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Pluripotent Stem Cells

PRDM14 Enters the Pluripotency Network

By Stuart P. Atkinson

Gene by gene, we are beginning to unravel and understand those members of the pluripotency network which give embryonic stem cells (ESCs) their identity. Other than giving us an understanding of the molecular networks, signalling pathways and regulatory mechanisms which exist in ESCs, such knowledge is also allowing us to make more and more critical studies of induced pluripotent stem cells (iPSCs) to establish whether these are bona fide “replacements” for embryo derived pluripotent cells. To this end, the group of Huck-Hui Ng utilising genome wide RNAi screens have attempted to further identify genes and pathways present in ESCs, with more than 21,000 genes targeted. This study, published in Nature, initially used an OCT4-GFP reporter to establish a list of potentially important genes for ESC pluripotency, which showed enrichment for transcription and translation factors. Further protein-protein interaction analysis found components of the INO80 chromatin remodelling complex, the mediator complex, the COP9 signalosome, the TAF complex, the eukaryotic initiation factor complex and the spliceosome complex which had not been associated with important functions in hESC.

First spinal cord injury patient enrolled for Geron stem cell trial

The first official clinical trial using stem cells to treat patients with spinal injury is now underway (also see ‘US give Geron Go-ahead for ESC Trial for Spinal Cord Injury’). The first patient to receive the trial treatment was enrolled on Monday at Shepherd Center in Atlanta, Georgia. Another 9 patients who have recently suffered spinal cord injuries will be enrolled from 6 other potential sites in the United States to be listed on the company’s website. Patients undergoing the trial treatment will receive transplants of hESC-derived oligodendrocyte progenitor cells within 14 days of the injury.

Rapid and highly efficient reprogramming of cells with RNA

Research published in the 30th September edition of Cell Stem Cell reports that human induced pluripotent stem cells (hiPSCs) can be rapidly and efficiently derived with messenger RNA (mRNA). This research, from the laboratory of Derrick Rossi shows that daily transfection of differentiated human cells with modified synthetic mRNAs encoding the four canonical Yamanaka factors KLF4, c-MYC, OCT4, and SOX2 can reprogram cells to pluripotency with conversion efficiencies and kinetics substantially superior to established viral protocols. The authors also demonstrate the directed differentiation of RNA-hiPSCs to terminally differentiated muscle cells. The reprogramming of human fibroblasts using exactly this strategy has already been published from the laboratory of David Givol, albeit with reduced efficiency.

Yamanaka Factors, Version 2.0

With each month’s Featured Lab Series, the Stem Cells Portal extend an invitation to one of the Featured Lab members to contribute a short review of a paper of their interest for feature on the Stem Cells Portal. This month, Minh Hong from the Kaufman Laboratory has contributed an article which focuses on a key paper published recently in PNAS that addresses the further evolution of reprogramming factors for induced pluripotency.

Gene Expression Goes Loopy for Mediator and Cohesin

By Stuart P. Atkinson

DNA looping to allow proximity of enhancers and promoter sequences has been suggested as a means to regulate gene expression, but the mechanisms by which this occurs and the factors involved are still to be fully understood. However an advance online publication from Nature uncovers a mechanism by which DNA-looping-mediated regulation of gene expression occurs in mouse embryonic stem cells (mESC).

Know which way to miRoam: Red means ‘GO’, Green ‘STOP’!

Know which way to miRoam: Red means ‘GO’, Green ‘STOP’!

By Carla B. Mellough

Induced pluripotent stem cells (iPSC) are shown to have many of the characteristics of human embryonic stem cells (hESC) including prolonged proliferative capacity and differentiation across all germ layers. The therapeutic potential of human iPSC (hiPSC), however, remains controversial. Whilst the use of hiPSC would overcome some of the ethical issues surrounding hESC, their suitability and usefulness as a replacement cell type has recently fallen into question. For example, concerns have been raised over the retention of epigenetic memory from the iPSC cell of origin (see iPSC don’t forget their origins) which questions their level of reprogramming, and may be the cause of their apparently biased pluripotent potential. However, conversely, it has been suggested that in fact iPSC and hESC are very similar (see Similar Human iPSC and ESC Chromatin States Suggests Usefulness in Regenerative Medicine). Various hiPSC clones differ with regards to their level of reprogramming and differentiation potential and being able to identify those of greatest potential therapeutic value would no doubt help the advancement of hiPSC research.

STEM CELLS’ Position Statement on hESC Research

STEM CELLS’ Position Statement on hESC Research

Durham, North Carolina, August 27, 2010 — The Journal STEM CELLS® has published many important and exciting achievements in the field of stem cells during its twenty-eight year history. Through scientific discovery, the Journal reports on both adult and human embryonic stem cells (hESCs). The Journal believes that the scientific community benefits from research on all stem cell types in order to maximize our basic biological knowledge and our ability to fight debilitating human diseases. Therefore, we applauded the US Food and Drug Administration (FDA) in July when it approved the first authorized clinical trials using hESCs to treat spinal cord injury.  This decision encouraged researchers, clinicians, and patients alike.

Similar Human iPSC and ESC Chromatin States Suggests Usefulness in Regenerative Medicine

From Cell Stem Cell

Research published in the 6th August edition of Cell Stem Cell suggests that human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) may be more similar than previously thought. This research, from the laboratory of Richard A. Young shows that genome-wide maps of H3K4me3 and H3K27me3 in a panel of hESC and hiPSCs showed little differences and similar gene expression profiles. Within the same edition of Cell Stem Cell, a study from the laboratory of James B. Cooper suggests that many changes between hESC and hiPSC observed may be due to the micro-environmental context in which the cells were grown and, perhaps, analysed. Also from the same edition comes a report from Kathrin Plath and William E. Lowry who discuss the meta-analyses employed when studying expression in hESC vs. hiPSCs in order to optimize “best practice” to minimize laboratory-borne differences between these cell types.

However this does contradict recent papers which suggest that iPSC, when at low passage, are transcriptionally and epigenetically different (see recent Editorial - iPSC don´t Forget their Origins) and also exhibit differences at imprinted genes at later passages. Perhaps an expansion to a panel of histone modifications and including DNA methylation and miRNA analysis may give us a clearer story of the relative similarities and differences between hESC and hiPSC.

References

Cell Stem Cell
Chromatin Structure and Gene Expression Programs of Human Embryonic and Induced Pluripotent Stem Cells
Matthew G. Guenther et al.

Cell Stem Cell
Lab-Specific Gene Expression Signatures in Pluripotent Stem Cells
Aaron M. Newman and James B. Cooper

Cell Stem Cell
Molecular Analyses of Human Induced Pluripotent Stem Cells and Embryonic Stem Cells
Mark H. Chin, Matteo Pellegrini et al.

Cell Stem Cell News Preview

Recreating Pluripotency?
Kyle M. Loh and Bing Lim

iPSC don´t Forget their Origins.

By Stuart P. Atkinson

Our latest news section recently highlighted the publication of two advance articles from Nature and Nature Biotechnology which suggest that induced pluripotent stem cells (iPSCs) retain memories of the differentiated cell type from which they were derived; their cell of origin. Understandably, this raises several questions about the comparability of iPSCs to human embryonic stem cells (hESCs), particularly since the concept of epigenetic memory has arisen in the production of cloned mammals using somatic cell nuclear transfer. Given the importance of this topic, here we provide a more in-depth discussion of these two articles.

A Nucleolar Link to Pluripotency and Reprogramming?

By Stuart P. Atkinson

Delineation of the mechanisms by which embryonic stem cells (ESC) remain pluripotent and maintain the ability to differentiate across all germ lineages has attracted many studies which altogether can be consolidated into an information network which combines transcription factors, chromatin and DNA modifications, small RNAs and signal transduction pathways. Analyses of the interactions within this network will unravel the mechanisms underlying these properties into something we can begin to understand and appreciate. Such analysis may also lend itself to the discovery of new ways to produce safer and better induced pluripotent stem cells (iPSC) reprogrammed from somatic cells. In order to uncover new mechanisms underlying pluripotency and lineage specification, researchers from the laboratory of Sheng Ding have taken a new approach, using individually-arrayed cDNA libraries representing more than 30,000 clones, for the identification of new genes which affect pluripotency. This new study is published online in Stem Cells.

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