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Query: UNIPROT:P06889 (Mol)
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The role of hematopoietic stem cells in blood cell development is reasonably understood, whereas the identity and the function of bone marrow stromal cells are much less clear. Using stromal cells in bone marrow cultures of the Dexter type, a favorite medium for the study of hematopoiesis, we show that stromal cells actually represent a unique cell type. Conventional wisdom has held that stromal cells in Dexter cultures comprise a mixture of macrophages, hematopoietic cells, adipocytes, osteoblasts, fibroblasts, muscle cells, and endothelial cells. Our findings demonstrate that Dexter cultures consist of three cell types: macrophages ( approximately 35%), hematopoietic cells ( approximately 5%), and nonhematopoietic cells ( approximately 60%). We have purified the nonhematopoietic cells free of macrophages and hematopoietic cells to produce compelling evidence that they in fact represent a single cell type (multidifferentiated mesenchymal progenitor cell, MPC) which coexpresses genes specific for various mesenchymal cell lineages including adipocytes, osteoblasts, fibroblasts, and muscle cells. We further show that these multi- or pluridifferentiated MPCs are capable of supporting hematopoiesis by demonstrating the expression of several hematopoietic growth factors and extracellular matrix receptors including G-CSF, SCF, VCAM-1, ICAM-1, and ALCAM. Since the MPCs can be easily purified to near homogeneity (95%), they can be of value in enhancing engraftment of hematopoietic stem cells. Also, this new understanding of bone marrow stromal cells as "one cell with many different faces" promises to advance our knowledge of regulatory cellular interactions within bone marrow.
Blood Cells Mol Dis 2000 Jun
PMID:Human bone marrow stromal cell: coexpression of markers specific for multiple mesenchymal cell lineages. 1095 Sep 44

An open-label, non-randomized study evaluated the feasibility and efficacy of filgrastim (recombinant methionyl human granulocyte colony-stimulating factor, r-metHuG-CSF) to prevent mucositis induced by accelerated hyperfractionated radiotherapy (1.6 Gy b.i.d., total dose 67.2 Gy in six weeks with a two-week split) and concomitant chemotherapy (cisplatin, 20 mg/m2/day, days 1-5 by continuous intravenous infusion) in patients with laryngeal carcinoma. Filgrastim 300 microg/day was administered on days 1, 3, and 5 in weeks 2-6 of radiotherapy, after the second fraction. Twenty patients (three stage II, six stage III, and eleven stage IV, according to AJCC) were enrolled in the trial. Oral mucosal toxicity was grade 2 in nine patients (45%), grade 3 in eight (40%), and grade 4 in three (15%). Severe hematological toxicity (WHO criteria) was uncommon. Nineteen patients (95%) completed the treatment in the planned time. Overall survival was 55% at three years. The administration of filgrastim with this regimen was feasible, and it appeared to reduce the severity and duration of mucositis induced by the combined treatment.
Cytokines Cell Mol Ther 2000 Mar
PMID:Hyperfractionated radiotherapy concomitant with cisplatin and granulocyte colony-stimulating factor (filgrastim) for laryngeal carcinoma. 1097 37

Myelodysplastic syndromes (MDS) are clonal disorders in which the proper differentiation of hematopoietic stem cells is impaired. There is no effective treatment for this stem cell disorder at present. In an attempt to find a new strategy that promotes the differentiation of MDS blast cells, we tried retroviral transduction of granulocyte colony-stimulating factor receptor (G-CSFR) into an interleukin-3-dependent MDS cell line, MDS-L, since expression of G-CSFR is known to be essential for the differentiation of myeloid progenitor cells and this expression is impaired in most MDS cells. Ectopic expression of human G-CSFR cDNA in MDS-L cells gave rise to granulocytic differentiation by G-CSF stimulation. G-CSF caused the transformants expressing G-CSFR to display a morphological characteristic of mature granulocytes, upregulated CD11b on the cell surface, and improved NBT reduction activity. These results demonstrate that MDS-L cells ecopically expressing G-CSFR are induced to granulocytic differentiation upon exposure to G-CSF, and shed light on the molecular mechanisms of maturation arrest in MDS cells.
Cytokines Cell Mol Ther 2000 Jun
PMID:Retrovirus-mediated gene transfer of granulocyte colony-stimulating factor receptor (G-CSFR) cDNA into MDS cells and induction of their differentiation by G-CSF. 1110 71

Administration of G-CSF may not always respond in rise of neutrophil counts in different patient population. In order to understand a possible inter-relationship between the G-CSF and GM-CSF induced leukocyte responses and expression levels of receptors for G-CSF (G-CSFr) and GM-CSF (GM-CSFr), the levels of each receptor and CSF were measured in patients with basophilia (8), eosinophilia (14) and bacterial infection showing neutrophilia (12) in comparison with normal healthy adults (12) and children (14). G-CSFr was expressed in neutrophils in the largest amount followed by monocytes, but GM-CSFr was expressed more in monocytes than neutrophils. Lymphocytes and basophils did not express G-CSFr or GM-CSFr. The amount of GM-CSFr in neutrophils was present less in patients with infection than normal control (P = 0.031). The neutrophils expressed more G-CSFr than GM-CSFr. The quantity of G-CSFr in eosinophil showed marked interval change, higher in acute stage. The plasma concentrations of G-CSF in patients with infection were much higher than normal adults or children (117.95 +/- 181.16 pg/ml, P < 0.05). Binding assay with excess amount of CSFs could discriminate the patient who did not show any response to G-CSF or GM-CSF administration. After incubation with excess CSFs, more receptors were blocked in children than in adults (G-CSF P = 0.024, GM-CSF P = 0.006). These results indicate that the amount of CSFr in leukocyte varies in different types of leukocyte, and changes according to the patients' condition even in the same type of leukocyte, and the CSFrs of children bind to CSFs more than those of adults.
Exp Mol Med 2000 Dec 31
PMID:Varying expression levels of colony stimulating factor receptors in disease states and different leukocytes. 1119 Feb 72

The ability to efficiently transduce hematopoietic stem and progenitor cells under serum-free conditions would be desirable for safety and standardization of clinical gene therapy protocols. Using rhesus macaques, we studied the transduction efficiency and engraftment ability of CD34-enriched SCF/G-CSF mobilized progenitor cells (PBSC) transduced with standard amphotropic marking vectors under serum-free and serum-containing conditions. Supernatants were collected from producer cells 16 hours after serum-free medium or medium containing 10% fetal calf serum was added. Vector titers were approximately two- to threefold higher when producer cells were cultured in serum-containing medium. However, retroviral transduction of rhesus CFU-GM was improved using serum-free vector-containing medium. For analysis of engraftment with transduced cells, three macaques had CD34+ peripheral blood stem cells split into two fractions for transduction. One fraction was transduced using serum-free vector-containing medium, and the other fraction was transduced using standard serum-containing medium. The two fractions were re-infused simultaneously following total body irradiation. In all three animals, there was equivalent marking from both vectors for 7-9 months post-transplantation. These data are encouraging regarding the removal of serum-containing medium from clinical hematopoietic cell transduction protocols, given the lack of a detrimental effect on transduction and engraftment with transduced cells.
Mol Ther 2002 Mar
PMID:Retroviral transduction and engraftment ability of primate hematopoietic progenitor and stem cells transduced under serum-free versus serum-containing conditions. 1186 22

Repopulating hematopoietic cell compartments after myeloablative chemotherapy remains a key factor in a successful chemotherapy program. Modified and chimeric cytokines have been developed to help reduce inflammation, fever and hospitalization time for patients. A chimeric cytokine, progenipoietin-1 (ProGP-1), containing the G-CSF and FL receptor agonists binds both the G-CSF receptor and FLT-3. It also stimulates the growth of dendritic cells, which play an important role in immunotherapy. While in vivo effects of ProGP-1 are well described, the mechanisms by which it stimulates growth are not well understood. We have investigated the effects of ProGP-1 on prevention of apoptosis in the human hematopoietic cell line OCI-AML.5. ProGP-1 promoted cellular proliferation better than G-CSF or FL separately but stimulated proliferation similar to their co-addition as demonstrated by growth curves and [3H]-thymidine incorporation. ProGP-1 prevented apoptosis to a greater degree than G-CSF or FL alone as determined by annexin V/propidium iodide binding and TUNEL assays. ProGP-1 promoted maintenance of the mitochondrial membrane potential better than G-CSF or FL alone. In addition, Pro-GP promoted a lower redox potential as higher levels of free radicals were detected after cytokine treatment than in cytokine-deprived cells implying increased respiration. These data indicate that ProGP-1 promotes the proliferation and prevents the apoptosis of human hematopoietic cells better than FL or G-CSF alone, and to a similar extent as their co-addition. Thus, ProGP-1 can be used to repopulate certain hematopoietic cells as a single entity rather than the introduction of two different cytokines.
Int J Mol Med 2002 Oct
PMID:Enhanced ability of the progenipoietin-1 to suppress apoptosis in human hematopoietic cells. 1223 83

Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by a specific deficiency in erythroid progenitors. Since some patients with DBA develop a reduction in thrombocytes and granulocytes with age, we asked whether multipotent hematopoietic progenitors from DBA patients had normal proliferative capacity in liquid expansion cultures. CD34(+) cells derived from DBA patients showed deficient proliferation in liquid culture containing IL-3, IL-6, and SCF. Single CD34(+) CD38(-) cells from DBA patients exhibited deficient proliferation recruitment in a limiting dilution assay containing IL-3, IL-6, SCF, Tpo, FL, and G-CSF or containing IL-3, IL-6, and SCF. Our findings suggest that the underlying hematopoietic defect in DBA may not be limited to the erythroid lineage. Since a fraction of DBA patients have a deficiency in ribosomal protein S19 (RPS19), we constructed lentiviral vectors containing the RPS19 gene for overexpression in hematopoietic progenitors from RPS19-deficient DBA patients. Enforced expression of the RPS19 transgene improved the proliferation of CD34(+) cells from DBA patients with RPS19 mutation. Similarly, enforced expression of RPS19 improved erythroid development of RPS19-deficient hematopoietic progenitors as determined by colony assays and erythroid differentiation cultures. These findings suggest that gene therapy for RPS19-deficient DBA is feasible.
Mol Ther 2003 May
PMID:Proliferation deficiency of multipotent hematopoietic progenitors in ribosomal protein S19 (RPS19)-deficient diamond-Blackfan anemia improves following RPS19 gene transfer. 1271 4

Recently, RD114 (feline endogenous retrovirus envelope protein)-pseudotyped retroviral particles have been shown to transduce human NOD/SCID repopulating cells efficiently. In this study, we compared directly transduction of repopulating cells with RD114-pseudotyped vector to that with standard amphotropic vector in the rhesus macaque model. G-CSF/SCF-mobilized CD34(+) rhesus peripheral blood cells were cultured in the presence of SCF, Flt-3 ligand, and MGDF on Retronectin-coated flasks. To assess directly the ability of the two pseudotypes to transduce primitive cells, both vectors were added simultaneously to the target cells every 24 h, for a total of four exposures in 96 h. The cells were reinfused after the animals received 1000 cGy total body irradiation. At the end of transduction, gene marking efficiency of CFU was higher with amphotropic LNL6 vector (mean 88.4%) vs RD114-G1Na vector (mean 18.5%). After long-term engraftment in three animals, total neo gene marking levels were 4-5% in PBMNCs and 1.5-4% in granulocytes. The RD114-G1Na marking levels were consistently higher in granulocytes than in mononuclear cells, while amphotropic LNL6 marking levels were higher in PBMNCs than in granulocytes. The differential gene marking patterns suggest that RD114 and amphotropic vectors may target distinct progenitor or stem cell populations. There was no clear advantage for RD114-pseudotyped vectors in this predictive preclinical model in terms of overall long-term marking levels; however, optimization of transduction conditions by increasing m.o.i. or inducing the receptor could potentially improve results with this novel vector system.
Mol Ther 2003 Oct
PMID:Direct comparison of RD114-pseudotyped versus amphotropic-pseudotyped retroviral vectors for transduction of rhesus macaque long-term repopulating cells. 1452 34

Modeling human hematopoietic progenitor cell gene therapy in nonhuman primates allows long-term evaluation of safety, maintenance of gene expression, and potential immune response against transgene products. We transplanted autologous G-CSF/SCF-mobilized CD34+ cells transduced with lentiviral vectors expressing EGFP into myeloablated rhesus macaques. To date, more than 4 years posttransplantation, 0.5-8% EGFP expression is maintained in multiple cell lineages. The animals remain healthy with no evidence of hematopoietic abnormalities or malignancies. To assess immune functions, we actively immunized two of our transplanted animals with purified rEGFP proteins and CpG adjuvant and demonstrated stable levels of EGFP+ cell populations maintained for over 29 months despite four active immunizations. We did not detect a persistent anti-EGFP antibody response or anti-EGFP T cell response in these immunized animals. Immune response to an irrelevant antigen was normal. Taken together, our data provide formal support that transplantation of lentivirally transduced CD34+ progenitor cells in myeloablated rhesus macaques induces specific immunological tolerance toward a foreign transgene.
Mol Ther 2003 Dec
PMID:Induction of transgene-specific immunological tolerance in myeloablated nonhuman primates using lentivirally transduced CD34+ progenitor cells. 1466 1

Several reports imply that bone marrow hematopoietic stem cells transdifferentiate into tissue-specific stem cells; however, the possibility of committed tissue-specific stem cells pre-existing in the bone marrow has not been dealt with adequately. We present here an alternative explanation of the so-called phenomenon of stem cell transdifferentiation. First, we postulate that tissue-committed stem/progenitor cells circulate in the peripheral blood and compete for tissue-specific niches. The circulation of these cells plays an important physiological role in maintaining a pool of stem cells in distant parts of the body and the number of these cells in peripheral blood can be increased by the administration of agents similar to those used for mobilization of hematopoietic stem cells. Second, we postulate that bone marrow tissue is a source of various stem-cell chemoattractants and survival factors and provides an environment that chemoattracts tissue-specific circulating stem/progenitor cells. In this context, we envision bone marrow as a "home" or "hide-out place" not only of hematopoietic stem cells but also of already differentiated circulating tissue-specific stem/progenitors. In support of this concept, we report here that mRNA of several early markers for muscle (Myf-5, Myo-D), neural (GFAP, nestin) and liver (CK19, fetoprotein) is detectable in circulating (adherent cell-depleted) peripheral blood mononuclear cells. Moreover, using real-time RT-PCR, we found that the level of expression of these markers increases in the peripheral blood of humans and mice after mobilization by G-CSF. Furthermore, using stromal-derived factor-1 (SDF-1) chemotaxis and real-time RT-PCR analysis, we present evidence that early tissue-specific stem cells reside in normal human and murine bone marrow, express the CXCR4 receptor on their surface and can be highly enriched (in humans and mice) after chemotaxis to SDF-1 gradient. All our experiments were performed on freshly isolated cells to exclude the potential contribution of transdifferentiated hematopoietic stem or mesenchymal cells in the culture. We maintain that any transdifferentiation studies employing populations of bone marrow cells should rule out the possibility that the apparently pure hematopoietic stem cell population could in fact contain pre-existing tissue-specific stem/progenitors.
Blood Cells Mol Dis
PMID:Tissue-specific muscle, neural and liver stem/progenitor cells reside in the bone marrow, respond to an SDF-1 gradient and are mobilized into peripheral blood during stress and tissue injury. 1475 13


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