Brain tumour stem cells and neural stem cells: still explored by the same approach?

Brain tumour stem cells (BTSCs) are chiefly responsible for the in vivo long-term growth and recurrence of malignant gliomas and may be a potential treatment target. They resemble neural stem cells (NSCs), so their self-renewal and differentiation are currently investigated by the same methods used to study NSCs. There are, however, essential differences between these cell types: in many cases the marker expression pattern of BTSCs does not match the CD133(+)/NSE(-)/FAP(-) pattern of NSCs; BTSC tumourigenicity is independent of marker expression; and while attachment, serum-containing medium and withdrawal of mitogens (epidermal growth factor [EGF] and basic fibroblast growth factor [bFGF]) are essential to induce NSCs to differentiate, they do not affect BTSC tumourigenicity. Evidence implies that research on the renewal and differentiation of BTSCs should be orientated towards tumourigenicity and is essentially a pharmaceutical problem. Such an approach may contribute to the development of an accurate definition of BTSCs and to the search for selective differentiation-inducing drugs for BTSCs.     

Cancer stem cells - A therapeutic target?

Cancer stem cells (CSCs) form a highly tumorigenic core in most human tumors. Although there is no consensus regarding CSC phenotype from different tumor types, CSCs from different cancers share a primitive undifferentiated nature, including a capacity to expand and differentiate, albeit aberrantly, into the major cell types observed in the corresponding tumor. This review focuses on the development of therapeutics targeting CSCs, for which new assays that replace those reporting the inhibition of cell division and rapid tumor shrinkage will be required to account for the quiescent nature and properties of CSCs. The inhibition of signaling pathways related to the stem cell nature of the CSCs may appear an attractive target for novel therapeutics, but these targets could result in significant unwanted off-target effects against essential healthy tissue stem cells. Instead, the ideal therapies targeting CSCs will be directed against functions that contribute to the oncogenic nature of CSCs relative to healthy stem cells, an altogether more challenging task.     

Efficient generation of functional hepatocytes from human embryonic stem cells and induced pluripotent stem cells by HNF4α transduction

Hepatocyte-like cells from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are expected to be a useful source of cells drug discovery. Although we recently reported that hepatic commitment is promoted by transduction of SOX17 and HEX into human ESC- and iPSC-derived cells, these hepatocyte-like cells were not sufficiently mature for drug screening. To promote hepatic maturation, we utilized transduction of the hepatocyte nuclear factor 4α (HNF4α) gene, which is known as a master regulator of liver-specific gene expression. Adenovirus vector-mediated overexpression of HNF4α in hepatoblasts induced by SOX17 and HEX transduction led to upregulation of epithelial and mature hepatic markers such as cytochrome P450 (CYP) enzymes, and promoted hepatic maturation by activating the mesenchymal-to-epithelial transition (MET). Thus HNF4α might play an important role in the hepatic differentiation from human ESC-derived hepatoblasts by activating the MET. Furthermore, the hepatocyte like-cells could catalyze the toxication of several compounds. Our method would be a valuable tool for the efficient generation of functional hepatocytes derived from human ESCs and iPSCs, and the hepatocyte-like cells could be used for predicting drug toxicity.     

The plastic liver: differentiated cells,stem cells,every cell?

The liver is capable of full regeneration following several types and rounds of injury, ranging from hepatectomy to toxin-mediated damage. The source of this regenerative capacity has long been a hotly debated topic. The damage response that occurs when hepatocyte proliferation is impaired is thought to be mediated by oval/dedifferentiated progenitor cells, which replenish the hepatocyte and ductal compartments of the liver. Recently, reports have questioned whether these oval/progenitor cells truly serve as the facultative stem cell of the liver following toxin-mediated damage. In this issue of the JCI, Kordes and colleagues use lineage tracing to follow transplanted rat hepatic stellate cells, a resident liver mesenchymal cell population, in hosts that have suffered liver damage. Transplanted stellate cells repopulated the damaged rat liver by contributing to the oval cell response. These data establish yet another cell type of mesenchymal origin as the progenitor for the oval/ductular response in the rat. The lack of uniformity between different damage models, the extent of the injury to the liver parenchyma, and potential species-specific differences might be at the core of the discrepancy between different studies. Taken together, these data imply a considerable degree of plasticity in the liver, whereby several cell types can contribute to regeneration.     

Immunotherapy targeting glioma stem cells – insights and perspectives

Introduction: Glioblastoma multiforme (GBM) is the most aggressive and lethal primary malignant brain tumor. Although progress has been made in current conventional therapies for GBM patients, the effect of these advances on clinical outcomes has been disappointing. Recent research into the origin of cancers suggest that GBM cancer stem cells (GSC) are the source of initial tumor formation, resistance to current conventional therapeutics and eventual patient relapse. Currently, there are very few studies that apply immunotherapy to target GSC.

Areas covered: CD133, a cell surface protein, is used extensively as a surface marker to identify and isolate GSC in malignant glioma. We discuss biomarkers such as CD133, L1-cell adhesion molecule (L1-CAM), and A20 of GSC. We review developing novel treatment modalities, including immunotherapy strategies, to target GSC.

Expert opinion: There are very few reports of preclinical studies targeting GSC. Identification and validation of unique molecular signatures and elucidation of signaling pathways involved in survival, proliferation and differentiation of GSC will significantly advance this field and provide a framework for the rational design of a new generation of antigen-specific, anti-GSC immunotherapy- and nanotechnology-based targeted therapyies. Combined with other therapeutic avenues, GSC-targeting therapies may represent a new paradigm to treat GBM patients.     

Cytotoxic T cells induce proliferation of chronic myeloid leukemia stem cells by secreting interferon-γ

Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia arising from the oncogenic break point cluster region/Abelson murine leukemia viral oncogene homolog 1 translocation in hematopoietic stem cells (HSCs), resulting in a leukemia stem cell (LSC). Curing CML depends on the eradication of LSCs. Unfortunately, LSCs are resistant to current treatment strategies. The host’s immune system is thought to contribute to disease control, and several immunotherapy strategies are under investigation. However, the interaction of the immune system with LSCs is poorly defined. In the present study, we use a murine CML model to show that LSCs express major histocompatibility complex (MHC) and co-stimulatory molecules and are recognized and killed by leukemia-specific CD8⁺ effector CTLs in vitro. In contrast, therapeutic infusions of effector CTLs into CML mice in vivo failed to eradicate LSCs but, paradoxically, increased LSC numbers. LSC proliferation and differentiation was induced by CTL-secreted IFN-γ. Effector CTLs were only able to eliminate LSCs in a situation with minimal leukemia load where CTL-secreted IFN-γ levels were low. In addition, IFN-γ increased proliferation and colony formation of CD34⁺ stem/progenitor cells from CML patients in vitro. Our study reveals a novel mechanism by which the immune system contributes to leukemia progression and may be important to improve T cell–based immunotherapy against leukemia.Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that arises from break point cluster region/Abelson murine leukemia viral oncogene homolog 1 (BCR/ABL)–transformed hematopoietic stem (HSCs) or early progenitor cells known as leukemia stem cells (LSCs; Kavalerchik et al., 2008). LSCs have been first characterized as the tumor-initiating cells in acute myeloid leukemia (Lapidot et al., 1994) and have also been defined in other hematopoietic neoplasms since then (Cox et al., 2004; Matsui et al., 2004).BCR/ABL-specific tyrosine kinase inhibitors (TKIs) such as Imatinib mesylate (Glivec) have revolutionized the therapy of CML (Druker et al., 2001a,b; Baccarani et al., 2006). Nevertheless, LSCs seem resistant to TKIs and traditional chemotherapy (Weiden et al., 1979; Deininger et al., 2000; Savona and Talpaz, 2008) and CML inevitably progresses to incurable acute leukemia (Faderl et al., 1999). Quiescent, self-renewing LSCs remain in the BM and are responsible for refractoriness and relapse of CML after treatment (Hughes et al., 2003). Therefore, novel cytotoxic agents that selectively target LSCs are under investigation (Jin et al., 2006; Guzman et al., 2007; Neviani et al., 2007; Ito et al., 2008; Bellodi et al., 2009; Majeti et al., 2009; Wang et al., 2010; Schürch et al., 2012).Another promising approach in the treatment of CML is immunotherapy. In fact, currently, the only curative treatment for CML remains allogeneic stem cell transplantation (alloSCT). The graft-versus-leukemia effect of alloSCT is most likely executed by donor CD8⁺ effector CTLs specific for minor histocompatibility antigens (Weiden et al., 1979; Kolb et al., 1990; Gale et al., 1994; Druker et al., 2002). Patients who receive T cell–depleted alloSCT grafts have a higher risk of disease relapse, and donor lymphocyte infusions are able to induce complete remission after relapse (Thomas et al., 1979; Horowitz et al., 1990; Kolb et al., 1995; Sehn et al., 1999). Furthermore, endogenous CTLs directed against leukemia antigens have been detected in the peripheral blood of chronic phase CML patients (Molldrem et al., 2000; Butt et al., 2005). Several proteins may potentially act as potent leukemia-specific antigens for T cells, including BCR/ABL, Wilms’ tumor 1 protein (WT1), and proteinase 3 (Pr3; Van Driessche et al., 2005). Peptides from the junctional region of BCR/ABL are not present in healthy individuals and therefore are leukemia-specific. Yotnda et al. (1998) identified a BCR/ABL junctional nonapeptide that binds to human leukocyte antigen (HLA)-A2.1 and elicits specific CTL responses in vitro and in vivo. Additional studies confirmed and extended the finding of immunogenic BCR/ABL junction peptides (Bocchia et al., 1996; Clark et al., 2001).CTLs have been shown to kill CML target cells in vitro via Fas-receptor triggering (Selleri and Maciejewski, 2000). In a BCR/ABL-induced murine CML model, we have shown that CD8⁺ T cells crucially contribute to disease control in vivo. However, programmed death ligand 1 (PD-L1) expression by the malignant cells induced T cell dysfunction leading to disease progression (Mumprecht et al., 2009b).Despite these advances in the understanding of the immunosurveillance of CML and the development of immunotherapy strategies, the interaction of effector CTLs with the disease-originating LSCs has not been analyzed so far. In the present study, we analyzed the immunogenicity of LSCs in vitro and in vivo using the glycoprotein of lymphocytic choriomeningitis virus (LCMV) as model leukemia antigen. LSCs expressed MHC and co-stimulatory molecules. LSCs isolated from CD8⁺ T cell–depleted CML mice were more immunogenic than LSCs from control CML mice, indicating that CD8⁺ T cells interact with LSCs in vivo and select for low immunogenic variants. To analyze whether LSCs can be recognized and lysed by activated leukemia-specific effector CTLs, we treated CML mice with large numbers of specific T cells. Although these effector CTLs efficiently lysed LSCs in vitro, adoptive immunotherapy in vivo failed to eradicate LSCs but paradoxically increased LSC numbers. LSC proliferation was induced by CTL-secreted IFN-γ. Specific effector CTLs secreted high amounts of IFN-γ when transferred to CML mice in advanced disease stage with high antigen load, but not after transfer to CML mice in early stage of disease. Importantly, our results were confirmed in a humanized CML model using HLA-A2.1 transgenic mice and a BCR/ABL b3a2 junctional peptide. In addition, IFN-γ induced the proliferation of primary CD34⁺ stem/progenitor cells from newly diagnosed CML patients.     

Mesh词表主题词扩展:造血干细胞-Hematopoietic stem cells

Hematopoietic stem cells(HSCs)are multipotent stem cells that give rise to all the blood cell types from the myeloid(monocytes and macrophages, neutrophils, basophils,eosinophils, erythrocytes, megakaryocytes/platelets,dendritic cells     

Autologous hematopoietic stem cells for refractory Crohn’s disease

Introduction: Autologous hematopoietic stem cells are gaining ground as an effective and safe treatment for treating severe refractory Crohn’s disease (CD). Autologous hematopoietic stem cell therapy (AHSCT) induces resetting of the immune system by de novo regeneration of T-cell repertoire and repopulation of epithelial cells by bone-marrow derived cells to help patients achieve clinical and endoscopic remission.

Areas covered: Herein, the authors discuss the use of AHSCT in treating patients with CD. Improvements in disease activity have been seen in patients with severe autoimmune disease and patients with severe CD who underwent AHSCT for a concomitant malignant hematological disease. Clinical and endoscopic remission has been achieved in patients treated with AHSCT for CD. The only randomized trial published to date, the ASTIC Trial, did not support further use of AHSCT to treat CD. Yet, critics of this trial have deemed AHSCT as a promising treatment for severe refractory CD.

Expert opinion: Even with the promising evidence presented for HSCT for refractory CD, protocols need to be refined through the collaboration of GI and hemato-oncology professionals. The goal is to incorporate safe AHSCT and restore tolerance by delivering an effective immune ‘cease fire’ as a treatment option for severe refractory CD.     

Mesh词表主题词扩展:成人干细胞-adult stem cells

Adult stem cells are undifferentiated cells,found throughout the body after embryonic development, that multiply by cell division to replenish dying cells and regenerate damaged tissues. Also known as somatic stem cells (from the body), they can be found     

Plasticity of stem cells: a change of paradigm?

Until a few years ago, an interest in stem cells, mostly of hematopoietic origin, was limited to a relatively small representation of scientists and clinicians seeking to understand the role of these rare cells in tissue homeostasis and to utilize their remarkable potential to regenerate an adult tissue following transplantation. Over the last few years, an ability of bone marrow-, brain-, muscle- and other tissue-derived stem cells to branch off, move between tissues and contribute to their repair was discovered. According to this novel view, at least a subset of stem cells may alter their fate in a manner that is more plastic and dynamic than previously thought, causing a fascination with these cells to spread to nearly all clinical disciplines. Expectations are high: stem cells are considered a future remedy for major diseases of our civilization. There are more questions raised than answers, and pressure grows to extend the knowledge and accelerate its implementation.     

Genetic instability in neural stem cells: an inconvenient truth?

The evolutionary struggles from which mutants arise have been documented in almost every living system. In this issue of the JCI, Varela and colleagues extend this list of systems to include neural derivatives of human embryonic stem cells, which they show exhibit a repeated gain of material from chromosome 1q. Although this raises safety issues for therapeutic use of such cells, the frequent observation of a particular change may direct screening strategies for detection and removal of these unwanted cellular variants.     

How do we mobilize and collect autologous peripheral blood stem cells?

Autologous stem cell transplantation (ASCT) with mobilized peripheral blood stem cells (PBSCs) has become a widely applied therapeutic approach for many hematologic and nonhematologic diseases. Adequate PBSC mobilization is critical to the success of ASCT. However, many factors can contribute to poor mobilization. Plerixafor is an effective yet costly adjunct agent that has been increasingly used to improve mobilization in a variety of diagnoses and clinical settings. However, to achieve both optimal cell collection yields and cost‐effectiveness, the role of plerixafor in PBSC mobilization needs to be well defined in terms of triggers for initiating its use and criteria for monitoring response. As one of the largest hematopoietic transplant centers in the country, we have developed an approach to PBSC mobilization and collection that incorporates patient laboratory assessments, monitoring of the collection yields, and judicious use of plerixafor as well as various patient support and education programs. These measures have resulted in an increase in our collection success rate and a decrease in the mean number of collection days. In this article we describe our approach to autologous PBSC mobilization and collection. Pertinent reports in the literature are also reviewed and discussed.     

Is CD133 a marker of metastatic colon cancer stem cells?

The concept of the so-called cancer stem cell (CSC) holds that only a minority of cells within a tumor have the ability to generate a new tumor. Over the last decade, a large body of literature has implicated the protein CD133 as a marker of organ-specific adult stem cells and in some cancers as a bona fide CSC marker. In this issue of the JCI, Shmelkov et al. challenge the view that CD133 is a marker of CSCs in colon cancer (see the related article beginning on page 2111). CD133 was thought previously to have a very restricted distribution within tissues; the authors have used genetic knock-in models to demonstrate that CD133 in fact is expressed on a wide range of differentiated epithelial cells in adult mouse tissues and on spontaneous primary colon tumors in mice. In primary human colon tumors, all of the epithelial cells also expressed CD133, whereas metastatic colon cancers isolated from liver had distinct CD133+ and CD133- epithelial populations. Intriguingly, the authors demonstrate that the CD133+ and CD133- populations were equally capable of tumor initiation in xenografts. In light of these new findings, the popular notion that CD133 is a marker of colon CSCs may need to be revised.     

Mesh词表词汇实用例句:间充质干细胞-Mesenchymal stem cells

例句:Mosonchynal stem cells(MSCs)are mu1tiPotent stem cells that can differentiate into a variety of cell types,including osteoblasts