Showing papers on "Cellular differentiation published in 2007"
TL;DR: Recent advances in understanding how epigenetic alterations participate in the earliest stages of neoplasia, including stem/precursor cell contributions, are reviewed and the growing implications of these advances for strategies to control cancer are discussed.
4,269 citations
TL;DR: It is concluded that colorectal cancer is created and propagated by a small number of undifferentiated tumorigenic CD133+ cells, which should therefore be the target of future therapies.
Abstract: Colon carcinoma is the second most common cause of death from cancer. The isolation and characterization of tumorigenic colon cancer cells may help to devise novel diagnostic and therapeutic procedures. Although there is increasing evidence that a rare population of undifferentiated cells is responsible for tumour formation and maintenance, this has not been explored for colorectal cancer. Here, we show that tumorigenic cells in colon cancer are included in the high-density CD133+ population, which accounts for about 2.5% of the tumour cells. Subcutaneous injection of colon cancer CD133+ cells readily reproduced the original tumour in immunodeficient mice, whereas CD133- cells did not form tumours. Such tumours were serially transplanted for several generations, in each of which we observed progressively faster tumour growth without significant phenotypic alterations. Unlike CD133- cells, CD133+ colon cancer cells grew exponentially for more than one year in vitro as undifferentiated tumour spheres in serum-free medium, maintaining the ability to engraft and reproduce the same morphological and antigenic pattern of the original tumour. We conclude that colorectal cancer is created and propagated by a small number of undifferentiated tumorigenic CD133+ cells, which should therefore be the target of future therapies.
3,945 citations
TL;DR: It is shown that normal and cancer human mammary epithelial cells with increased aldehyde dehydrogenase activity (ALDH) have stem/progenitor properties and these cells contain the subpopulation of normal breast epithelium with the broadest lineage differentiation potential and greatest growth capacity in a xenotransplant model.
3,766 citations
TL;DR: The use of nanoscale disorder is demonstrated to stimulate human mesenchymal stem cells (MSCs) to produce bone mineral in vitro, in the absence of osteogenic supplements, which has implications for cell therapies.
Abstract: A key tenet of bone tissue engineering is the development of scaffold materials that can stimulate stem cell differentiation in the absence of chemical treatment to become osteoblasts without compromising material properties. At present, conventional implant materials fail owing to encapsulation by soft tissue, rather than direct bone bonding. Here, we demonstrate the use of nanoscale disorder to stimulate human mesenchymal stem cells (MSCs) to produce bone mineral in vitro, in the absence of osteogenic supplements. This approach has similar efficiency to that of cells cultured with osteogenic media. In addition, the current studies show that topographically treated MSCs have a distinct differentiation profile compared with those treated with osteogenic media, which has implications for cell therapies.
2,249 citations
TL;DR: The isolation, characterization, and preclinical and clinical application of adipose-derived stem cells (ASCs) are reviewed in this article.
Abstract: The emerging field of regenerative medicine will require a reliable source of stem cells in addition to biomaterial scaffolds and cytokine growth factors. Adipose tissue represents an abundant and accessible source of adult stem cells with the ability to differentiate along multiple lineage pathways. The isolation, characterization, and preclinical and clinical application of adipose-derived stem cells (ASCs) are reviewed in this article.
2,189 citations
TL;DR: It is indicated that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth.
Abstract: Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence. Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies. To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma. We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth.
2,166 citations
TL;DR: It is shown that cell lines can be derived from the epiblast, a tissue of the post-implantation embryo that generates the embryo proper, and interrogated to understand how pluripotent cells generate distinct fates during early development.
Abstract: The application of human embryonic stem (ES) cells in medicine and biology has an inherent reliance on understanding the starting cell population. Human ES cells differ from mouse ES cells and the specific embryonic origin of both cell types is unclear. Previous work suggested that mouse ES cells could only be obtained from the embryo before implantation in the uterus. Here we show that cell lines can be derived from the epiblast, a tissue of the post-implantation embryo that generates the embryo proper. These cells, which we refer to as EpiSCs (post-implantation epiblast-derived stem cells), express transcription factors known to regulate pluripotency, maintain their genomic integrity, and robustly differentiate into the major somatic cell types as well as primordial germ cells. The EpiSC lines are distinct from mouse ES cells in their epigenetic state and the signals controlling their differentiation. Furthermore, EpiSC and human ES cells share patterns of gene expression and signalling responses that normally function in the epiblast. These results show that epiblast cells can be maintained as stable cell lines and interrogated to understand how pluripotent cells generate distinct fates during early development.
2,134 citations
TL;DR: IL-6 orchestrates a series of 'downstream' cytokine-dependent signaling pathways that, in concert with TGF-β, amplify RORγt-dependent differentiation of TH-17 cells.
Abstract: T helper cells that produce interleukin 17 (IL-17; 'T(H)-17 cells') are a distinct subset of proinflammatory cells whose in vivo function requires IL-23 but whose in vitro differentiation requires only IL-6 and transforming growth factor-beta (TGF-beta). We demonstrate here that IL-6 induced expression of IL-21 that amplified an autocrine loop to induce more IL-21 and IL-23 receptor in naive CD4(+) T cells. Both IL-21 and IL-23, along with TGF-beta, induced IL-17 expression independently of IL-6. The effects of IL-6 and IL-21 depended on STAT3, a transcription factor required for the differentiation of T(H)-17 cells in vivo. IL-21 and IL-23 induced the orphan nuclear receptor RORgammat, which in synergy with STAT3 promoted IL-17 expression. IL-6 therefore orchestrates a series of 'downstream' cytokine-dependent signaling pathways that, in concert with TGF-beta, amplify RORgammat-dependent differentiation of T(H)-17 cells.
2,046 citations
TL;DR: The vitamin A metabolite retinoic acid is identified as a key regulator of TGF-β–dependent immune responses, capable of inhibiting the IL-6–driven induction of proinflammatory TH17 cells and promoting anti-inflammatory Treg cell differentiation, indicating that a common metabolite can regulate the balance between pro- and anti- inflammatory immunity.
Abstract: The cytokine transforming growth factor-beta (TGF-beta) converts naive T cells into regulatory T (Treg) cells that prevent autoimmunity. However, in the presence of interleukin-6 (IL-6), TGF-beta has also been found to promote the differentiation of naive T lymphocytes into proinflammatory IL-17 cytokine-producing T helper 17 (T(H)17) cells, which promote autoimmunity and inflammation. This raises the question of how TGF-beta can generate such distinct outcomes. We identified the vitamin A metabolite retinoic acid as a key regulator of TGF-beta-dependent immune responses, capable of inhibiting the IL-6-driven induction of proinflammatory T(H)17 cells and promoting anti-inflammatory Treg cell differentiation. These findings indicate that a common metabolite can regulate the balance between pro- and anti-inflammatory immunity.
1,937 citations
TL;DR: Let-7 regulates multiple BT-IC stem cell-like properties by silencing more than one target, and miRNA expression in self-renewing and differentiated cells from breast cancer lines and in breast T-IC and non-BT-IC from 1 degrees breast cancers is compared.
1,909 citations
TL;DR: Genome-wide analysis of two key histone modifications indicated that iPS cells are highly similar to ES cells, and data show that transcription factor-induced reprogramming leads to the global reversion of the somatic epigenome into an ES-like state.
TL;DR: It is shown that mice can be rescued after transplantation with hematopoietic progenitors obtained in vitro from autologous iPS cells, providing proof of principle for using transcription factor–induced reprogramming combined with gene and cell therapy for disease treatment in mice.
Abstract: It has recently been demonstrated that mouse and human fibroblasts can be reprogrammed into an embryonic stem cell-like state by introducing combinations of four transcription factors. However, the therapeutic potential of such induced pluripotent stem (iPS) cells remained undefined. By using a humanized sickle cell anemia mouse model, we show that mice can be rescued after transplantation with hematopoietic progenitors obtained in vitro from autologous iPS cells. This was achieved after correction of the human sickle hemoglobin allele by gene-specific targeting. Our results provide proof of principle for using transcription factor-induced reprogramming combined with gene and cell therapy for disease treatment in mice. The problems associated with using retroviruses and oncogenes for reprogramming need to be resolved before iPS cells can be considered for human therapy.
TL;DR: By genetic deletion, it is shown that, although they are prone to differentiate, embryonic stem cells can self-renew indefinitely in the permanent absence of Nanog, and it is surmised that Nanog stabilizes embryonicstem cells in culture by resisting or reversing alternative gene expression states.
Abstract: Nanog is a divergent homeodomain protein found in mammalian pluripotent cells and developing germ cells. Deletion of Nanog causes early embryonic lethality, whereas constitutive expression enables autonomous self-renewal of embryonic stem cells. Nanog is accordingly considered a core element of the pluripotent transcriptional network. However, here we report that Nanog fluctuates in mouse embryonic stem cells. Transient downregulation of Nanog appears to predispose cells towards differentiation but does not mark commitment. By genetic deletion we show that, although they are prone to differentiate, embryonic stem cells can self-renew indefinitely in the permanent absence of Nanog. Expanded Nanog null cells colonize embryonic germ layers and exhibit multilineage differentiation both in fetal and adult chimaeras. Although they are also recruited to the germ line, primordial germ cells lacking Nanog fail to mature on reaching the genital ridge. This defect is rescued by repair of the mutant allele. Thus Nanog is dispensible for expression of somatic pluripotency but is specifically required for formation of germ cells. Nanog therefore acts primarily in construction of inner cell mass and germ cell states rather than in the housekeeping machinery of pluripotency. We surmise that Nanog stabilizes embryonic stem cells in culture by resisting or reversing alternative gene expression states.
TL;DR: It is shown that the evolutionarily conserved microRNA-155 has an important role in the mammalian immune system, specifically in regulating T helper cell differentiation and the germinal center reaction to produce an optimal T cell–dependent antibody response.
Abstract: MicroRNAs are small RNA species involved in biological control at multiple levels. Using genetic deletion and transgenic approaches, we show that the evolutionarily conserved microRNA-155 (miR-155) has an important role in the mammalian immune system, specifically in regulating T helper cell differentiation and the germinal center reaction to produce an optimal T cell-dependent antibody response. miR-155 exerts this control, at least in part, by regulating cytokine production. These results also suggest that individual microRNAs can exert critical control over mammalian differentiation processes in vivo.
TL;DR: It is established that CFU-ECs are not EPCs and the role of these cells in angiogenesis must be re-examined prior to further clinical trials, whereas ECFCs may serve as a potential therapy for vascular regeneration.
TL;DR: These findings suggest that full acquisition of pathogenic function by effector TH-17 cells is mediated by IL-23 rather than by TGF-β and IL-6, which 'drive' initial lineage commitment but also 'restrain' the pathogenic potential of TH- 17 cells.
Abstract: Studies have shown that transforming growth factor-beta (TGF-beta) and interleukin 6 (IL-6) are required for the lineage commitment of pathogenic IL-17-producing T helper cells (T(H)-17 cells). Unexpectedly, here we found that stimulation of myelin-reactive T cells with TGF-beta plus IL-6 completely abrogated their pathogenic function despite upregulation of IL-17 production. Cells stimulated with TGF-beta plus IL-6 were present in the spleen as well as the central nervous system, but they failed to upregulate the proinflammatory chemokines crucial for central nervous system inflammation. In addition, these cells produced IL-10, which has potent anti-inflammatory activities. In contrast, stimulation with IL-23 promoted expression of IL-17 and proinflammatory chemokines but not IL-10. Hence, TGF-beta and IL-6 'drive' initial lineage commitment but also 'restrain' the pathogenic potential of T(H)-17 cells. Our findings suggest that full acquisition of pathogenic function by effector T(H)-17 cells is mediated by IL-23 rather than by TGF-beta and IL-6.
TL;DR: The biological basis and the therapeutic implications of the stem cell model of cancer, first developed in human myeloid leukemias, is reviewed, which is today being extended to solid tumors, such as breast and brain cancer.
Abstract: Although monoclonal in origin, most tumors appear to contain a heterogeneous population of cancer cells. This observation is traditionally explained by postulating variations in tumor microenvironment and coexistence of multiple genetic subclones, created by progressive and divergent accumulation of independent somatic mutations. An additional explanation, however, envisages human tumors not as mere monoclonal expansions of transformed cells, but rather as complex tridimensional tissues where cancer cells become functionally heterogeneous as a result of differentiation. According to this second scenario, tumors act as caricatures of their corresponding normal tissues and are sustained in their growth by a pathological counterpart of normal adult stem cells, cancer stem cells. This model, first developed in human myeloid leukemias, is today being extended to solid tumors, such as breast and brain cancer. We review the biological basis and the therapeutic implications of the stem cell model of cancer.
TL;DR: It is concluded that satellite cells are a heterogeneous population composed of stem cells and committed progenitors, and this work provides critical insights into satellite cell biology and open new avenues for therapeutic treatment of neuromuscular diseases.
TL;DR: The p38MAPK pathway is a key regulator of pro-inflammatory cytokines biosynthesis at the transcriptional and translational levels, which makes different components of this pathway potential targets for the treatment of autoimmune and inflammatory diseases.
TL;DR: It is shown that human and mouse tendons harbor a unique cell population, termed tendon stem/progenitor cells (TSPCs), that has universal stem cell characteristics such as clonogenicity, multipotency and self-renewal capacity and could regenerate tendon-like tissues after extended expansion in vitro and transplantation in vivo.
Abstract: The repair of injured tendons remains a great challenge, largely owing to a lack of in-depth characterization of tendon cells and their precursors. We show that human and mouse tendons harbor a unique cell population, termed tendon stem/progenitor cells (TSPCs), that has universal stem cell characteristics such as clonogenicity, multipotency and self-renewal capacity. The isolated TSPCs could regenerate tendon-like tissues after extended expansion in vitro and transplantation in vivo. Moreover, we show that TSPCs reside within a unique niche predominantly comprised of an extracellular matrix, and we identify biglycan (Bgn) and fibromodulin (Fmod) as two critical components that organize this niche. Depletion of Bgn and Fmod affects the differentiation of TSPCs by modulating bone morphogenetic protein signaling and impairs tendon formation in vivo. Our results, while offering new insights into the biology of tendon cells, may assist in future strategies to treat tendon diseases.
TL;DR: This work reveals the let-7 microRNA to be a master regulator of cell proliferation pathways and shows that multiple genes involved in cell cycle and cell division functions are also directly or indirectly repressed byLet-7.
Abstract: MicroRNAs play important roles in animal development, cell differentiation, and metabolism and have been implicated in human cancer. The let-7 microRNA controls the timing of cell cycle exit and terminal differentiation in Caenorhabditis elegans and is poorly expressed or deleted in human lung tumors. Here, we show that let-7 is highly expressed in normal lung tissue, and that inhibiting let-7 function leads to increased cell division in A549 lung cancer cells. Overexpression of let-7 in cancer cell lines alters cell cycle progression and reduces cell division, providing evidence that let-7 functions as a tumor suppressor in lung cells. let-7 was previously shown to regulate the expression of the RAS lung cancer oncogenes, and our work now shows that multiple genes involved in cell cycle and cell division functions are also directly or indirectly repressed by let-7. This work reveals the let-7 microRNA to be a master regulator of cell proliferation pathways.
TL;DR: A complete understanding of the complex interplay between neoplastic and myelomonocytic cells might offer novel targets for therapeutic intervention aimed at depriving tumor cells of important growth support and enhancing the antitumor immune response.
Abstract: Tumors require a constant influx of myelomonocytic cells to support the angiogenesis and stroma remodeling needed for their growth This is mediated by tumor-derived factors, which cause sustained myelopoiesis and the accumulation and functional differentiation of myelomonocytic cells, most of which are macrophages, at the tumor site An important side effect of the accumulation and functional differentiation of these cells is that they can induce lymphocyte dysfunction A complete understanding of the complex interplay between neoplastic and myelomonocytic cells might offer novel targets for therapeutic intervention aimed at depriving tumor cells of important growth support and enhancing the antitumor immune response
TL;DR: It is shown that increasing miR-181a expression in mature T cells augments the sensitivity to peptide antigens, while inhibition in the immature T cells reduces sensitivity and impairs both positive and negative selection.
TL;DR: The RANKL signaling pathway has promise as a strategy for suppressing the excessive osteoclast formation characteristic of a variety of bone diseases and is controlled by an epigenetic mechanism, which has profound implications for the general mechanism of irreversible cell fate determination.
TL;DR: In this paper, the authors identify, isolate, and characterize the CSC population that drives and maintains hepatocellular carcinoma (HCC) growth and metastasis using a severe partial hepatectomy model.
TL;DR: The conserved role for PGE2 in the regulation of vertebrate HSC homeostasis indicates that modulation of the prostaglandin pathway may facilitate expansion of HSC number for therapeutic purposes.
Abstract: Haematopoietic stem cell (HSC) homeostasis is tightly controlled by growth factors, signalling molecules and transcription factors. Definitive HSCs derived during embryogenesis in the aorta-gonad-mesonephros region subsequently colonize fetal and adult haematopoietic organs. To identify new modulators of HSC formation and homeostasis, a panel of biologically active compounds was screened for effects on stem cell induction in the zebrafish aorta-gonad-mesonephros region. Here, we show that chemicals that enhance prostaglandin (PG) E2 synthesis increased HSC numbers, and those that block prostaglandin synthesis decreased stem cell numbers. The cyclooxygenases responsible for PGE2 synthesis were required for HSC formation. A stable derivative of PGE2 improved kidney marrow recovery following irradiation injury in the adult zebrafish. In murine embryonic stem cell differentiation assays, PGE2 caused amplification of multipotent progenitors. Furthermore, ex vivo exposure to stabilized PGE2 enhanced spleen colony forming units at day 12 post transplant and increased the frequency of long-term repopulating HSCs present in murine bone marrow after limiting dilution competitive transplantation. The conserved role for PGE2 in the regulation of vertebrate HSC homeostasis indicates that modulation of the prostaglandin pathway may facilitate expansion of HSC number for therapeutic purposes.
TL;DR: Compared with bone marrow‐derived mesenchymal stem cells, adipose tissue‐derived stromal cells (ADSC) do have an equal potential to differentiate into cells and tissues of mesodermal origin, such as adipocytes, cartilage, bone, and skeletal muscle, but the easy and repeatable access to subcutaneous adipOSE tissue and the simple isolation procedures provide a clear advantage.
Abstract: Compared with bone marrow-derived mesenchymal stem cells, adipose tissue-derived stromal cells (ADSC) do have an equal potential to differentiate into cells and tissues of mesodermal origin, such as adipocytes, cartilage, bone, and skeletal muscle. However, the easy and repeatable access to subcutaneous adipose tissue and the simple isolation procedures provide a clear advantage. Since extensive reviews focusing exclusively on ADSC are rare, it is the aim of this review to describe the preparation and isolation procedures for ADSC, to summarize the molecular characterization of ADSC, to describe the differentiation capacity of ADSC, and to discuss the mechanisms and future role of ADSC in cell therapy and tissue engineering. An initial effort has also been made to differentiate ADSC into hepatocytes, endocrine pancreatic cells, neurons, cardiomyocytes, hepatocytes, and endothelial/vascular cells. Whereas the lineage-specific differentiation into cells of mesodermal origin is well understood on a molecular basis, the molecular key events and transcription factors that initially allocate the ADSC to a lineage-specific differentiation are almost completely unknown. Decoding these molecular mechanisms is a prerequisite for developing novel cell therapies.
TL;DR: Although its function is required for Tr cell suppressor activity, Foxp3 to a large extent amplifies and fixes pre-established molecular features of Tr cells, including anergy and dependence on paracrine IL-2.
Abstract: Regulatory CD4+ T cells (Tr cells), the development of which is critically dependent on X-linked transcription factor Foxp3 (forkhead box P3), prevent self-destructive immune responses Despite its important role, molecular and functional features conferred by Foxp3 to Tr precursor cells remain unknown It has been suggested that Foxp3 expression is required for both survival of Tr precursors as well as their inability to produce interleukin (IL)-2 and independently proliferate after T-cell-receptor engagement, raising the possibility that such 'anergy' and Tr suppressive capacity are intimately linked Here we show, by dissociating Foxp3-dependent features from those induced by the signals preceding and promoting its expression in mice, that the latter signals include several functional and transcriptional hallmarks of Tr cells Although its function is required for Tr cell suppressor activity, Foxp3 to a large extent amplifies and fixes pre-established molecular features of Tr cells, including anergy and dependence on paracrine IL-2 Furthermore, Foxp3 solidifies Tr cell lineage stability through modification of cell surface and signalling molecules, resulting in adaptation to the signals required to induce and maintain Tr cells This adaptation includes Foxp3-dependent repression of cyclic nucleotide phosphodiesterase 3B, affecting genes responsible for Tr cell homeostasis
TL;DR: It is reported that stem cell Polycomb group targets are up to 12-fold more likely to have cancer-specific promoter DNA hypermethylation than non-targets, supporting a stem cell origin of cancer in which reversible gene repression is replaced by permanent silencing, locking the cell into a perpetual state of self-renewal and thereby predisposing to subsequent malignant transformation.
Abstract: Embryonic stem cells rely on Polycomb group proteins to reversibly repress genes required for differentiation. We report that stem cell Polycomb group targets are up to 12-fold more likely to have cancer-specific promoter DNA hypermethylation than non-targets, supporting a stem cell origin of cancer in which reversible gene repression is replaced by permanent silencing, locking the cell into a perpetual state of self-renewal and thereby predisposing to subsequent malignant transformation.
National Institute for Biological Standards and Control1, University of Sheffield2, Karolinska Institutet3, Technion – Israel Institute of Technology4, Leeds Teaching Hospitals NHS Trust5, Monash University6, Hebrew University of Jerusalem7, Thermo Fisher Scientific8, National Institutes of Health9, University of Cambridge10, University of Kansas11, University of Toronto12, Academy of Sciences of the Czech Republic13, Masaryk University14, Uppsala University15, Stanford University16, Newcastle University17, Pierre-and-Marie-Curie University18, WiCell19, University of Helsinki20, King's College London21, Kyoto University22, Hudson Institute23
TL;DR: The International Stem Cell Initiative characterized 59 human embryonic stem cell lines from 17 laboratories worldwide and found that despite diverse genotypes and different techniques used for derivation and maintenance, all lines exhibited similar expression patterns for several markers ofhuman embryonic stem cells.
Abstract: The International Stem Cell Initiative characterized 59 human embryonic stem cell lines from 17 laboratories worldwide. Despite diverse genotypes and different techniques used for derivation and maintenance, all lines exhibited similar expression patterns for several markers of human embryonic stem cells. They expressed the glycolipid antigens SSEA3 and SSEA4, the keratan sulfate antigens TRA-1-60, TRA-1-81, GCTM2 and GCT343, and the protein antigens CD9, Thy1 (also known as CD90), tissue- nonspecific alkaline phosphatase and class 1 HLA, as well as the strongly developmentally regulated genes NANOG, POU5F1 (formerly known as OCT4), TDGF1, DNMT3B, GABRB3 and GDF3. Nevertheless, the lines were not identical: differences in expression of several lineage markers were evident, and several imprinted genes showed generally similar allele-specific expression patterns, but some gene-dependent variation was observed. Also, some female lines expressed readily detectable levels of XIST whereas others did not. No significant contamination of the lines with mycoplasma, bacteria or cytopathic viruses was detected.