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At least 469 records · Page 26Linked to original sources
PubMed1999

Pluripotent stem cells of the mouse as a potential in vitro model for mammalian germ cells. Sister chromatid exchanges induced by MMC and ENU in undifferentiated cell lines compared to differentiated cell lines.

We tried to develop an in-vitro test system which could serve as a model for mammalian germ cells in vivo. Two pluripotent cell types were used, because they express some germ cell specific immunological and biochemical markers: (1) Embryonal carcinoma cells (ECC) of the line P19 had been isolated from a teratocarcinoma of murine primordial germ cells (PGC). (2) Embryonal stem cells (ESC) are obtained from the inner cell mass of mouse blastocysts. Sister chromatid exchanges (SCE) induced by mitomycin C and ethylnitrosourea (ENU) were analysed in the two undifferentiated cell lines, ECC and ESC, to detect differences in their sensitivity compared with differentiated cell lines of the mouse. Neither of the model cell lines have shown a greater sensibility after exposure to MMC and ENU. In contrary, the carcinoma cell line was able to tolerate higher concentrations of these genotoxicants. Therefore, SCE analysis in the ECC and ESC lines used does not provide a suitable model for genotoxicity testing on mammalian germ cells.

Animals↗
PubMed2003

Murine embryonic stem cell in vitro differentiation: applications to the study of vascular development.

The present review summarizes knowledge accumulated during the last decade concerning in vitro endothelial differentiation from embryonic stem (ES) cells. There is now growing evidence that ES cells may provide a powerful model system to determine the cellular and molecular mechanisms of vascular development. ES cells differentiate into the endothelial lineage by successive maturation steps recapitulating in vivo events observed in the embryo. Further maturation of ES-derived embryoid bodies either in three dimensional gels or in confrontation cultures with tumor spheroids can also provide a model of physiological or tumoral angiogenesis. The data obtained from experimental in vitro differentiation of genetically modified mouse ES cells highlight the potential and the complementarity of this model system to in vivo gene knock out studies. We also consider and discuss some of the potential applications of ES cell technology in vascular biology for future directions in basic research and medicine, by manipulation of differentiation and the generation of cell populations for analysis and transplantation for therapeutic use.

Animals↗
PubMed2001

In vitro autoreactivity against skin in rheumatoid arthritis: are peripheral blood mononuclear cells of patients with rheumatoid arthritis able to lyze autologous keratinocytes?

An in vitro skin explant model was originally developed to predict the occurrence and severity of acute graft-versus-host disease in allogeneic hematopoietic stem cell transplants. In previous studies we reported that peripheral blood mononuclear cells of patients with rheumatoid arthritis were able to induce graft-versus-host-like histopathological changes when co-cultured in vitro with autologous skin explants. The aim of the present study was to verify if observed skin damage was really of autoimmune origin. Using a 51chromium release cytotoxic assay we found that peripheral blood mononuclear cells of patients lyzed autologous keratinocytes (n=5 patients with rheumatoid arthritis) but not autologous lymphoblasts (n=4 with rheumatoid arthritis, n=8 patients with juvenile idiopathic arthritis). No specific lysis of keratinocytes or lymphoblasts was observed in healthy controls (n=15). We hypothesize that autologous peripheral blood mononuclear cells might recognize similar autoantigen(s) expressed on epidermal cells, which gives rise to an autoimmune response in the synovium.

Adolescent↗
PubMed2006

Diverse epigenetic profile of novel human embryonic stem cell lines.

Human embryonic stem cells (hESCs) are a promising model for studying mechanisms of regulation of early development and differentiation. OCT4, NANOG, OCT4-related genes and some others were recently described to be important in pluripotency maintenance. Lesser is known about molecular mechanisms involved in their regulation. Apart from genetic regulation of gene expression epigenetic events, particularly methylation, play an important role in early development. Using RT-PCR we studied the expression of pluripotency-related genes OCT4, NANOG, DPPA3 and DPPA5 during hESCs differentiation to embryoid bodies. Analysis of methylation profiles of promoter or putative regulatory regions of the indicated genes demonstrated that expression of the pluripotency-maintaining genes correlated with their methylation status, whereas methylation of DPPA3 and DPPA5 varied between cell lines. We propose that DNA methylation underlies the developmental stage-specific mechanisms of pluripotency-related genes expression and reactivation and may have an impact on differentiation potential of hESC lines.

5' Flanking Region↗
PubMed2000

Embryonic stem cell-derived chondrogenic differentiation in vitro: activation by BMP-2 and BMP-4.

Differentiation of mouse embryonic stem (ES) cells via embryoid bodies was established as a suitable model to study development in vitro. Here, we show that differentiation of ES cells in vitro into chondrocytes can be modulated by members of the transforming growth factor-beta family (TGF-beta(1), BMP-2 and -4). ES cell differentiation into chondrocytes was characterized by the appearance of Alcian blue-stained areas and the expression of cartilage-associated genes and proteins. Different stages of cartilage differentiation could be distinguished according to the expression pattern of the transcription factor scleraxis, and the cartilage matrix protein collagen II. The number of Alcian-blue-stained areas decreased slightly after application of TGF-beta(1), whereas BMP-2 or -4 induced chondrogenic differentiation. The inducing effect of BMP-2 was found to be dependent on the time of application, consistent with its role to recruit precursor cells to the chondrogenic fate.

Aggrecans↗
PubMed2005

Bovine mammary progenitor cells: current concepts and future directions.

Although cell number is positively correlated with milk production, much remains to be learned about the bovine mammary stem cell and progenitor cells. Bovine mammary development is driven by many of the same classic mammogenic hormones studied in murine models, yet histologic features of bovine mammary development differ from that of rodent models. Most notably, terminal end buds, as they have been described for murine models, do not exist in the bovine mammary gland. However, among the most important common features of mammary development in disparate species is the involvement of histologically distinct, lightly staining epithelial cells as putative stem and progenitor cells. Although stem cell research has often focused on mammary development, mammary stem cells seemingly provide the basis for mammary growth and cell turnover in the mature animal. These cells provide an obvious focus for research aimed at increasing the efficiency of milk production. This review addresses recent findings concerning the histology and molecular physiology of putative bovine mammary stem and progenitor cell populations, areas where more study is critically needed, and areas where studies of bovine mammary physiology may present a unique opportunity to better understand mammary physiology in many species.

Animals↗
PubMed2001

Regulation of hemangioblast development.

The in vitro differentiation of embryonic stem (ES) cells provides a powerful approach for studying the earliest events involved in the commitment of the hematopoietic and endothelial lineages. Using this model system, we have identified a precursor with the potential to generate both primitive and definitive hematopoietic cells as well as cells with endothelial characteristics. The developmental potential of this precursor suggests that it represents the in vitro equivalent of the hemangioblast, a common stem cell for both lineages. ES cells deficient for the transcription factor scl/tal-1 are unable to generate hemangioblasts, while those deficient for Runx1 generate reduced numbers of these precursors. These findings indicate that both genes play pivotal roles at the earliest stages of hematopoietic and endothelial development. In addition, they highlight the strength of this model system in studying the function of genes in embryonic development.

Animals↗
PubMed1988

Canine model for gene therapy: inefficient gene expression in dogs reconstituted with autologous marrow infected with retroviral vectors.

Successful retroviral gene transfer into murine hematopoietic stem cells indicates the potential for somatic gene therapy in the treatment of certain human hereditary diseases. We developed a canine model to test the applicability of these techniques to a preclinical model of human marrow transplantation. Previously we reported that canine CFU-GM could be infected with retroviral vectors carrying either the gene for a mutant dihydrofolate reductase (DHFR) or neomycin phosphotransferase (NEO). This study reports six lethally irradiated dogs transplanted with autologous marrow cocultivated with retroviral vector-producing cells. This procedure conferred drug resistance to 3% to 13% of the CFU-GM. Three dogs infected with either the NEO or DHFR virus engrafted, but we detected no drug-resistant CFU-GM. Three dogs were given marrow infected with a DHFR virus and received methotrexate (MTX) as in vivo selection; all three had evidence of engraftment. In the surviving dog, we detected 0.03% to 0.1% MTX-resistant CFU-GM at 3 to 5 weeks posttransplant during in vivo selection. These results indicate that we can reconstitute lethally irradiated dogs with autologous marrow exposed to retroviral vectors and suggest that gene transfer into hematopoietic cells is feasible on a large scale. However, the low-level transient gene expression indicates that considerable obstacles remain before human gene therapy can be considered.

Animals↗
PubMed2006

Juvenile syndecan-1 null mice are protected from carcinogen-induced tumor development.

We previously showed that mice with a null mutation in syndecan-1 (Sdc1; CD138) were resistant to Wnt1-induced mammary tumor initiation. The absence of Sdc1 inhibited the increase in the mammary stem cell fraction that is characteristic of preneoplasia in this model. As the tumor precursor cells are recruited from the stem/progenitor cell compartment, tumor development was also inhibited (Liu et al., 2004; PNAS 101, 4158). Although Sdc1-/- mice are grossly normal, they are systemically smaller, suggesting that developmental abnormalities may extend further than their mammary glands. We have therefore evaluated the multi-organ response of Sdc1-/- mice to carcinogen-induced tumor development (7,12-dimethylbenz[a]anthracene, DMBA), and find these mice to be resistant to tumorigenesis in all the predominant carcinogen-susceptible lineages. Thus, Sdc1-/- mice administered DMBA during juvenile development are resistant not only to epithelial tumors, including liver (60-80%) and lung tumors (C57BL6 mice, 60-80%), but also to lymphoma (over 70%, depending upon strain and carcinogen dose). We demonstrate that CD138 is expressed (heterogeneously) in the hematopoietic stem cell fraction (and not only in pre-B and plasma cells), and that tumors arise in both myeloid and lymphoid lineages. Furthermore, carcinogen-induced mammary tumors are bilineal, implying a bipotent precursor cell. Both observations imply that the DMBA-induced tumor precursor cells are drawn from the stem/progenitor fraction, and we suggest that pathogenic activation of these cells could be abnormal in Sdc1-/- mice.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2006

Development and differentiation of neural rosettes derived from human embryonic stem cells.

Neurons and glia are important targets of human embryonic stem cell research, promising a renewable source of these differentiated cells for biomedical research and regenerative medicine. Neurons and glia are derived in vivo from the neuroepithelium of the neural tube. Concomitant to development along the anterior to posterior axis, gradients of morphogens across the dorsal and ventral axis of the neural tube establish positional codes that generate distinct progenitor domains and ultimately specify subtype identity. The neural rosette is the developmental signature of neuroprogenitors in cultures of differentiating embryonic stem cells; rosettes are radial arrangements of columnar cells that express many of the proteins expressed in neuroepithelial cells in the neural tube. In addition to similar morphology, neuroprogenitors within neural rosettes differentiate into the main classes of progeny of neuroepithelial cells in vivo: neurons, oligodendrocytes, and astrocytes. Despite these similarities, important differences exist and the extent to which neural rosettes can model neurogenesis in vivo is not yet clear. Here, the authors review the recent studies on the development and differentiation of neural rosettes from human embryonic stem cells. The authors focus on efforts to generate motor neurons and oligodendrocytes in vitro as representative of the challenges to obtaining the progeny of a single progenitor domain with in vitro methods. Opportunities for further progress are discussed.

Embryonic Stem Cells↗
PubMed2001

IL-7 enhances the responsiveness of human T cells that develop in the bone marrow of athymic mice.

The beige/nude/xid/human (bnx/hu) model of human hematopoiesis provides a unique opportunity to study extrathymic human T lymphocyte development in an in vivo system. Purified human hematopoietic stem cells develop into mature T lymphocytes and immature progenitors in the bone marrow of athymic bnx mice. The human T cells are all TCR alpha beta(+) and display a restricted TCRV beta repertoire. In the current studies, we examined the effects of systemic human IL-7 (huIL-7) administration on the phenotype and the activation status of the bnx/hu T cells. In the majority of the mice that did not have huIL-7 administration, a higher frequency of human CD3(+)/CD8(+) than CD3(+)/CD4(+) T cells developed in the bone marrow. This phenomenon is also frequently observed in human bone marrow transplant recipients. Extremely low levels of IL-2 were expressed by human CD3(+) cells isolated from these mice, in response to PMA plus ionomycin and to CD3 and CD28 cross-linking. IL-4 was not expressed by cells exposed to either stimulus, demonstrating a profound inability of the bnx/hu T cells to produce this cytokine. Systemic production of huIL-7 from engineered stromal cells transplanted into the mice increased the human CD4 to CD8 ratios, and increased the ratio of memory to naive CD4(+) and CD8(+) T cells. The human CD3(+) cells recovered from mice that had systemic huIL-7 and equivalent numbers of CD3(+)/CD4(+) and CD3(+)/CD8(+) cells in the marrow were still unable to produce IL-4 in response to any condition tested, but were capable of normal levels of IL-2 production following stimulation.

Adjuvants, Immunologic↗
PubMed2005

Stem cells in mammary development and carcinogenesis: implications for prevention and treatment.

Recently, substantial progress has been made in the identification and characterization of stem and progenitor cells in the mouse and human mammary gland. Furthermore, there is increasing evidence that a variety of neoplasms, including breast cancer, may result from transformation of normal stem and progenitor cells. Consistent with this model of carcinogenesis, a breast cancer stem cell population, with the phenotype CD24-CD44+ lineage, was recently identified utilizing flow-cytometry based cell sorting and nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice xenografts. As few as 200 cells of this cancer stem cell population were capable of generating tumors in animals, whereas the bulk of the tumor population was tumorigenic only when implanted in high numbers. Like their normal counterparts, the cancer stem cells have the ability to self-renew, driving tumorigenicity and possibly recurrence and metastasis, and have the ability to differentiate, generating the heterogeneity of the tumors. This stem cell model of carcinogenesis has important implications for understanding the basic biology of breast cancer, as well as other cancers. Furthermore, the concept of cancer as a disease of stem and progenitor cells has profound implications for the development of new strategies for cancer prevention and therapy.

Animals↗
PubMed1996

Inherited and acquired risk factors in colonic neoplasia and modulation by chemopreventive interventions.

The progressively abnormal development of epithelial cells prior to tumor development leads to widely differing chemopreventive approaches. The diversity of these approaches has resulted in different assays to measure the activities of the agents. To apply these assays to preclinical studies, we have developed rodent models in which different stages of evolution of colonic neoplasia are expressed. In one model mice carrying a truncated Apc allele with a nonsense mutation in exon 15 have been generated by gene targeting and embryonic stem cell technology (Apc 1638 mice). These mice develop multiple gastrointestinal lesions including adenomas and carcinomas, focal areas of high grade dysplasia (FAD) and polypoid hyperplasias with FADS. The incidence of inherited colonic neoplasms has now been modulated by a chemopreventive regimen. Colonic lesions significantly increased in Apc 1638 mice on a Western-style diet, compared to Apc 1638 mice on AIN-76A diet which has lower fat content and higher calcium and vitamin D. These studies have also been carried out in normal mice, and have demonstrated without any chemical carcinogen that a Western-style diet induced colonic tumorigenesis. Modulation of cell proliferation has also been induced by Western-style diets in other organs including mammary gland, pancreas and prostate. These findings are leading to the development of new preclinical models for evaluating the efficacy of many classes of chemopreventive agents.

Animals↗
PubMedDate not supplied

Human embryonic stem cells: origin, properties and applications.

Human embryonic stem cells originate from the human preimplantation embryo. The derivation of the first human embryonic stem cells was reported in 1998. Since then we have learnt a great deal about how to isolate and culture these cells. Additionally, their stem cell phenotype and differentiation competence have been determined. Although it is expected that many basic biological properties, such as self-renewal and cell specification, are evolutionary conserved, at least from the mouse, we lack significant knowledge about the molecular events that regulate the unique stem cell features of human embryonic stem cells. The pluripotent nature of human embryonic stem cells has attracted great interest in using them as a source of cells and tissues in cell therapy. Recent progress in human somatic cell nuclear transfer suggests that there may be a solution to the immunotolerance problems associated with the use of human embryonic stem cells in cell-replacement therapy. Thus, human embryonic stem cells supply the research community with unique research tools to study basic biological processes in human cells, model human genetic diseases and develop new cell-replacement therapies.

Animals↗
PubMed1999

Transgenic models in the study of reproduction.

The development of techniques to manipulate genes within mouse embryonic stem (ES) cells has allowed investigators to study the functions of many genes in vivo. We have used these techniques to functionally mutate genes to study how the loss of the gene affects development, oncogenesis, and reproduction. Genes affecting development include members of the transforming growth factor-beta (TGF-beta) superfamily and their signaling pathway. We have shown that mutations in this complicated signaling network affect a wide range of embryonic developmental processes including craniofacial morphogenesis, dentition and muscle development. One specific member of TGF-beta family, inhibin alpha, has been identified as a novel tumor suppressor in the testes, ovaries, and adrenal glands. Another focus of research in the laboratory is the analysis of roles of proteins in the hypothalamic-pituitary-gonadal axis and the affect of disrupting this pathway on reproductive function. We have demonstrated that several genes expressed in the pituitary and gonads are required for folliculogenesis leading to female infertility and in two cases are important for Sertoli cell proliferation in males. The studies using ES cell technology has enabled us to dissect two complex networks in animal models.

Animals↗
PubMed1997

Consideration of tissue response in the application of the two-mutation model to radiation carcinogenesis.

The Moolgavkar-Venzon-Knudson (MVK) two-mutation model of carcinogenesis is an analytical model that predicts the variation of cancer yield-rate with time, and with dose of a carcinogen. The model is biologically based, and assumes that a specific mutation in a stem-cell will increase its rate of proliferation compared with that of unmutated cells, so that a clone of pre-malignant cells develops; a second specific mutation in any one of these will make it malignant, and a cancer will start to grow. The model has been used in recent years to analyse a number of sets of epidemiological data on carcinogenesis. The purpose of this paper is to point to a problem in the use of this model for radiation-induced carcinogenesis, namely that ionizing radiation causes reproductive death of stem cells, which leads to regenerative division and hence a change in the number of stem-cells at risk. The possible effects of such changes on the predictions of the model are discussed. At low dose-rates of continuous or chronic irradiation and at low doses of acute irradiation, it is expected that pre-malignant cells will be killed along with the unmutated cells, and that the regenerative division of the surviving pre-malignant cells will restore the numbers of both stem cells and pre-malignant cells to what they would have been in the absence of cell killing; hence, no net effect of the tissue regeneration is expected. At high dose-rates, the initial delay in regenerative division and subsequent faster proliferation are expected to lead to an initial reduction in tumour yield-rate with time (compared with that predicted by the MVK model) followed by a faster increase. For acute irradiation, in the particular case of beta-particle irradiation of the skin, at high doses where there are practically no surviving cells in the irradiated area, repopulation by unirradiated cells from the margin is predicted to lead to a decrease in tumour yield-rate with dose. The predictions have been compared with published data on the induction of osteosarcoma in mouse by repeated injection of 89Sr, the induction of skin tumours in rat by acute and chronic irradiation with electrons, and the induction of skin tumours in mouse by acute irradiation with beta-particles. At low doses and dose-rates the basic MVK model fitted the data well. At higher doses and dose-rates the expected effects of tissue regeneration were observed qualitatively, although there were some discrepancies in detail; these are discussed.

Animals↗
PubMed2002

Enzymatically labeled chromosomal probes for in situ identification of human cells in xenogeneic transplant models.

Analysis of the viability, differentiation, clonogenicity and function of human stem/progenitor cells requires suitable xenograft models. However, the identification of transplanted cells has been generally difficult. Fluorescence in situ hybridization is a tedious method for analyzing tissues, and localization of transplanted cells with X or Y chromosome probes is limited by the sparse signals produced. Therefore, we examined the possibility of generating either pan-nuclear signals with a total human DNA probe or multiple nuclear signals with a pan-centromeric human DNA probe. The probes were labeled with digoxigenin to make reaction products visible by light microscopy and to allow the use of immunohistochemistry methods incorporating various color schemes to demonstrate specific properties of transplanted cells. The ability to localize all types of nucleated human cells with such probes will facilitate studies of stem cell biology and cell and gene therapy, as well as the development of new animal models.

Animals↗
PubMed1995

A stochastic model for multistage tumorigenesis in developing and adult mice.

A stochastic process model for one-, two-, and three-stage malignant transformation has been developed for embryonic and adult mice. The model has been used to study the influence of mutation rate, number of stages required for transformation, and number of stem cells at risk on the kinetics of spontaneous appearance of malignant tumors. As expected, tumors appeared earlier with fewer required mutational stages, higher mutation rate, and greater number of stem cells at risk. However, a notable observation was that tumor latency was more strongly influenced by number of stages and by stem cell number at lower mutation rates than at higher rates. This implies that tumor latency may be a less useful observation when the spontaneous mutation rate is high. In the future, the model will be applied to analysis of tumorigenesis experiments in transgenic mice with p53 genetic abnormalities, subjected to irradiation or chemical tumorigenesis at different stages of development.

Animals↗