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Damage Removal by Alternate Proteasome in ESCs

“Removal of damaged proteins during ES cell fate specification requires the proteasome activator PA28”

Embryonic stem cells (ESCs) have been shown to contain relatively high levels of ‘damaged’ proteins such as carbonylated proteins (Hernebring et al 2006), which are eliminated upon differentiation and are also observed to accumulate in aging cells, (Hernebring et al 2006). Additionally, immunoproteasome subunit expression, required for the production of peptide antigens for display by antigen-presenting cells (Strehl et al) has been noted to be significantly altered during ESC differentiation (Atkinson and Collin et al), suggesting that the specific proteasomal subunits may be dynamically regulated during ESC self-renewal and differentiation. Now, in Scientific Reports, researchers from the laboratory of  Thomas Nyström at the Department of Chemistry and Molecular Biology, University of Gothenburg, Sweden have shown that damaged protein removal during ESC differentiation is associated with the induction of the proteasome activator PA28, normally associated with the immunoproteasome (Hernebring et al).

Modelling AD in iPSCs Provides Therapeutic Clues

“Modeling Alzheimer’s Disease with iPSCs Reveals Stress Phenotypes Associated with Intracellular Aß and Differential Drug Responsiveness”

Oligomerisation of amyloid-β peptide (Aβ) leading to amyloid plaques in the brain is thought to play a role in the pathogenesis of Alzheimer’s disease (AD) in humans (Kuo et al,  Noguchi et al and Shankar et al) but the mechanism involved is still unclear. Induced pluripotent stem cell (iPSC) technology now provides a means to study the development of this disease and the effects of Aβ oligomers and will also allow for the screening of therapeutic drugs. To this end, researchers from the laboratory of Nobuhisa Iwata and Haruhisa Inoue have reported the derivation and neuronal/astroglial differentiation of iPSCs derived from patients carrying various AD-associated genetic mutations, and have found that Aβ oligomers are not proteolytically resistant and that docosahexaenoic acid (DHA) treatment attenuated cellular stress phenotypes of AD neural cells containing Aβ oligomers (Kondo et al).

 

Corrected iPSC-Mediated DMD Therapy

“An ex vivo gene therapy approach to treat muscular dystrophy using inducible pluripotent stem cells”

Induced pluripotent stem cell (iPSC)-derived myogenic progenitors are considered a possible treatment for Duchenne muscular dystrophy (DMD), a progressive and incurable neuromuscular disease. This would involve the ex vivo correction of the mutation in the Dystrophin gene which causes DMD, a strategy shown to be successful in mouse models of sickle cell anaemia (Hanna et al) and β-thalassaemia (Wang et al). In a recent report in Nature Communications, the laboratory of Rita C. R. Perlingeiro at the Lillehei Heart Institute, University of Minnesota, USA have  combined an ex vivo genetic correction strategy and their efficient protocol to generate skeletal muscle stem/progenitor cells with significant regeneration potential (Darabi et al) to produce cells which have the capacity to promote substantial muscle regeneration in vivo accompanied by functional improvement (Filareto et al).

 

Adult Disease Model from iPSC Progeny

“Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs”

Modelling genetic disorders using induced pluripotent stem cells (iPSCs) is an emerging tool for researchers;  however cells derived from iPSCs, such as cardiomyocytes (CMs), have not yet been qualified as useful models of adult disease phenotypes. Now researchers from the group of Huei-Sheng Vincent Chen at the Sanford-Burnham Medical Research Institute, California, USA have studied the inherited heart disease arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) (Calkins and Marcus) an inherited heart disease characterized by pathological fatty infiltration and cardiomyocyte loss in the right ventricle. From patient-specific mutation bearing fibroblasts they generated iPSCs and subsequently iPSC-CMs; finding that induction of adult-like metabolism has a critical role in establishing an adult-onset disease model (Kim et al).

Promise of Therapeutically Relevant T Cells

“Regeneration of Human Tumor Antigen-Specific T Cells from iPSCs Derived from Mature CD8+ T Cells” and “Generation of Rejuvenated Antigen-Specific T Cells by Reprogramming to Pluripotency and Redifferentiation” 

Antigen-specific T cells have been proposed as a potentially important therapeutic cell type in the prevention or treatment of cancer or viral infections and, while cytotoxic T lymphocytes (CTLs) have been used in a clinical setting (Sensi and Anichini), there remains problems with the generation of sufficient numbers of fully functional cells for wider therapeutic use. Now, two groups (Hiroshi Kawamoto at the RIKEN Research Center for Allergy and Immunology, Yokohama, Japan and Shin Kaneko and Hiromitsu Nakauchi at the Center for Stem Cell Biology and Regenerative Medicine at The University of Tokyo, Japan) have proposed that induced pluripotent stem cell (iPSC) production from T cells and subsequent redifferentiation back into T cells could be an answer to this problem. In these two studies they describe the generation of iPSCs from a cancer-epitope specific T cell (Vizcardo, Masuda and Yamada et al) and an HIV type 1-epitope specific T cell (Nishimura et al) which both give rise to fully functional epitope-specific mature T cell progeny.

iPSC-Progeny Aid Remyelination

“Human iPSC-Derived Oligodendrocyte Progenitor Cells Can Myelinate and Rescue a Mouse Model of Congenital Hypomyelination”

Human embryonic stem cells (hESCs) (Hu et al, Izrael et al and Keirstead et al) and foetal and adult human brain tissue (Dietrich et al, Roy et al and Windrem et al 2004) have both been used as sources of human glial progenitor cells capable of oligodendrocytic maturation and myelination for cell-based repair of demyelinated lesions. The problem of immune rejection, however, looms over these strategies. However, a recent study from the laboratory of Steven A. Goldman at the Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, NY, USA has demonstrated that oligodendrocyte progenitor cells (OPCs) can be effectively generated from patient-specific skin-derived human induced pluripotent stem cells (hiPSCs) which can differentiate into myelinogenic oligodendrocytes, and also astrocytes, which can mediate myelination in the brain in a mouse model of congenital hypomyelination (Wang et al); altogether outlining a new resource of less immunogenic cells for this approach.

Source of ESC Genomic Instability Uncovered

Original article from STEM CELLS

"Decrease in Abundance of Apurinic-Apyrimidinic Endonuclease Causes Failure of Base Excision Repair in Culture-Adapted Human Embryonic Stem Cells"

Unfortunately, one of the characteristics of long term cultivation of human embryonic stem cells (hESCs) in vitro is the accumulation of chromosomal abnormalities (Spits et al and Lefort et al) which may be selected for to allow continued proliferation of hESCs under sub-optimal in vitro growth conditions (Spits et al, Baker et al and Harrison et al) . Failure of base excision repair (BER), one mode of DNA damage repair, is associated with the increase in mutant frequency in germ cells with increasing parental age and is associated with the downregulation of apurinic/apyrimidinic endonuclease 1 (APE1) (Intano et al), which led researchers from the laboratory of Vladimír Rotrekl at Masaryk University, Brno, Czech Republic to study if such a mechanism may lead to the accumulation of mutations in hESCs. They now report in Stem Cells that BER is less efficient during prolonged in vitro growth of hESCs and is correlated to a decrease in APE1 expression; thereby suggesting that this may be an important source of genomic instability and may allow for culture adaptation (Krutá et al).

Rb-Mediated Stem Cell Control Delineated

Original article from STEM CELLS

"An Oct4-pRb Axis, Controlled by MiR-335, Integrates Stem Cell Self-Renewal and Cell Cycle Control"

The Retinoblastoma (pRb) protein has been linked to the regulation of the self-renewal capabilities of mouse embryonic stem cells (mESCs) (Dannenberg et al and Kim et al) and also their differentiation, through the modulation of the cell cycle program (Ballabeni et al, Savatier et al and White et al). Overall these studies demonstrate that the inactivation of the pRb pathway inhibits mESC differentiation and consequently enhances the self-renewal potential of mESC. Now further studies of pRb in mESCs by researchers from the group of Roberta Benetti at the Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Trieste, and Università degli Studi di Udine, Italy, have recently reported in Stem Cells the existence of a new regulatory circuit comprising miR-335, Oct4, and the pRb pathway which functions to control mESC self-renewal and differentiation (Schoeftner and Scarola et al).

A Role for Mitochondrial Genetics in ESCs Described

Original article from STEM CELLS

"Mitochondrial DNA Haplotypes Define Gene Expression Patterns in Pluripotent and Differentiating Embryonic Stem Cells"

The mitochondrial genome (mtDNA) encodes some of the key subunits of the electron transfer chain (ETC), essential for the generation of ATP through oxidative phosphorylation.    mtDNA haplotypes have evolved which lead to the existence of several different phenotypes (see paper for extended references), although what links mtDNA haplotypes and the mature phenotype is relatively unknown.   A great deal of research has however suggested that mtDNA is integral to cell differentiation and thus the cell phenotype (Crespo et al, Inoue et al, Mandal et al and Wang et al).   The effect of mtDNA haplotypes can be studied through the generation of cytoplasmic hybrids (cybrids) which can be made to have different mtDNA haplotypes through the use of divergent strains or species of animal (Kenyon and Moraes, McKenzie and Trounce and McKenzie et al).   Now, researchers from the laboratory of Justin C. St. John at Monash Institute of Medical Research, Monash University, Victoria, Australia, using mouse embryonic stem cell lines (mESCs) harbouring mitochondrial DNA haplotypes from different species, have found haplotype-specific expression of genes involved in pluripotency, differentiation, mitochondrial energy metabolism, and DNA methylation and their influence on differentiation is reported (Kelly et al).

Deadly Duo beat Resistant Breast Cancer

 “Synergistic Effect of the γ-Secretase Inhibitor PF-03084014 and Docetaxel in Breast Cancer Models”

From Stem Cells Translational Medicine

Notch signaling, which plays a role in a variety of developmental processes by controlling cell fate decisions through the regulation of interactions between physically adjacent cells, has also been linked to tumourigenesis, especially breast cancer (Ranganathan et al).   Activation of this pathway leads to the γ-secretase-mediated cleavage of Notch and the release of the Notch intracellular domain (NICD), which translocates to the nucleus and activates a cascade of transcriptional events that mediate cellular proliferation, differentiation, and apoptosis. With regards to breast cancer, elevated levels of Notch signalling have been observed in  breast cancer tumour-initiating cells (TICs) compared with bulk tumour cells (Grudzien et al, Farnie and Clarke and Wright et al) suggesting that Notch may be an effective target for anti-tumourigenic therapies. Indeed previous efforts to inhibit Notch signalling, by the blockade of Notch ligands Dll4 (Hoey et al) and the γ-secretase inhibitor (GSI) (Grudzien et al and Kondratyev et al], reduced TIC numbers, while the γ-secretase inhibitor PF-03084014 has been shown to be effective in haematological and breast xenograft models (Wei et al and Zhang et al). Now, researchers from the group of James G. Christensen at the Oncology Research Unit, Pfizer Global Research and Development, San Diego, USA have studied the synergistic effects of PF-03084014 with docetaxel, a common chemotherapeutic, in triple-negative breast cancer, finding that PF-03084014 significantly enhanced the antitumor activity of docetaxel and report on the mechanisms behind this effect (Zhang et al).

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