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Pluripotent Stem Cells

Muse-ings on Reprogramming: Multilineage-differentiating stress-enduring (Muse) cells are a primary source of induced pluripotent stem cells in human fibroblasts

From PNAS
By Stuart P. Atkinson

Many questions surrounding induced pluripotent stem cells (iPSCs) still remain, including a definitive answer to the question of the origin of the cells which ultimately undergo reprogramming. Two models exist; the stochastic model which suggests that random cells from an initial culture will eventually become iPSCs, and the elite model, which posits that only a few cells from within a culture have the ability to become reprogrammed, hence the low relative efficiency of the reprogramming process. In the elite model, it is supposed that such cells may be tissue-specific stem/progenitor cells which might already express certain factors required for the reprogramming process. A recent study in Stem Cells from the lab of Rudolf Jaenisch (Kim et al), also reported on the Stem Cells Portal (Reprogramming of Postnatal Neurons into Induced Pluripotent Stem Cells by Defined Factors) suggested that a pure terminally differentiated population of cells could be reprogrammed with the expression of Oct4, Sox2, Klf4 and Myc (OSKM) but only with expression of Rest and under conditions of p53 inhibition, giving some credence towards the stochastic model. However, a study in PNAS from the lab of Mari Dezawa at the Tohoku University Graduate School of Medicine, Sendai, Japan, suggest that only a small sub-population of cells from a naïve dermal fibroblast culture which express stem cell-like properties can be reprogrammed (Wakao et al), thus instead supporting the elite model.

Immunogenicity of Induced Pluripotent Stem Cells

From Nature
By Stuart P. Atkinson

For many, induced pluripotent stem cell (iPSC) generation holds the key to the generation of patient-specific (autogenic) cells and tissues which could be used to treat various conditions and diseases. Therefore, one would expect that cells differentiated from iPSC which have been generated from our own somatic cells would be immune-tolerated. However, this assumption has never been tested. A recent proof (Zhao et al) published as an advanced online article on Nature from the lab of Yang Xu at the Division of Biological Sciences, University of California, San Diego now begins to address this concern.

Single Transcription Factor Reprogramming of Hair Follicle Dermal Papilla Cells to Induced Pluripotent Stem Cells

From the June 2011 Issue of Stem Cells
Paper Commentary by Stuart P. Atkinson

A safe and accessible source of somatic cells which are amenable to reprogramming and the generation of induced pluripotent stem cells (iPSCs) is currently very much sought after. While some adult stem cell sources are readily reprogrammable with one or two factors, neural progenitor cells are not a readily accessible population (Kim et al and Kim et al). So, can we find another source? Skin dermal papilla (DP) cells are a specialised mesenchymal stem cell type involved in hair morphogenesis and regeneration. Previous studies into the reprogramming of DP cells have shown that Sox2, Klf4 and Myc were already expressed and so DP cells could be reprogrammed using forced expression of Oct4 and Klf4 alone (Rendl et al and Tsai et al). The next step was to try the reprogramming process with only one factor, and a study (Tsai et al) which is presented in the June edition of Stem cells from the group of Michael Rendl at the Mount Sinai School of Medicine, New York, USA does just that – with Oct4.

Snail and the microRNA-200 Family Act in Opposition to Regulate Epithelial-to-Mesenchymal Transition and Germ Layer Fate Restriction in Differentiating ESCs

From the May 2011 Issue of Stem Cells
Paper Commentary by Stuart P. Atkinson

Recent high impact studies have shown that the reprogramming of somatic cells towards pluripotency requires a mesenchymal-to-epithelial transition (MET) (Li et al and Samavarchi-Tehrani et al) which is in part mediated by the function of microRNA (miRNA) species (Liao et al and Subramanyam et al). However, the role of the epithelial-to-mesenchymal transition (EMT) during the differentiation of embryonic stem cells (ESCs) and its potential role in fate commitment have not yet been studied in great detail. Now, in a study published in the May edition of Stem Cells, researchers from the lab of Kenneth M. Murphy at the Washington University School of Medicine, St. Louis, Missouri, USA have begun to unravel the important pathways required for the early differentiation and fate commitment in ESC, and indicate an important role for the tight regulation of EMT controlled by miRNA (Gill et al).

Reprogramming of Postnatal Neurons into Induced Pluripotent Stem Cells by Defined Factors

From the June 2011 Issue of Stem Cells
Paper Commentary by Stuart P. Atkinson

The field of induced pluripotent stem cells (iPSCs) grows and expands with every passing day, fuelled by the seemingly graspable prize of a bona fide source of patient-specific pluripotent cells for regenerative medicine, be it for cell replacement therapy, drug screening or developmental studies. However underlying questions still remain pertaining to the cell type which undergoes reprogramming and ultimately their long term usefulness. In a new study (Kim et al) published in the June edition of Stem Cells, researchers from the laboratory of Rudolf Jaenisch at Massachusetts Institute of Technology, Cambridge, now try to answer some of these questions. Although iPSC have been generated from an increasing number of somatic cell types, the heterogeneity and the lack of markers for said cell types has not yet allowed the thorough study of the reprogramming of terminally differentiated somatic cells.

Differentiation of Swine iPSC into Rod Photoreceptors and Their Integration into the Retina

From the May 2011 Issue of Stem Cells

Paper Commentary by Carla Mellough

Stem cell therapy remains one of the most promising options for restoration of the degenerative retina. Featured in the May edition of Stem Cells are two articles (Zhou et al. and Kokkinaki et al.) which demonstrate that induced pluripotent stem cells (iPSC) can be differentiated into various components of the mature retina. These articles individually address two important considerations; the first, discussed herein, shows that iPSC-derived photoreceptors can integrate and start to develop features typical of morphological maturation following transplantation into the degenerative retina, and the other that retinal pigmented epithelium (RPE) generated from iPSC is capable of acting in a functional manner (see the link to this paper commentary on the Stem Cell Portal homepage). The light-sensitive photoreceptors reside in the outer nuclear layer (ONL) of the retina and are supported by the underlying RPE. The RPE transfers oxygen and nutrients to the photoreceptors from the choroidal blood supply and performs many functions essential for the health of the photoreceptors, including phagocytosis of shed photoreceptor outer segments and the removal of the waste products of the visual cycle. The article by Zhou et al. from the Department of Ophthalmology at Central South University in China and multiple collaborative centres at the University of Louisville, describes the differentiation of cells from a swine iPSC line into rod photoreceptors and their integration within a swine model of retinal degeneration.

Human iPS-derived Retinal Pigment Epithelium (RPE) Cells Exhibit Transport, Membrane Potential, Polarized VEGF Secretion and Gene Expression Pattern Similar to Native RPE

From the May 2011 Issue of Stem Cells

Paper Commentary by Carla Mellough

Complimentary to another article involving the retina, also featured in the May edition of Stem Cells, the potential for induced pluripotent stem cells (iPSC) to generate replacement retinal components is further demonstrated in an article by Kokkinaki et al. from Georgetown University in Washington DC, which reports that iPSCs can be differentiated into retinal pigmented epithelium (RPE) that can perform many of the normal functions of native RPE. The health of the light sensitive photoreceptors that reside at the back of the retina are dependent on a functional RPE, in fact the two cell types are interdependent. Within the eye, the apical membrane of the RPE cells face the outer segments of the photoreceptors and not only phagocytose shed photoreceptor outer segments but perform a number of other functions including the release of growth factors and isomerisation of retinal from the phototransduction cycle. Various forms of retinal disease require the replacement of dysfunctional RPE with new functional RPE, such as age-related macular degeneration (AMD), where impaired RPE function in turn causes the death of macular photoreceptors. Many reports have shown the facile generation of RPE from both human embryonic stem cells (hESC) and induced pluripotent stem cells (RPE), making these cell types an attractive source of replacement RPE.

The Controlled Generation of Functional Basal Forebrain Cholinergic Neurons from Human Embryonic Stem Cells

From the May 2011 Issue of Stem Cells

Paper Commentary by Stuart P. Atkinson

Dementia, and specifically Alzheimer's disease (AD), may be among the most costly diseases for society in Europe and the United States, and with the continual increase in the aged population promises only to get worse, with 1 in 85 persons worldwide of all ages predicted to suffer by the year 2050 (Brookmeyer et al). Therefore, treatment for this type of disease, in particular cell replacement therapy, is highly sought after. A constant feature of AD is the loss of basal forebrain cholinergic neurons (BFCNs) and is associated with problems in spatial learning and memory, and therefore a source of these cells for possible replacement therapy would be of great advantage. Using data known about BFCNs arising from studies of the mouse median ganglionic eminence (MGE), the laboratory of John A. Kessler at the Northwestern University's Feinberg School of Medicine, Chicago, Illinois, USA set out to determine a suitable source of cells for cell replacement therapy. This study (Bissonnette et al) is published in the May 2011 edition of Stem Cells.

So how different are they? - New Analyses show the Equivalence of Karyotypic Abnormalities in iPSC and ESC

From Nature Biotechnology.

Recent correspondence in Nature Biotechnology has suggested that there are no notable differences in the incidence of chromosomal aberrations between ESC and iPSC. The paper (Taapken et al) from Karen D Montgomery of the WiCell Research Institute in Wisconsin analysed 552 cultures of 219 human iPSC lines and 1,163 cultures from 40 human ESC lines from 97 investigators in 29 laboratories - no mean feat. Their analysis showed that 12.5% of the iPSC lines had an abnormal karyotype while the figure in the ESC lines was 12.9%.This wide study is generally at odds with multiple recent publications (See Genetic Instability in Induced Pluripotent Stem Cells: One Step Forward in Understanding, Two Steps Back from the Clinic?).

Ectopic Expression of Nup98-HoxA10 Augments Erythroid Differentiation of Human Embryonic Stem Cells

From the April 2011 Issue of Stem Cells

Paper Commentary by Stuart P. Atkinson

HOX genes are a group of related genes that act to determine the basic structure and orientation of an organism and contain a DNA-binding domain called the homeodomain which can bind to enhancer sequences of other genes to control their transcription. Many HOX genes are expressed in human primitive haematopoietic stem and progenitor cells but have also been identified as fusion partners in leukaemia’s. One of the most common fusion partners for HOX genes is NUP98 (Slape and Aplan), a nucleoporin protein which is part of the nuclear pore complex (NPC). NA10 is an artificially engineered fusion of the NUP98 gene and the homeodomain of HOXA10, a key regulator of primitive hematopoietic cell expansion and erythroid/megakaryocytic lineage choice (Magnusson et al) and has been shown to potently stimulate the in vitro expansion of murine haematopoietic stem cells (HSCs) (Ohta et al). Given this action of NA10, researchers in the lab of Mickie Bhatia at the Stem Cell and Cancer Research Institute at McMaster University decided to investigate the role of NA10 in regulating early haematopoiesis from human embryonic stem cells (hESCs), a study now presented (Ji et al.) in the April Edition of Stem Cells.

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