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Query: UNIPROT:P06889 (Mol)
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In recent years, numerous reports have identified in mouse different sources of myogenic cells distinct from satellite cells that exhibited a variable myogenic potential in vivo. Myogenic stem cells have also been described in humans, although their regenerative potential has rarely been quantified. In this study, we have investigated the myogenic potential of human muscle-derived cells based on the expression of the stem cell marker CD133 as compared to bona fide satellite cells already used in clinical trials. The efficiency of these cells to participate in muscle regeneration and contribute to the renewal of the satellite cell pool, when injected intramuscularly, has been evaluated in the Rag2(-/-) gammaC(-/-) C5(-/-) mouse in which muscle degeneration is induced by cryoinjury. We demonstrate that human muscle-derived CD133+ cells showed a much greater regenerative capacity when compared to human myoblasts. The number of fibers expressing human proteins and the number of human cells in a satellite cell position are all dramatically increased when compared to those observed after injection of human myoblasts. In addition, CD133+/CD34+ cells exhibited a better dispersion in the host muscle when compared to human myoblasts. We propose that muscle-derived CD133+ cells could be an attractive candidate for cellular therapy.
Mol Ther 2009 Oct
PMID:In vivo myogenic potential of human CD133+ muscle-derived stem cells: a quantitative study. 1962 64

The aim of the present study was to develop and validate a good manufacturing practice (GMP) compliant procedure for the preparation of bone marrow (BM) derived CD133(+) cells for cardiovascular repair. Starting from available laboratory protocols to purify CD133(+) cells from human cord blood, we implemented these procedures in a GMP facility and applied quality control conditions defining purity, microbiological safety and vitality of CD133(+) cells. Validation of CD133(+) cells isolation and release process were performed according to a two-step experimental program comprising release quality checking (step 1) as well as 'proofs of principle' of their phenotypic integrity and biological function (step 2). This testing program was accomplished using in vitro culture assays and in vivo testing in an immunosuppressed mouse model of hindlimb ischemia. These criteria and procedures were successfully applied to GMP production of CD133(+) cells from the BM for an ongoing clinical trial of autologous stem cells administration into patients with ischemic cardiomyopathy. Our results show that GMP implementation of currently available protocols for CD133(+) cells selection is feasible and reproducible, and enables the production of cells having a full biological potential according to the most recent quality requirements by European Regulatory Agencies.
J Cell Mol Med 2010 Jun
PMID:GMP-based CD133(+) cells isolation maintains progenitor angiogenic properties and enhances standardization in cardiovascular cell therapy. 1962 97

The reparative properties of bone marrow stromal cells (BMSCs) have been attributed in part to the paracrine action of secreted factors. We isolated typical human BMSCs by plastic adherence and compared them with BMSC sub-populations isolated by magnetic-activated cell sorting against CD133 (CD133-derived BMSCs, CD133BMSCs) or CD271 [p75 low-affinity nerve growth factor receptor (p75LNGFR), p75BMSCs]. Microarray assays of expressed genes, and enzyme-linked immunosorbent assays (ELISAs) of selected growth factors and cytokines secreted under normoxic and hypoxic conditions demonstrated that the three transit-amplifying progenitor cell populations were distinct from one another. CD133BMSC-conditioned medium (CdM) was superior to p75BMSC CdM in protecting neural progenitor cells against cell death during growth factor/nutrient withdrawal. Intracardiac (arterial) administration of concentrated CD133BMSC CdM provided neuroprotection and significantly reduced cortical infarct volumes in mice following cerebral ischemia. In support of the paracrine hypothesis for BMSC action, intra-arterial infusion of CD133BMSC CdM provided significantly greater protection against stroke compared with the effects of CD133BMSC (cell) administration. CdM from CD133BMSCs also provided superior protection against stroke compared with that conferred by CdM from p75BMSCs or typically isolated BMSCs. CD133 identifies a sub-population of nonhematopoietic stem/progenitor cells from adult human bone marrow, and CD133BMSC CdM may provide neuroprotection for patients with stroke.
Mol Ther 2009 Nov
PMID:CD133 identifies a human bone marrow stem/progenitor cell sub-population with a repertoire of secreted factors that protect against stroke. 1969 May 21

The development of synovial sarcoma, a translocationally defined soft tissue tumor of unknown histogenesis with considerable resistance to systemic therapy and a poor prognosis, may involve cancer stem-like cells. Recent studies suggest that synovial sarcoma arises from a primitive progenitor-type cell and have shown that synovial sarcomas contain subpopulations with enhanced tumorigenic potential; however, little is known about cancer stem-like cells in synovial sarcoma. Histologic and gene expression studies have reported features of synovial sarcoma that are reminiscent of neural development, suggesting that a neural cancer stem-like cell marker, such as CD133, may mark cancer stem-like cells in synovial sarcoma, allowing for further characterization. Here, the immunohistochemical expression of CD133 in primary synovial sarcoma tumor tissue and synovial sarcoma cell lines is determined. Subpopulations of CD133 expressing cells are present in all primary synovial sarcomas (5/5) and synovial sarcoma cell lines (3/3) examined. Histologically, CD133 positive cells are dispersed and seem to have dendritic processes. This study demonstrates the presence of CD133 expressing cells in synovial sarcoma for the first time and validates 3 synovial sarcoma cell lines as models for further study of the CD133+ subpopulation. The relationship between CD133 expression and cancer stem-like cells suggests that CD133 expressing synovial sarcoma cells may represent cancer stem-like cells in synovial sarcoma, which has significant implications for understanding the pathogenesis of this tumor and developing effective therapies.
Appl Immunohistochem Mol Morphol 2010 Mar
PMID:Expression of CD133 in synovial sarcoma. 1975 21

Hedgehog signaling is aberrantly activated in glioma, medulloblastoma, basal cell carcinoma, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, breast cancer, and other tumors. Hedgehog signals activate GLI family members via Smoothened. RTK signaling potentiates GLI activity through PI3K-AKT-mediated GSK3 inactivation or RAS-STIL1-mediated SUFU inactivation, while GPCR signaling to Gs represses GLI activity through adenylate cyclase-mediated PKA activation. GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin. Hedgehog signals are fine-tuned based on positive feedback loop via GLI1 and negative feedback loop via PTCH1, PTCH2, and HHIP1. Excessive positive feedback or collapsed negative feedback of Hedgehog signaling due to epigenetic or genetic alterations leads to carcinogenesis. Hedgehog signals induce cellular proliferation through upregulation of N-Myc, Cyclin D/E, and FOXM1. Hedgehog signals directly upregulate JAG2, indirectly upregulate mesenchymal BMP4 via FOXF1 or FOXL1, and also upregulate WNT2B and WNT5A. Hedgehog signals induce stem cell markers BMI1, LGR5, CD44 and CD133 based on cross-talk with WNT and/or other signals. Hedgehog signals upregulate BCL2 and CFLAR to promote cellular survival, SNAI1 (Snail), SNAI2 (Slug), ZEB1, ZEB2 (SIP1), TWIST2, and FOXC2 to promote epithelial-to-mesenchymal transition, and PTHLH (PTHrP) to promote osteolytic bone metastasis. KAAD-cyclopamine, Mu-SSKYQ-cyclopamine, IPI-269609, SANT1, SANT2, CUR61414 and HhAntag are small-molecule inhibitors targeted to Smoothened, GANT58, GANT61 to GLI1 and GLI2, and Robot-nikinin to SHH. Hedgehog signaling inhibitors should be used in combination with RTK inhibitors, GPCR modulators, and/or irradiation for cancer therapy.
Curr Mol Med 2009 Sep
PMID:Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation. 1986 Jun 66

The insulin-like growth factor (IGF) system is involved in cell migration, which plays an important role in cancer progression. It has been shown that cancer progression correlates with the level of circulating human hematopoietic stem and progenitor cells (HSPCs) expressing CD34 and/or CD133. However, it is unknown whether factors released from cancer cells, including soluble compounds of the IGF system, recruit these HSPCs via enhancing their migration. Our study showed the expression of type I IGF receptor (IGF-IR) in human HSPCs expressing CD34 and/or CD133. In an indirect co-culture model, soluble factors released from human lung epithelial cancer cells (H358, H322) increased the migration of CD34-/CD133+ cells towards cancer cells, whereas migration of CD34+/CD133+ or CD34+/CD133- cells remained unchanged. The lung epithelial cancer cell lines H358 and H322, exhibited a high expression of IGFBP-2, -4 and -6 but not IGF-I and IGFBP-3. Subsequent analyses with those soluble compounds of the IGF system revealed a dose-dependent stimulating effect of the IGFBP-2 and -4 on the migration of CD34-/CD133+ cells. In contrast, IGF-I and IGFBP-3 and -6 did not influence the migration of CD34-/CD133+ cells. Because IGFBPs are involved in cell migration via IGF-dependent and -independent mechanisms, our study indicates that IGFBP-2 and -4, which are expressed in lung epithelial cancer cells, enhance the migration of CD34-/CD133+ HSPCs independent of IGF-I.
Int J Mol Med 2010 Jan
PMID:Insulin-like growth factor binding proteins-2 and -4 enhance the migration of human CD34-/CD133+ hematopoietic stem and progenitor cells. 1995 6

The transcription factor OCT4 plays a crucial role in the earliest differentiation of the mammalian embryo and in self-renewal of embryonic stem cells. However, it remains controversial whether this gene is also expressed in somatic tissues. Here, we use a combination of RT-PCR on whole and microdissected tissues, in situ hybridization, immunohistochemistry and western blotting to show that OCT4 and SOX2 together with downstream targets, UTF1 and REX1/ZFP42, are expressed in the human male urogenital tract. We further support these results by the analysis of DNA methylation of a region in the OCT4 promoter. In culture, human primary epididymal cells formed spheres that continued to express the investigated genes for at least 20 days. Transcriptomic analysis of cultured cells showed up-regulation of CD29, CD44 and CD133 that are normally associated with sphere-forming cancer stem cells. Furthermore, stimulation with retinoic acid resulted in down-regulation of OCT4 expression, however, without multilineage differentiation. Our results show that OCT4 and associated genes are expressed in somatic epithelial cells from the urogenital tract and that these cells can form spheres, a general marker of stem cell behaviour.
Mol Hum Reprod 2010 Nov
PMID:OCT4 and downstream factors are expressed in human somatic urogenital epithelia and in culture of epididymal spheres. 2012 3

The present study has been undertaken to establish the therapeutic benefit of cotargeting epidermal growth factor receptor (EGFR) and sonic hedgehog pathways by using gefitinib and cyclopamine, respectively, for improving the efficacy of the current chemotherapeutic drug docetaxel to counteract the prostate cancer progression from locally invasive to metastatic and recurrent disease stages. The data from immuofluorescence analyses revealed that EGFR/Tyr(1173)-pEGFR, sonic hedgehog ligand, smoothened coreceptor, and GLI-1 were colocalized with the CD133(+) stem cell-like marker in a small subpopulation of prostate cancer cells. These signaling molecules were also present in the bulk tumor mass of CD133(-) prostate cancer cells with a luminal phenotype detected in patient's adenocarcinoma tissues. Importantly, the results revealed that the CD133(+)/CD44(high)/AR(-/low) side population (SP) cell fraction endowed with a high self-renewal potential isolated from tumorigenic and invasive WPE1-NB26 cells by the Hoechst dye technique was insensitive to the current chemotherapeutic drug, docetaxel. In contrast, the docetaxel treatment induced significant antiproliferative and apoptotic effects on the CD133(-)/CD44(low)/AR(+) non-SP cell fraction isolated from the WPE1-NB26 cell line. Of therapeutic interest, the results have also indicated that combined docetaxel, gefitinib, and cyclopamine induced greater antiproliferative and apoptotic effects on SP and non-SP cell fractions isolated from WPE1-NB26 cells than individual drugs or two-drug combinations. Altogether, these observations suggest that EGFR and sonic hedgehog cascades may represent the potential therapeutic targets of great clinical interest to eradicate the total prostate cancer cell mass and improve the current docetaxel-based therapies against locally advanced and invasive prostate cancers, and thereby prevent metastases and disease relapse.
Mol Cancer Ther 2010 Mar
PMID:Cytotoxic effects induced by docetaxel, gefitinib, and cyclopamine on side population and nonside population cell fractions from human invasive prostate cancer cells. 2017 63

During development, renal stem cells reside in the nephrogenic blastema. Wilms' tumour (WT), a common childhood malignancy, is suggested to arise from the nephrogenic blastema that undergoes partial differentiation and as such is an attractive model to study renal stem cells leading to cancer initiation and maintenance. Previously we have made use of blastema-enriched WT stem-like xenografts propagated in vivo to define a 'WT-stem' signature set, which includes cell surface markers convenient for cell isolation (frizzled homolog 2 [Drosophila] - FZD2, FZD7, G-protein coupled receptor 39, activin receptor type 2B, neural cell adhesion molecule - NCAM). We show by fluorescenceactivated cell sorting analysis of sphere-forming heterogeneous primary WT cultures that most of these markers and other stem cell surface antigens (haematopoietic, CD133, CD34, c-Kit; mesenchymal, CD105, CD90, CD44; cancer, CD133, MDR1; hESC, CD24 and putative renal, cadherin 11), are expressed in WT cell sub-populations in varying levels. Of all markers, NCAM, CD133 and FZD7 were constantly detected in low-to-moderate portions likely to contain the stem cell fraction. Sorting according to FZD7 resulted in extensive cell death, while sorted NCAM and CD133 cell fractions were subjected to clonogenicity assays and quantitative RT-PCR analysis, exclusively demonstrating the NCAM fraction as highly clonogenic, overexpressing the WT 'stemness' genes and topoisomerase2A (TOP2A), a bad prognostic marker for WT. Moreover, treatment of WT cells with the topoisomerase inhibitors, Etoposide and Irinotecan resulted in down-regulation of TOP2A along with NCAM and WT1. Thus, we suggest NCAM as a marker for the WT progenitor cell population. These findings provide novel insights into the cellular hierarchy of WT, having possible implications for future therapeutic options.
J Cell Mol Med 2009 Aug
PMID:Developmental tumourigenesis: NCAM as a putative marker for the malignant renal stem/progenitor cell population. 2018 2

The majority of tumors, including melanoma, are phenotypically heterogeneous in that they contain various cell populations with differential expression of cell surface antigens such as CD133/Prominin-1. We have used fluorescence-activated cell sorting (FACS) technology to purify CD133(+) and CD133(-) cellular subsets from mouse melanoma models for high-quality total RNA practical for downstream applications such as expression profiling. Implementation of this strategy can lead to higher resolution of transcripts that are potentially important for the survival and functionality of one cancer cell population relative to another. Suboptimal extraction of RNA after FACS is common and can ultimately result in misinterpretations that impede the effective design of novel therapies. Here, we describe a number of methods that have been amenable to the successful isolation of high-quality total RNA after FACS of CD133(+) and CD133(-) mouse melanoma cell fractions.
Methods Mol Biol 2010
PMID:Isolation of total RNA from transgenic mouse melanoma subsets using fluorescence-activated cell sorting. 2021 69


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