitor cells were assayed in vitro. Colonies derived from erythroid burst-forming units (BFU-e) were undetectable in one patient and reduced in two. The number of colonies derived from erythroid colony-forming units (CFU-e)) were also reduced in two of the three patients. In the two patients with detectable colony growth prior to treatment, colony number decreased by day 8 of the first cycle, followed by a subsequent increase. Continued treatment with azacitidine led to normalization of the number of CFU-e derived colonies as well as an increase in the number of BFU-e derived colonies. This improvement in erythroid colony number correlated with the spontaneous rise in hemoglobin levels and red cell transfusion independence.(ABSTRACT TRUNCATED AT 400 WORDS)
Aged↗
The genetic program of hematopoietic stem cells.
Blood cell production originates from a rare population of multipotent, self-renewing stem cells. A genome-wide gene expression analysis was performed in order to define regulatory pathways in stem cells as well as their global genetic program. Subtracted complementary DNA libraries from highly purified murine fetal liver stem cells were analyzed with bioinformatic and array hybridization strategies. A large percentage of the several thousand gene products that have been characterized correspond to previously undescribed molecules with properties suggestive of regulatory functions. The complete data, available in a biological process-oriented database, represent the molecular phenotype of the hematopoietic stem cell.
Amino Acid Sequence↗
Noninvasive monitoring and tracking of muscle stem cell transplants.
BACKGROUND: Efficient techniques to noninvasively monitor stem cell transplants will accelerate the development of stem cell therapies. Magnetic resonance (MR) imaging of labeled stem cells is a noninvasive approach that can provide images with high spatial resolution. In this report, we have evaluated the ability of a commercially available, FDA-approved contrast agent to allow for the monitoring of therapeutic stem cell transplants in murine dystrophic muscle. METHODS: Multipotent, muscle-derived stem cells were labeled by incubation with ferumoxide:polycation complexes. Labeled stem cells were evaluated for the ability to differentiate into mature myotubes and be detected by high resolution MR images in vitro and in vivo. RESULTS: Endosomal accumulation of superparamagnetic iron-oxide resulted in changes in the MR contrast T(2) and T(2)*, allowing for three dimensional, noninvasive detection of labeled cells. Relaxivity measurements on cell phantoms indicate that less than eight labeled cells could be detected by MR imaging. Furthermore, therapeutic cellular grafts transplanted into dystrophic muscle could be imaged sequentially and these noninvasive images correlated with histological images obtained by conventional microscopy. Additional studies revealed that MR imaging is applicable to tracking the migration of a small number of labeled cells following arterial delivery. CONCLUSIONS: MR monitoring is a highly sensitive technique that is applicable to muscle stem cell transplantation. We anticipate that it will enhance stem cell investigations by reducing the need for invasive tissue harvests and biopsies.
Animals↗
Gene expression analysis of purified hematopoietic stem cells and committed progenitors.
Lifelong self-renewal is a unique property of somatic stem cells. Recently, several primitive multipotent yet committed (non-self-renewing) hematopoietic progenitor populations were identified in mouse bone marrow. We have characterized the expression of 1200 selected mouse genes using the Atlas cDNA array in highly purified hematopoietic stem cells (HSCs) and 6 closely related progenitor populations: common myeloid progenitors (CMPs), granulocyte-macrophage progenitors (GMPs), megakaryocyte-erythrocyte progenitors (MEPs), common lymphoid progenitors (CLPs), and pro-T and pro-B cells. Cluster analysis revealed that nearly half of all differentially expressed transcripts are associated with HSCs, supporting the notion of an active transcriptional status of HSCs. Genes found enriched in the HSC cluster encompass many developmentally regulated genes, some previously associated with HSC self-renewal. In contrast, genes that are enriched in committed progenitors are mostly associated with hematopoietic differentiation, immune regulation, and metabolism. Thus, the transition from HSCs toward committed progenitors correlates with the down-regulation of a large number of HSC-associated genes and progressive up-regulation of a limited number of lineage-specific genes. These genetic analyses revealed both quantitative and qualitative differences between the transcripts associated with HSCs versus downstream progenitors and produced a list of the candidate genes, potentially involved in HSC self-renewal.
Animals↗
Self-renewal and differentiation of a basic fibroblast growth factor-dependent multipotent hematopoietic cell line derived from embryonic stem cells.
Despite the accumulation of informat on on the origin of hematopoietic stem cells, it is still unclear how these cells are generated in ontogeny. Isolation of cell lines equivalent to early embryonic hematopoietic progenitor cells can be helpful. A multipotent hematopoietic progenitor cell line, A-6, was isolated from H-1 embryonic stem (ES) cells. The self-renewal of A-6 cells was supported by basic-fibroblast growth factor (b-FGF) and their differentiation into definitive erythroid cells, granulocytes and macrophages was induced after co-culture with ST-2 stromal cells. A-6 cells were positive for the surface markers of hematopoietic stem cell, c-kit, CD31, CD34, Flt3/Flk2, PgP-1, and HSA, but were negative for that of the differentiated cells. Reverse transcription-polymerase chain reaction analysis showed that A-6 cells produced mRNA from SCL/tal-1 and GATA-2 genes. Among various cytokines examined, on y stem cell factor (SCF) and Flt3/Flk2 ligand (FL) supported the proliferation of A-6 cells instead of b-FGF. The FL, as well as b-FGF, supported the self-renewal of A-6 cells, whereas SCF induced differentiation into myeloid cells. A-6 cells will be useful for the characterization of hematopoietic progenitor cells derived from ES cells and provide a model system to realize the control mechanisms between self-renewal and different ation of hematopoietic stem cells.
Animals↗
Isolation of renal progenitor cells from adult human kidney.
We describe here isolation and characterization of CD133+ cells derived from normal adult human kidney. These cells lacked the expression of hematopoietic markers and expressed PAX-2, an embryonic renal marker, suggesting their renal origin. Renal tissue-derived CD133+ cells and clones of individual cells were capable of expansion and limited self-renewal and differentiated in vitro into epithelial or endothelial cells. On subcutaneous implantation in SCID mice, the undifferentiated cells formed tubular structures expressing renal epithelial markers. At variance, when differentiated in endothelial cells, these cells formed functional vessels. On intravenous injection in SCID mice with glycerol-induced tubulonecrosis, the in vitro expanded renal-derived CD133+ cells homed into the injured kidney and integrated in tubules. We propose that CD133+ cells from kidney represent a multipotent adult resident stem cell population that may contribute to the repair of renal injury.
AC133 Antigen↗
Endogenous growth factor patterns modulate hemopoietic lineage development.
Hemopoietic growth factors play an important role during stem cell differentiation, and multipotent hemopoietic cells expressing abl oncogenes can cause stem cell diseases in mice. To further elucidate the mechanism of disease development, we examined the initial changes of normal and abl-transduced progenitor cells early in culture, including the endogenous production of growth factors. From 2-3 days methylcellulose cultures, we isolated colonies of early cells and subjected them to RT-PCR analysis. They were found to produce endogenous IL-1 alpha and IL-4. Treatment of these early cells with the antisense oligonucleotides directed against the mRNA of the growth factors did not prevent colony formation. However, the percentage of pure macrophage colonies in cultures containing the antisense IL-1 alpha was increased from 26-60%. This effect was not observed when the antisense oligomers were added 2 days after initiation of culture. We also transduced the progenitor cells with retrovirus vectors carrying either a neor gene (N2) or a v-abl oncogene (A-MuLV or NSabl). After their culture in methylcellulose, we examined the types of colonies developed, growth factor expression by the early cells and their proliferation rate. While the ratio of erythroid to non-erythroid hemopoietic colonies in uninfected culture and N2-infected culture was 0.8, the ratio in A-MuLV-infected culture was 6.0, and in NSabl-infected culture, 3.1. RT-PCR analysis on colonies of abl-transduced cells from 2-3 day cultures indicated a reduction of IL-4 and IL-1 alpha in these cells, and they entered cell division sooner. Our data suggest that hematopoietic lineage development may be a function of the pattern of endogenous as well as exogenous growth factors, and alteration of this pattern either through antisense treatment or v-abl transduction affects the hemopoietic differentiation program.
Animals↗
Transplanted clonal neural stem-like cells respond to remote photic stimulation following incorporation within the suprachiasmatic nucleus.
Multipotent neural stem-like cells (NSCs) obtained from one brain region and transplanted to another region appear to differentiate into neuronal and glial phenotypes indigenous to the implantation site. Whether these donor-derived cells are appropriately integrated remains unanswered. In order to test this possibility, we exploited the suprachiasmatic nucleus (SCN) of the hypothalamus, site of a known circadian clock, as a novel engraftment target. When a clone of NSCs initially derived from neonatal mouse cerebellum was transplanted into mouse embryos, the cells incorporated within the SCN over a narrow gestational window that corresponded to the conclusion of SCN neurogenesis. Immunocytochemical staining suggested that donor-derived cells in the SCN synthesized a peptide neurotransmitter (arginine vasopressin) characteristic of SCN neurons. Donor-derived SCN cells reacted to light pulses by expressing immunoreactive c-Fos protein in a pattern that is appropriate for native SCN cells. This region-specific and physiologically appropriate response to the natural stimulation of a remote sensory input implies that donor-derived and endogenous cells formed true SCN chimeras, suggesting that exogenous NSCs engrafted to ectopic locations can integrate in a meaningful fashion.
Animals↗
In vitro and in vivo arterial differentiation of human multipotent adult progenitor cells.
Many stem cell types have been shown to differentiate into endothelial cells (ECs); however, their specification to arterial or venous endothelium remains unexplored. We tested whether a specific arterial or venous EC fate could be induced in human multipotent adult progenitor cells (hMAPCs) and AC133(+) cells (hAC133(+)). In vitro, in the presence of VEGF(165), hAC133(+) cells only adopted a venous and microvascular EC phenotype, while hMAPCs differentiated into both arterial and venous ECs, possibly because hMAPCs expressed significantly more sonic hedgehog (Shh) and its receptors as well as Notch 1 and 3 receptors and some of their ligands. Accordingly, blocking either of those pathways attenuated in vitro arterial EC differentiation from hMAPCs. Complementarily, stimulating these pathways by addition of Delta-like 4 (Dll-4), a Notch ligand, and Shh to VEGF(165) further boosted arterial differentiation in hMAPCs both in vitro and in an in vivo Matrigel model. These results represent the first demonstration of adult stem cells with the potential to be differentiated into different types of ECs in vitro and in vivo and provide a useful human model to study arteriovenous specification.
AC133 Antigen↗
Differential fate of multipotent and lineage-restricted neural precursors following transplantation into the adult CNS.
Multiple classes of precursor cells have been isolated and characterized from the developing spinal cord including multipotent neuroepithelial (NEP) stem cells and lineage-restricted precursors for neurons (NRPs) and glia (GRPs). We have compared the survival, differentiation and integration of multipotent NEP cells with lineage-restricted NRPs and GRPs using cells isolated from transgenic rats that express the human placental alkaline phosphatase gene. Our results demonstrate that grafted NEP cells survive poorly, with no cells observed 3 days after transplant in the adult hippocampus, striatum and spinal cord, indicating that most CNS regions are not compatible with transplants of multipotent cells derived from fetal CNS. By contrast, at 3 weeks and 5 weeks post-engraftment, lineage-restricted precursors showed selective migration along white-matter tracts and robust survival in all three CNS regions. The grafted precursors expressed the mature neuronal markers NeuN and MAP2, the astrocytic marker GFAP, the oligodendrocytic markers RIP, NG2 and Sox-10, and the synaptic marker synaptophysin. Similar behavior was observed when these precursors were transplanted into the injured spinal cord. Predifferentiated, multipotent NEP cells also survive and integrate, which indicates that lineage-restricted CNS precursors are well suited for transplantation into the adult CNS and provide a promising cellular replacement candidate.
Journal Article↗
Molecular characterization of retinal stem cells and their niches in adult zebrafish.
BACKGROUND: The persistence in adult teleost fish of retinal stem cells that exhibit all of the features of true 'adult stem cells'--self-renewal, multipotency, and the capacity to respond to injury by mitotic activation with the ability to regenerate differentiated tissues--has been known for several decades. However, the specialized cellular and molecular characteristics of these adult retinal stem cells and the microenvironmental niches that support their maintenance in the differentiated retina and regulate their activity during growth and regeneration have not yet been elucidated. RESULTS: Our data show that the zebrafish retina has two kinds of specialized niches that sustain retinal stem cells: 1) a neuroepithelial germinal zone at the interface between neural retina and ciliary epithelium, called the ciliary marginal zone (CMZ), a continuous annulus around the retinal circumference, and 2) the microenvironment around some Müller glia in the differentiated retina. In the uninjured retina, scattered Müller glia (more frequently those in peripheral retina) are associated with clusters of proliferating retinal progenitors that are restricted to the rod photoreceptor lineage, but following injury, the Müller-associated retinal progenitors can function as multipotent retinal stem cells to regenerate other types of retinal neurons. The CMZ has several features in common with the neurogenic niches in the adult mammalian brain, including access to the apical epithelial surface and a close association with blood vessels. Müller glia in the teleost retina have a complex response to local injury that includes some features of reactive gliosis (up-regulation of glial fibrillary acidic protein, GFAP, and re-entry into the cell cycle) together with dedifferentiation and re-acquisition of phenotypic and molecular characteristics of multipotent retinal progenitors in the CMZ (diffuse distribution of N-cadherin, activation of Notch-Delta signaling, and expression of rx1, vsx2/Chx10, and pax6a) along with characteristics associated with radial glia (expression of brain lipid binding protein, BLBP). We also describe a novel specific marker for Müller glia, apoE. CONCLUSION: The stem cell niches that support multi-lineage retinal progenitors in the intact, growing and regenerating teleost retina have properties characteristic of neuroepithelia and neurogenic radial glia. The regenerative capacity of the adult zebrafish retina with its ability to replace lost retinal neurons provides an opportunity to discover the molecular regulators that lead to functional repair of damaged neural tissue.
Aging↗
[Identification of cancer stem cells in the "side population"].
Both normal somatic stem cells and cancer cells are thought to be capable of unlimited proliferation. Paradoxically, however, some cancers seem to contain stem-like cells (cancer stem cells). There is increasing evidence that cancers might contain their own stem cells. Many cancers, like normal organs, seem to be maintained by a hierarchical organization that includes slowly dividing stem cells,rapidly dividing transit amplifying cells (precursor cells), and differentiated cells. Malignant gliomas, for example,often contain both undifferentiated and differentiated cells and sometimes contain cells that express neuronal markers as well as cells that express glial markers, suggesting that they may contain multipotent neural stem cell-like cells. We have shown that some cancer cell lines contain a small side population (SP), which, in many normal tissues, is thought to contain the stem cells of the tissue. We provide evidence that SP cells in the C6 glioma cell line can produce both neurons and glial cells and thus have cancer stem cell property. Taken together with studies on normal neural stem cells, studies on cancer stem cells will help us to understand a link between normal stem cells and cancer stem cells.
Animals↗
Secondary prevention of type 1 diabetes mellitus: stopping immune destruction and promoting beta-cell regeneration.
Type 1 diabetes mellitus results from a cell-mediated autoimmune attack against pancreatic beta-cells. Traditional treatments involve numerous daily insulin dosages/injections and rigorous glucose control. Many efforts toward the identification of beta-cell precursors have been made not only with the aim of understanding the physiology of islet regeneration, but also as an alternative way to produce beta-cells to be used in protocols of islet transplantation. In this review, we summarize the most recent studies related to precursor cells implicated in the regeneration process. These include embryonic stem cells, pancreas-derived multipotent precursors, pancreatic ductal cells, hematopoietic stem cells, mesenchymal stem cells, hepatic oval cells, and mature beta-cells. There is controversial evidence of the potential of these cell sources to regenerate beta-cell mass in diabetic patients. However, clinical trials using embryonic stem cells, umbilical cord blood or adult bone marrow stem cells are under way. The results of various immunosuppressive regimens aiming at blocking autoimmunity against pancreatic beta-cells and promoting beta-cell preservation are also analyzed. Most of these regimens provide transient and partial effect on insulin requirements, but new regimens are beginning to be tested. Our own clinical trial combines a high dose immunosuppression with mobilized peripheral blood hematopoietic stem cell transplantation in early-onset type 1 diabetes mellitus.
Adolescent↗