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A Brief History of Pluripotent Cells for Huntington’s Disease

Huntington’s Disease (HD) is an autosomal-dominant progressive neurodegenerative disease, characterized by movement, cognitive, and emotional disorders caused by an expanded CAG repeat in exon 1 of the Huntingtin (HTT) gene resulting in an expanded polyglutamine stretch known as the polyQ region or stretch.   Generally, fewer than 36 CAG repeats in the polyQ region is observed in healthy patients but the presence of more than 40 CAGs invariably causes disease onset within a normal lifespan, and longer repeats predict younger disease presentation.   The classic clinical features, typically of adult onset, are progressive motor impairment, cognitive decline, chorea and seizures caused by neural degeneration, particularly of striatal medium spiny neurons (MSNs) expressing dopamine- and cAMP-regulated phosphoprotein (DARPP-32).   Animal studies (Heng et al and Davies et al) have not been found to reflect all HD pathologies adequately and thus so far have not led to successful humantherapies.Therefore, embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) represent the best resources for modelling HD both for understanding disease mechanisms and uncovering potential therapeutic targets.

Hearing restoration using human embryonic stem cells in deafened gerbils

An estimated 250 million people worldwide have a disabling hearing impairment (WHO, 2001). This figure has risen dramatically in the last 15 years due to improvements in diagnosis, increasing longevity of the population and a combination of other factors including noise/occupational induced hearing loss and ototoxicity (damage to the Cochlea or auditory nerve), particularly from the use of aminoglycoside antibiotics.

Did Viruses Drive Mammalian Development? “Embryonic stem cell potency fluctuates with endogenous retrovirus activity”

Previous studies have shown that embryonic stem cell (ESC) cultures are heterogeneous with respect to certain transcription factors (e.g. Dppa3, Nanog, Sox17 and Gata6) and could imbue specific cells with distinct attributes (Hayashi et al and Singh et al). Now in a study in Nature, researchers from the group of Samuel L. Pfaff at The Salk Institute for Biological Studies, California have identified a transient cell population in both ESC and induced pluripotent stem cell (iPSC) cultures that expresses genes usually observed in the totipotent 2-cell embryo (Macfarlan et al). The group go on to demonstrate that this expression profile is driven by regulatory regions of endogenous retroviruses, which are known to be actively expressed at the 2-cell stage (Evsikov et al, Kigami et al and Peatson et al) but repressed thereafter (Ribet et al and Svoboda et al), and that this regulatory mechanism may have helped to drive cell-fate regulation in placental mammals (Macfarlan et al).

Early Human Progenitor Identification for Therapy and Research “Isolation of primitive endoderm, mesoderm, vascular endothelial and trophoblast progenitors from human pluripotent stem cells”

The scarcity of progenitor cells obtained directly from human embryos for application in basic research and the development of cellular therapies leaves human pluripotent stem cells (hPSCs), such as human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), as the most useful cell types to this end. However, the identification of progenitors from hPSC sources suffers from some impediments; the pleiotropic expression patterns of embryonic genes and the heterogeneity of the cultures. Now, in a study published in Nature Biotechnology, researchers from the laboratories of Irving L Weissman & Yoav Soen have identified early committed progenitors exhibiting gene signatures of mesoderm, trophoblast and vascular endothelium from hESCs and hiPSCs through large scale antibody screening, population identification and transcriptional analysis. Such work provides the means to purify clinically relevant progenitors for therapy, in addition to their use as tools to study progenitor commitment from pluripotent cells (Drukker et al).

‘miR’ members of the miR-290 family implicated in pluripotency

Original article from STEM CELLS

‘miR-290 Cluster Modulates Pluripotency by Repressing Canonical NF-ĸB Signaling’

MicroRNAs (miRNA) have emerged as central players in regulating multiple aspects of cellular function, including the induction and control of pluripotency. The mir-290 cluster on chromosome 7 is the most abundant miRNA family in mouse embryonic stem cells (mESCs), this region alone encoding for 14 mature miRNAs. These regulate important cellular processes by inhibiting the transcription of numerous target mRNAs, and deficiency of the mir-290 cluster causes partially penetrant embryonic lethality and defective germ cells. Yet the interaction between this cluster and its target genes is still not clearly understood. In a report from Lüningschrör et al.1 from the University of Bielefeld in Germany, it has been revealed that the nuclear factor kappa B (NF-ĸB) subunit p65 is a major target of mir-290 family members miR-291b-5p and miR-293, and that these miRNAs mediate their effects by targeting the p65 coding sequence (cds).

HIF-only Stem Cells Could Help Tissue Regeneration!

Original article from STEM CELLS

HIF-2α Suppresses p53 to Enhance the Stemness and Regenerative Potential of Human Embryonic Stem Cells

Tissue stem cells are understood to contribute to the repair and regeneration of the inflamed and damaged tissues through the secretion of growth factors and antioxidants (Prockop 2009) which they express at high levels (Kim et al). Similarly, human embryonic stem cells (hESCs) have been reported to exert cytoprotective activity following tissue injury. However, as sites of injury and inflammation are characterized by hypoxia and production of reactive oxygen species (ROS) which induce p53 activation (Momcilovic et al), it has been suggested that stem cells may have specific mechanisms to maintain an undifferentiated state at the area of injury in order to serve their cytoprotective activity, such as the suppression of p53 during hypoxia and oxidative stress. Das et al now report that their studies using hESCs as a model system have uncovered a mechanism by which some hESCs, when exposed to hypoxia or oxidative stress, induce HIF-2a (Maxwell 2005) leading to a reduction in p53 levels and enhanced levels of Oct4 and Nanog. This elicits a highly cytoprotective and pluripotent state in hESCs which may benefit the surrounding tissues during the process of tissue regeneration.

More Me: More iPSC?

Original article from STEM CELLS

DNA Hypermethylation in Somatic Cells Correlates with Higher Reprogramming Efficiency

Widespread epigenetic remodelling is acknowledged as being a critical process in the reprogramming of somatic cells to induced pluripotent stem cells (iPSCs), and the incomplete erasure of the epigenetic signature of somatic cells (“epigenetic memory”) can influence their differentiation properties (Kim et al and Polo et al). While many comparisons have found iPSCs and embryonic stem cells (ESCs) to be very similar, stochastic differences and differences shared between independent iPSC lines have been observed (Bock et al, Lister et al and Ohi et al). However, within these comparisons, no studies have analysed the differences in epigenetic patterns in iPSCs derived from somatic cells which have different reprogramming efficiencies. Researchers from the laboratories of Manel Esteller and Juan Carlos Izpisua Belmonte now propose that higher reprogramming efficiency correlates with the hypermethylation of tissue-specific genes rather than with a more permissive pluripotency gene network through their studies in reprogramming human keratinocytes, fibroblasts and their comparison to hESCs (Barrero and Berdasco et al).

Pluripotency Factors Worm their Way towards Mammals

Original article from STEM CELLS

A Comparative Transcriptomic Analysis Reveals Conserved Features of Stem Cell Pluripotency in Planarians and Mammals

Planarians are free-living freshwater flatworms well-known for their extreme regenerative abilities linked to the existence of a large population of pluripotent adult stem cells (ASCs) (Wagner et al 2011) that comprise approximately 10–20% of the cells in the animal (Eisenhoffer et al 2008). While the existence of stem cells is ancestral to multicellular animals (Watanabe et al 2009 and Bosch 2009) it is unknown whether stem cells from diverse species share conserved transcriptional networks associated with stem cells, pluripotency and self-renewal. Now in a study from the laboratory of Bret J. Pearson, the transcriptomes of planarian adult stem cells and those of human (hESCs) and mouse embryonic stem cells (mESCs) have been compared, which has uncovered conserved factors that can affect the stem cell-associated functions in planarians (Labbé et al 2012).

p21 Regulation Uncovered in ESCs

Original article from STEM CELLS

miRNAs Regulate p21Waf1-Cip1 Protein Expression and the DNA Damage Response in hESCs

p53-p21-mediated regulation of the G1/S checkpoint pathway of the human cell cycle is a vital control point of proliferation, and the molecular pathways governing the G1/S transition are also known to play a key role in the DNA damage response (DDR).   Human embryonic stem cells (hESCs) appear to have a unique cell cycle, with a shortened G1 phase (Becker et al)which only becomes lengthened upon differentiation (Filipczyk et al).   Further, a lack of p21 protein but, importantly, not of mRNA in hESCs has suggested that p21 plays no role in the G1/S transition (Bárta et al) and therefore the “canonical” p53-p21 axis of the G1/S checkpoint pathway is described as non-functional in hESCs, becoming activated only upon differentiation (Neganova and Lako).   Indeed, it has been proposed that the lack of an active p53-p21 pathway is required to prevent premature differentiation of hESCs (Maimets et al).   Now, a study from the laboratory of Ales Hampl has confirmed that while p53 is active in hESCs following DNA damage, p21 protein is not produced as part of the DNA damage response (DDR).   Furthermore they provide data suggesting that this is due to the actions of multiple microRNA (miRNA) families on p21 mRNA also suggesting that this mode of regulation is important in governing the G1/S transition and cell cycle checkpoint in undifferentiated hESCs (Dolezalova and Mraz et al).

A “Stiff” Examination Leads to Alternate 2i

Original article from STEM CELLS

Dual Inhibition of Src and GSK3 Maintains mESCs, Whose Differentiation Is Mechanically Regulated by Src Signaling

Much is known about the effects of soluble factors and how they impact signalling pathways to control the basic biology of embryonic stem cells (ESCs).   Recent studies have revealed that the mechanical environment can also influence the behaviour and function of mouse ESCs (mESCs) (Chowdury et al and Sun et al) but the signalling pathways which are involved are relatively unknown.   Now, findings from the laboratory of Yasuhiro Sawad at the National University of Singapore reveal a role for Src-ShcA-MAP kinase signaling in the mechanical regulation of mESC properties and that dual inhibition of MAPK and Src represents a new method to derive and maintain mESCs in serum-free conditions (Shimizu et al).

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