Human embryonic stem cells

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Resveratrol ameliorates the maturation process of β-cell-like cells obtained from an optimized differentiation protocol of human embryonic stem cells.

Resveratrol ameliorates the maturation process of β-cell-like cells obtained from an optimized differentiation protocol of human embryonic stem cells.

Human embryonic stem cells (hESCs) retain the extraordinary capacity to differentiate into different cell types of an adult organism, including pancreatic β -cells. For this particular line- age, although a lot of effort has been made in the last ten years to achieve an efficient and reproducible differentiation protocol, it was not until recently that this aim was roughly ac- complished. Besides, several studies evidenced the impact of resveratrol (RSV) on insulin secretion, even though the mechanism by which this polyphenol potentiates glucose- stimulated insulin secretion (GSIS) is still not clear. The aim of this study was to optimize an efficient differentiation protocol that mimics in vivo pancreatic organogenesis and to investi- gate whether RSV may improve the final maturation step to obtain functional insulin- secreting cells. Our results indicate that treatment of hESCs (HS-181) with activin-A in- duced definitive endoderm differentiation as detected by the expression of SOX17 and FOXA2. Addition of retinoic acid (RA), Noggin and Cyclopamine promoted pancreatic differ- entiation as indicated by the expression of the early pancreatic progenitor markers ISL1, NGN3 and PDX1. Moreover, during maturation in suspension culture, differentiating cells assembled in islet-like clusters, which expressed specific endocrine markers such as PDX1, SST, GCG and INS. Similar results were confirmed with the human induced Pluripo- tent Stem Cell (hiPSC) line MSUH-001. Finally, differentiation protocols incorporating RSV treatment yielded numerous insulin-positive cells, induced significantly higher PDX1 ex- pression and were able to transiently normalize glycaemia when transplanted in streptozo- tocin (STZ) induced diabetic mice thus promoting its survival. In conclusion, our strategy allows the efficient differentiation of hESCs into pancreatic endoderm capable of generating β -cell-like cells and demonstrates that RSV improves the maturation process.
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21 Lee mas

Cancer genes hypermethylated in human embryonic stem cells.

Cancer genes hypermethylated in human embryonic stem cells.

Intriguingly, not all the genes frequently hypermethylated in CCLs were completely unmethylated in all the NTTs analyzed (Figure 1, and Tables 1 and S1). The frequency of hypermethylation in normal tissues is only of moderate importance for the Class A classical cancer methylated genes, as most of them (78.83%; 350/444 sequences) are unmethylated in NPTs. On the other hand, only 20 sequences corresponding to Class B genes were unmethylated in all the NTTs analyzed (Table 1). When a gene is methylated in some but not all normal tissues, the methylation is probably involved in the specification of a tissue type during development [12]. When the gene is not hypermethy- lated in hESCs, tissue-type-dependent selective methylation must Figure 1. DNA methylation profiling in human embryonic stem cells (hESCs), normal primary tissues, and cancer cell lines. (A) Methylation profiles of Class A-I (350), A-II (94), B-I (20), and B-II (107) genes in hESCs (8), normal (21), and cancer (21) samples obtained by Illumina arrays. The methylation levels vary from fully methylated (red) to fully unmethylated (white). The right-hand columns show the methylation status of histone H3 and Polycomb occupancy of the same genes obtained from previously published data [5,12,16]. Blue, methylation at K4 and K27; orange, methylation at K4 alone; green, no methylation at K4 or K27; black, presence of the Polycomb protein SUZ12. (B) Enrichment of the Polycomb protein SUZ12, the bivalent chromatin signature (K4/K27) or the absence of both marks (none) in Class A and Class B genes (upper panel) and Class I and Class II genes (lower panel).
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12 Lee mas

TítuloHuman amniotic membrane as an alternative source of stem cells for regenerative medicine

TítuloHuman amniotic membrane as an alternative source of stem cells for regenerative medicine

The recent use of autologous or allogenic stem cells has been suggested as an alternative therapeutic approach for treatment of cartilage defects (Jung et al., 2009). MSCs have the capability to self-renew and are responsible for repair and repopulation of damaged tissues in the adult (Hombach-Klonisch et al., 2008, Pittenger, 2008 and Tsai et al., 2007). The use of autologous MSCs represents the advantage of avoiding the problem of immunological rejection of the allotransplant and the ethical conflict of using human embryonic stem cells (hESCs). Due to the low number of MSCs that can be isolated from a tissue biopsy, proliferation in vitro is necessary to obtain adequate cell numbers for their implant into the patient. Nevertheless, the number of mitotic divisions of MSCs in culture must be limited because MSCs age during in vitro culture, causing a reduction in their proliferative and multi-differentiation potential (Banfi et al., 2000, Bonab et al., 2006 and Izadpanah et al., 2006). The conservation of phenotype and differentiation capacity of MSCs is proportional to telomerization (Abdallah et al., 2005). Telomeres are normally shortened in successive cell divisions, however, in embryonic stem cells the telomere length is restored by telomerase enzyme activity. On the other hand, MSCs lack (Zimmermann et al., 2003) adequate levels of telomerase activity to achieve telomeric restoration (Izadpanah et al., 2006, Parsch et al., 2004 and Yanada et al., 2006). Patient age also influences the characteristics of MSCs because their proliferative capacity is reduced by aging (Stenderup et al., 2003).
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17 Lee mas

Las patentes de células madre embrionarias humanas: ¿Amigas o enemigas de las barreras morales?

Las patentes de células madre embrionarias humanas: ¿Amigas o enemigas de las barreras morales?

later, following the rulings from the Edinburgh case, the enlarged board of appeal of the european Patent office rejected the WARF patent app- lication (ePo board of appeal decision G002/06, 2008), related to an invention made by dr. James thomson in 1996, who claimed a cell cul- ture comprising human embryonic stem cells with a desired list of cha- racteristics. at that time, such composition could only be made by a process that involved the destruction of human embryos. In the de- fence of this patent claims, the warF argued that the ePo should con- sider the destruction of the embryos as a step preceding the invention rather than as one of the stages in the commercial exploitation of the invention (sterckx and cockbain, 2010).
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14 Lee mas

Derivation of HVR1, HVR2 and HVR3 human embryonic stem cell lines from IVF embryos after preimplantation genetic diagnosis (PGD) for monogenic disorder.

Derivation of HVR1, HVR2 and HVR3 human embryonic stem cell lines from IVF embryos after preimplantation genetic diagnosis (PGD) for monogenic disorder.

From 106 human blastocyts donate for research after in vitro fertilization (IVF) and preimplantation genetic di- agnosis (PGD) for monogenetic disorder, 3 human embryonic stem cells (hESCs) HVR1, HVR2 and HVR3 were successfully derived. HVR1 was assumed to be genetically normal, HVR2 carrying Becker muscular dystrophy and HVR3 Hemophilia B. Despite the translocation t(9;15)(q34.3;q14) detected in HVR2, all the 3 cell lines were characterised in vitro and in vivo as normal hESCs lines and were registered in the Spanish Stem Cell Bank. © 2016 Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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5 Lee mas

The impact of transposable element activity on therapeutically relevant human stem cells

The impact of transposable element activity on therapeutically relevant human stem cells

TET proteins: While the primary mechanism under- lying DNA demethylation during the early embryonic period is replication-coupled dilution of 5mC [199, 200], an active mechanism dependent on TET enzymes has recently been uncovered to erase DNA methylation at specific loci in this period [170, 201–203]. TET en- zymes catalyze the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine (5hmC), and further to 5-for- mylcytosine (5fC) and 5-carboxylcytosine (5caC), which can be replaced with unmodified cytosine by base excision repair [204, 205]. Some of the TET proteins are highly expressed in ESCs and blastocysts [206], and it was re- ported that TET binding and demethylation at particular TE classes, such as LTR retrotransposons, acts in concert with pluripotency factors Nanog, Oct4 and Sox2 to main- tain expression of a subset of genes in ESCs [170]. Deple- tion of TET1 and TET2 in mESCs has been shown to cause loss of 5hmC in the 5′ region of L1 [207]. In hESCs, TET proteins were shown to preferentially bind to evolu- tionary young, functional L1 elements, and participate in their active demethylation, but do not interact with older, inactive subfamilies. Although TETs drive L1 demethyla- tion, L1s can be kept repressed through the TET-dependent recruitment of the transcriptional repres- sor SIN3A. The SIN3A co-repressive complex binds func- tional L1s in mouse and human ESCs ensuring their repression in a TET-dependent manner [92, 170]. Thus, and instead of being only positive regulators of L1 expres- sion, TET enzymes may have a dual role in TE regulation by also recruiting SIN3A to demethylated L1 elements. A recent report provided evidence that the methyl-CpG binding domain as well as the adjacent non-sequence spe- cific DNA binding domain of MeCP2 mediate repression of TET1-induced L1 mobilization [208]. Also, the KZFP/ KAP1 complex was recently reported to maintain hetero- chromatin and DNA methylation at TEs in naïve murine ESCs partly by protecting these loci from TET-mediated demethylation [209].
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23 Lee mas

Human Mesenchymal Stem Cells Prevent Neurological Complications of Radiotherapy

Human Mesenchymal Stem Cells Prevent Neurological Complications of Radiotherapy

Studies in brain cancer patients and rodent evidences that radiation-related neurofunctional sequelae are associated with a variety of anatomical changes that occur in the irradiated non-tumoral tissue (Makale et al., 2017). Immediately after radiation, brain exhibits vascular damages, oligodendrocyte loss, demyelination and neuroinflammation. Radiation-induced brain injury also disrupts the neurogenic niches located at the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricles. Moreover, brain injury also affects neuronal dendritic spines and white matter, leading to necrosis of specific areas. The discovery of the negative effects induced by radiation in the non- tumoral tissue has promoted the development of strategies to minimize radiotherapy side effects. In this context, stem cell-based therapy represents a novel alternative to attenuate radiation-induced brain injury (Acharya et al., 2011, 2015; Joo et al., 2012; Piao et al., 2015). In this line, Joo et al. (2012) described the benefits of supplementing whole-brain irradiated mice with fetal mouse neural stem cells (NSCs), which were injected via tail vein 24 h after radiation. The irradiated brain induced homing of the exogenous NSCs, which differentiated along glial and neuronal lineages. Two months after NSC administration, mice showed inhibited radiation-induced hippocampus atrophy and preserved short-term memory. Similarly, human embryonic stem cell-derived oligodendrocyte progenitors (hOPCs) have provided promising results. After bilateral injections into the corpus callosum of rats, hOPCs were able to remyelinate the brain and ameliorate radiation- induced cognitive dysfunction (Piao et al., 2015). However, stem cell-based therapies proposed in current studies present some restrictions that need to be solved if translation to human is sought (Ramos-Zuriga et al., 2012). First, several studies used stem cells with scarce availability and whose isolation procedure is highly invasive (e.g., NSCs). Second, the routes used for administration have limited effectiveness (e.g., systemic transplantation renders reduced concentration of transplanted cells in the brain) or requires invasive techniques that risk host safety (e.g., intracranial injections). Here we explored the non-invasive intranasal delivery of human mesenchymal stem cells (hMSCs) derived from adipose tissue to prevent radiation-induced brain damage in a mouse model of whole- brain radiation. Our results demonstrated that transplanted hMSCs promoted neuroprotection and improved neurological function after irradiation, without compromising survival of glioma-bearing mice.
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14 Lee mas

TítuloProteomic applications in the study of human mesenchymal stem cells

TítuloProteomic applications in the study of human mesenchymal stem cells

Abstract: Mesenchymal stem cells (MSCs) are undifferentiated cells with an unlimited capacity for self-renewal and able to differentiate towards specific lineages under appropriate conditions. MSCs are, a priori, a good target for cell therapy and clinical trials as an alternative to embryonic stem cells, avoiding ethical problems and the chance for malignant transformation in the host. However, regarding MSCs, several biological implications must be solved before their application in cell therapy, such as safe ex vivo expansion and manipulation to obtain an extensive cell quantity amplification number for use in the host without risk accumulation of genetic and epigenetic abnormalities. Cell surface markers for direct characterization of MSCs remain unknown, and the precise molecular mechanisms whereby growth factors stimulate their differentiation are still missing. In the last decade, quantitative proteomics has emerged as a promising set of techniques to address these questions, the answers to which will determine whether MSCs retain their potential for use in cell therapy. Proteomics provides tools to globally analyze cellular activity at the protein level. This proteomic profiling allows the elucidation of connections between broad cellular pathways and molecules that were previously impossible to determine using only traditional biochemical analysis. However; thus far, the results obtained must be orthogonally validated with other approaches. This review will
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19 Lee mas

Biotechnological approaches to cardiac differentiation of human induced pluripotent stem cells

Biotechnological approaches to cardiac differentiation of human induced pluripotent stem cells

useful source of autologous cardiac stem cells (Messina et al., 2004), but their benefit are inconsistent. The first cell type to be injected into ischemic myocardium was skeletal myoblasts (Menasche et al., 2003). It improved left ventricular function and volumes, probably through mechanical or scaffolding effect, but there was little evidence of transdifferentiation to cardiomyocytes (Menasche, 2008) and cells weren’t able to electrically integrate, arising chances of arrhythmias (Menasche et al., 2008). The greatest potential for organ regeneration is a characteristic of embryonic stem cells, which are derived from the inner mass of a developing embryo during the blastocyst stage (Segers & Lee, 2008). Their transplant in animal models of experimental myocardial infarction and non-ischemic cardiomyopathy, caused a significant improvement in cardiac function and structure (Behfar & Terzic, 2007). But, for clinical translation, they have the disadvantage of the immunological mismatch due to their allogeneic origin (Saric, Frenzel, & Hescheler, 2008). Moreover, embryonic stem cells are obtained with methods that have raised social and ethical concerns, hampering the research both in the preclinical and clinical areas (Murry & Keller, 2008; Passier, van Laake, & Mummery, 2008). That’s why iPSC represent a fundamental breakthrough, because they are cells with characteristics similar to embryonic stem cells, but they are generated from somatic tissue, like adult fibroblasts. iPSC are obtained through reprogramming using ectopic expression of genes related to pluripotency (Hochedlinger & Jaenisch, 2006) (Takahashi et al., 2007). They provide an alternative source, easily accessible from patients through a simple skin biopsy, from which it is possible to generate cell lines with cardiogenic potential without the use of embryos. In addition, this strategy can be used to develop patient-specific stem cells, which could be a unique resource in studying genetic mechanisms of disease development, drug mechanisms, and regenerative medicine.
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180 Lee mas

FGF2 plays a key role in embryonic cerebrospinal fluid trophic properties over chick embryo neuroepithelial stem cells

FGF2 plays a key role in embryonic cerebrospinal fluid trophic properties over chick embryo neuroepithelial stem cells

For the different sets of experiments, cultures were made only in a serum- free medium (400 μ l per dish) as negative controls, or alternatively they were supplemented with the following: (1) E-CSF from H.H. 25 chick embryos at 1/ 7 v/v, as a positive control; (2) E-CSF + 2 μ l of FGF2 antibody, diluted 1/100 (Sigma F-3393), to gauge the effect of the specific immunodeprivation of FGF2 in the E-CSF; (3) E-CSF + 2 μ l of FGF2 antibody diluted 1/100 (Sigma F3393), previously blocked with FGF2 at a 1/10 ratio (human recombinant Sigma F0291-25UG), to assess the blocking capacity of FGF2's biological activity by the FGF2 antibody employed; (4) 60 ng of FGF2 (human recombinant, Sigma F0291-25UG) in 400 μ l culture medium in order to confirm the effect of this isolated factor; and (5) E-CSF + 2 μ l of NGF antibody (Sigma N-6655) at 1/100 dilution, to discard any unspecific effects of the antibody added to the culture medium. It is important to note that according to the supplier, both antibodies block the biological activity of the recognized molecule. Occasionally we carried out neuroepithelial explants cultured with a medium previously conditioned by notochord. This took place as follows: fragments of cephalic notochord from 25 H.H. stage chick embryo were dissected with tungsten needles under microscope. Culture plates with 400 μ l of specific medium (DMEM F12, supplemented with 1% ascorbic acid), plus 3 fragments of notochord per dish, were cultured for 24 h under the conditions explained above; after the notochord fragments were removed, use was made of the specific medium for neuroepithelium culture already described. Occasionally we did cultures with a notochord-conditioned medium + FGF2 antibody (2 μ l of FGF2 antibody, diluted 1/100) to verify that the effect of the conditioned medium is due to the presence of this factor.
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15 Lee mas

Low concentrations of nitric oxide delay the differentiation of embryonic stem cells and promote their survival.

Low concentrations of nitric oxide delay the differentiation of embryonic stem cells and promote their survival.

Nitric oxide (NO) is an intracellular messenger in several cell systems, but its contribution to embryonic stem cell (ESC) biology has not been characterized. Exposure of ESCs to low concentrations (2–20 lM) of the NO donor diethylenetriamine NO adduct confers protection from apoptosis elicited by leukaemia inhibitory factor (LIF) withdrawal. NO blocked caspase 3 activation, PARP degradation, downregulation of the pro-apoptotic genes Casp7, Casp9, Bax and Bak1 and upregulation of the anti- apoptotic genes Bcl-2 111, Bcl-2 and Birc6. These effects were also observed in cells overexpressing eNOS. Exposure of LIF-deprived mESCs to low NO prevented the loss of expression of self-renewal genes (Oct4, Nanog and Sox2) and the SSEA marker. Moreover, NO blocked the differentiation process promoted by the absence of LIF and bFGF in mouse and human ESCs. NO treatment decreased the expression of differentiation markers, such as Brachyury, Gata6 and Gata4. Constitutive overexpression of eNOS in cells exposed to LIF deprivation maintained the expression of self-renewal markers, whereas the differentiation genes were repressed. These effects were reversed by addition of the NOS inhibitor L-NMMA. Altogether, the data suggest that low NO has a role in the regulation of ESC differentiation by delaying the entry into differentiation, arresting the loss of self-renewal markers and promoting cell survival by inhibiting apoptosis.
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11 Lee mas

Proposals for embryonic stem cell production without destroying human embryos: scientific and bioethical challenges

Proposals for embryonic stem cell production without destroying human embryos: scientific and bioethical challenges

Through several sequential experiments to determine which genes were essential for this reprogramming process, Takahashi and Yamanaka identified 4 genes which, when injected into skin fibroblasts, were more efficient in producing what they called induced plu- ripotent stem cells (iPSC). These cells demonstrated some of the typical characteristics of ESC: pluripotency markers, capacity to form teratomas and to produce fetal chimeras when injected in a mouse blastocyst. The researchers were surprised that the NANOG gene, known for its importance in maintaining pluri- potency, was not one of the essential genes to produce iPSC. With the reprogramming process through the transduction of the four genes, the NANOG gene and some other endogenous genes involved in the pluripotent state of the cells were expressed, but not the endogenous Oct4 gene. This demonstrates that the introduction of the genes produces a vast modification of the transcription state of the cells. Although the cells had similar characteristics to ESC they were different in some aspects: There was some dissimilarity in gene expression and none of the fetal chimeras produced with these cells developed into an adult mouse. The epigenetic reprogramming was done first with mouse embryonic fibroblasts and then with adult mouse fibroblasts obtained from the tail-tip.
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12 Lee mas

Bioethical implications of research on embryonic stem-cells

Bioethical implications of research on embryonic stem-cells

Abstract: Embryonic stem-cells are capable of differentiation in diverse cellular types and be used, in the future, for treating degenerative pathologies and deficiencies. This study aimed at analyzing the main bioethical implications of research with embryonic stem cells and was based on a bibliographic revision of articles from the Virtual Health Library and the CAPES Portal de Periódicos. This analysis demonstrated that science is still incapable of establishing when human life begins, that the use of embryos for obtaining cells does not achieve consensus among researchers and that medical treatment based on stem cells are still not a reality. It is important to stress the importance of studies with embryonic stem cells but advances do not mean immediate application that may not correspond to expectations and need social control.
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9 Lee mas

Generation of human dopaminergic neurons from induced pluripotent stem cells to model Parkinson's disease

Generation of human dopaminergic neurons from induced pluripotent stem cells to model Parkinson's disease

The specification of a permissive region for DA neuron generation is an essential event that occurs early in mDA neuronal development. The region where mDA neurons are born is characterized by the presence of two instructive signals: fibroblast growth factor 8 (FGF8) expressed at the midbrain-hindbrain border (isthmus) and sonic hedgehog (SHH) expressed in the ventricular zone (reviewed in Smidt and Burbach,2007). Wnt1 and Wnt5a are also expressed in this region and are essential for the formation of the midbrain (reviewed in Smidt and Burbach,2007). The presence of FGF8, SHH and Wnt1 within this area leads to the generation of mDA progenitors that express the following subset of transcription factors: LIM homeo box transcription factor one alpha and beta (LMX1a and LMX1b), MSX homoeobox 1 (MSX1), ortohdenticle homeobox 2 (OTX2), NK6 homeobox 1 (NKX6.1), Engrailed 1 (En1) and achaete-scute complex homolog 1 (MASH1). It has been described that SHH induces the expression of LMX1a, a crucial determinant of mDA neuron fate development (Andersson et al., 2006)(Figure 17). Andersson and colleagues showed that overexpression of Lmx1a in ventral midbrain of chick embryos promoted the generation of DA neurons over other neuronal cell types. This role was confirmed in mouse embryonic stem cells (mESC) overexpressing Lmx1a, where the authors showed higher levels of mDA neurons in overexpressing cells (Friling et al., 2009). It has also been described that Lmx1a starts a signaling cascade that leads to the activation of Msx1a, a transcription factor required for neuronal differentiation. Msx1a, in turn, activates the expression of Ngn2, a transcription factor that activates neurogenesis and inhibits the transcription factor NKX6.1, thus inhibiting alternate fates (Figure 17). Moreover, LMX1A also activates the expression of NURR1 at early and late differentiation stages and of PITX3 during the maturation stage, the latter controlling DA phenotype and survival (Chung et al., 2009). Additionally, SHH and FOXA2 reciprocally induce the expression of one another. FOXA2 is a transcription factor responsible for the activation of NURR1, an essential gene during DA neuron generation (Figure 17) (Chung et al., 2009). LMX1b belongs to the same family of LMX1a and has been shown to have some overlapping functions with LMX1a, although it is also expressed in other brain regions.
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111 Lee mas

Protocols to differentiate embryonic stem cells into insulin-producing cells

Protocols to differentiate embryonic stem cells into insulin-producing cells

Embryonic stem cells represent an interesting alternative to treat dia- betes due to their two main properties: self-renewal by symmetric divisions, and the potential for cell differentiation into insulin-express- ing cells under certain culture conditions. Achieving the latter implies the modification of the culture medium adding specific growth fac- tors and/or reprogramming the cells by transfecting specific DNA constructs. Several laboratories have used one or a combination of such strategies in order to obtain insulin-positive cells with different degrees of success. The main obstacles posed in the different pro- tocols concern the amounts of intracellular insulin stored and se- creted in response to different stimuli, the correct processing of the hormone, the risk of forming teratomas and the immune rejection once cells are transplanted. Promising results have been obtained from protocols which try to recapitulate the pancreas ontogeny in the culture dish. To this end, it is instrumental to understand the embry- onic development process of the human pancreas from definitive endoderm to the adult, as well as its molecular markers and the functional traits of the obtained cells in order to achieve a transplant- able product to cure diabetes. This manuscript explores published protocols following this objective, analyzing the main features that could contribute to elaborate a more definitive strategy. The final protocol must be universal, easily transferable to the clinical practice and, most importantly, liberate patients from the insulin injections without the development of secondary complications.
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10 Lee mas

Cancer Stem Cells are Depolarized Relative to Normal Stem Cells Derived from Human Livers

Cancer Stem Cells are Depolarized Relative to Normal Stem Cells Derived from Human Livers

The results of the present study indicate that primary CSCs derived from human HCC are significantly depo- larized relative to NSCs derived from the same livers. They also indicate that the differences in membrane PDs are associated with differences in GABA A receptor subu- nit expression which favor phasic rather than tonic GABAergic innervation and thereby, a more depolarized state for CSCs. Finally, they demonstrate that CSCs and NSCs can be hyperpolarized by the addition of specific GABA A receptor agonists.

7 Lee mas

Terapia celular dirigida contra la sordera: estudio de la capacidad de transdiferenciación de células madre mesenquimales humanas y de fibroblastos hacia células sensoriales del oído interno

Terapia celular dirigida contra la sordera: estudio de la capacidad de transdiferenciación de células madre mesenquimales humanas y de fibroblastos hacia células sensoriales del oído interno

The presence of stem cells in the post-natal inner ear appears contradictory with the observed lack of regeneration in the mature cochlea following otic damage. However, lower numbers of sphere-forming cells in early postnatal cochleae compared to embryonic tissue have been reported by Savary and co-workers (2008), and Oshima and colleagues (2007) recently demonstrated that there is a radical loss of stem cells in the mammalian cochlea during postnatal maturation of the auditory system. While cochlear tissues isolated from mice not older than 3 weeks of age harbour sphere- forming cells, this capacity appears to be practically absent in the cochlea of older mice. This seems to be due to either death of these stem/progenitor types or to a loss of their stem cell features. Regarding this latter possibility, in the young mammalian cochlea it is not yet clear which cell population stem cells are derived from. Zhai and co-workers (2005) isolated a population of HC progenitors from the lesser epithelial ridge (LER) of neonatal rats. This tissue is juxtaposed to the outer hair cells and, together with the medially located greater epithelial ridge (GER), it has been proposed as a potential source for HC progenitors, as both of these tissues may give rise to HCs when forced to express Atoh1 (Zheng and Gao, 2000; Shou et al., 2003; Zhai et al., 2005). Zhai and colleagues (2005) demonstrated that isolated LER cells grown as spheres in the presence of EGF proliferated and could differentiate into HC-like and SC-like cells when co-cultured with utricular mesenchymal cells, in a pattern reminiscent of the sensory epithelium in vivo. In another set of experiments, Malgrange and colleagues (2002) detected nestin expression in the GER region and below the IHC of rats between embryonic day 19 (E19) and postnatal day 7 (P7); they observed that in vitro non-adherent culture of nestin-positive cells isolated from the newborn
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224 Lee mas

Células madre mesenquimales para la regeneración de tejidos: ¿Por qué siguen siendo una promesa sin cumplir?

Células madre mesenquimales para la regeneración de tejidos: ¿Por qué siguen siendo una promesa sin cumplir?

Since they were initially identified more than 40 years ago, mesenchymal stem cells (MSCs) were recognized as an important therapeutic alternative for diseases characterized by acute or chronic loss of tissue, thanks to their proliferation and differentiation ability, which would allow the replacement of lost cells and their structural and functional recuperation. Evidence suggesting the therapeutic potential of these cells for a vast group of diseases increases day by day, at least in preclinical experimental models. However, clinical trials have been unable to obtain consistent and categorical results to demonstrate this capacity. This review aims to provide, an overview on the current status of the conceptual development on the therapeutic properties of MSCs, and a critical analysis of some factors which have hindered the application of this therapeutic option in daily clinical practice.
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10 Lee mas

TítuloProstate carcinoma and stem cells

TítuloProstate carcinoma and stem cells

Stem cells, as classically defined, are cells with a capacity to self-renew and to generate daughter cells that can differentiate down several cell lineages to form all of the cell types that are found in the mature tissue. Stem cells and tumour cells have many similar features, including infinite lifespan, self-renewal, multidrug resistance, telomerase expression and, in the instance of the prostate, androgen independence. Evidence supports a role for stem cells in the etiology of many types of cancer. The evolution of androgen-independent prostate carcinoma may reflect the emergence of stem like prostate tumour cells. Because cancer may be a disease of stem cell lineages and Shh-Gli signalling controls the behaviour of precursors and of cells with stem cell properties in the mammalian tissues, prostate cancer might derive from inappropriate expansion of prostatic epithelial stem cell lineages caused by abnormal Shh-Gli function. This review attempts to integrate these recent results.
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18 Lee mas

Material agency in the laboratory and the clinic

Material agency in the laboratory and the clinic

6 shape the experiences of clinicians and researchers who come into contact with them. In countering the universalizing tendencies of the ELSI literatures to view embryos, researchers and clinicians as abstract entities functioning within a much larger community, the social worlds literature seeks to locate and identify the specificity of the experiences of practitioners obliged to work within the ethical, legal and moral frameworks of communities which often have strongly conflicting ideas about how embryos should be treated. For us, of interest here is that embryos are defined and used in most cases as though they are entirely passive objects on which the processes of human cultural institutions act. In other words, we are arguing here that the ‘moral landscapes’ that researchers, clinicians and other professionals engaged in the conduct of embryo research adopt seem to arise without consideration of how such landscapes could be influenced by the actual topology of the material facticity of human embryos. We thus propose here that instead of seeing in-vitro embryos as passive objects of culture they may rather be imagined in terms of their material agency.
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17 Lee mas

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