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Conversion of Sox17 into a pluripotency reprogramming factor by reengineering its association with Oct4 on DNA --

From the June 2011 Issue of Stem Cells
By Carla Mellough

The selective dimerization of transcription factors with binding partners can allow those factors lacking site-specific DNA binding capability to elicit transcriptional control. This type of synergistic action between the Sox and POU (Oct) family members of transcription factors is well known. Co-operation between various members facilitates numerous key regulatory roles, for example the well documented interaction between Sox2 and Oct4 in stem cells and more recently the cooperation of Sox17 with Oct4 for mesodermal development. Interestingly, both Sox2 and Sox17 interact with Oct4 during early development, yet both yield different effects and Sox17 cannot replace Sox2 as a pluripotency or reprogramming factor. An article published in the June issue of Stem Cells by Jauch et al., now begins to unravel the mechanisms underlying the competitive interactions between Sox2 and Sox17 for binding to Oct4.

Conversion of Sox17 into a pluripotency reprogramming factor by reengineering its association with Oct4 on DNA --

From the June 2011 Issue of Stem Cells
By Carla Mellough

The selective dimerization of transcription factors with binding partners can allow those factors lacking site-specific DNA binding capability to elicit transcriptional control. This type of synergistic action between the Sox and POU (Oct) family members of transcription factors is well known. Co-operation between various members facilitates numerous key regulatory roles, for example the well documented interaction between Sox2 and Oct4 in stem cells and more recently the cooperation of Sox17 with Oct4 for mesodermal development. Interestingly, both Sox2 and Sox17 interact with Oct4 during early development, yet both yield different effects and Sox17 cannot replace Sox2 as a pluripotency or reprogramming factor. An article published in the June issue of Stem Cells by Jauch et al., now begins to unravel the mechanisms underlying the competitive interactions between Sox2 and Sox17 for binding to Oct4.

To the Heart of the Matter: De novo cardiomyocytes from within the activated adult heart after injury

From Nature
By Stuart P. Atkinson

The potential for cell replacement through the differentiation of embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) is a promising means of therapeutic intervention in many disease states, but may be limited by several problems, such as limited graft survival, restricted homing to the site of injury and host immune rejection. An alternative to this is the possibility of stimulating resident adult stem cells within the tissue to aid repair. It is generally assumed that the cells of the adult epicardium (the outer layer of heart tissue) are quiescent, incapable of migration or differentiation, while cells of the embryonic epicardium possess an innate ability to proliferate, migrate and differentiate into a number of mature cardiovascular cell types. However, data now suggests that resident stem/progenitor cells in the adult heart may produce de novo cardiomyocytes following injury.

To the Heart of the Matter: De novo cardiomyocytes from within the activated adult heart after injury

From Nature
By Stuart P. Atkinson

The potential for cell replacement through the differentiation of embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) is a promising means of therapeutic intervention in many disease states, but may be limited by several problems, such as limited graft survival, restricted homing to the site of injury and host immune rejection. An alternative to this is the possibility of stimulating resident adult stem cells within the tissue to aid repair. It is generally assumed that the cells of the adult epicardium (the outer layer of heart tissue) are quiescent, incapable of migration or differentiation, while cells of the embryonic epicardium possess an innate ability to proliferate, migrate and differentiate into a number of mature cardiovascular cell types. However, data now suggests that resident stem/progenitor cells in the adult heart may produce de novo cardiomyocytes following injury.

A Motherly Gift to Reprogrammers : Direct reprogramming of somatic cells is promoted by maternal transcription factor Glis1

From Nature
By Stuart P. Atkinson

Of the most widely used transcription factors in reprogramming experiments, MYC is often considered the “problem child”. Although MYC boosts the efficiency of induced pluripotent stem cell (iPSC) generation, it also increases the tumorigenic nature of the resultant cells thereby presenting clear cautionary implications for clinical use (Nakagawa et al). It is for this reason that studies have attempted to describe protocols for iPSC generation which remove MYC from the reprogramming cocktail or attempt to replace it with alternative reprogramming factors or small-molecules in order to generate “safer” iPSCs. Maekawa et al from the lab of Shinya Yamanaka now show that GLIS1, a GLI-related Kruppel-like zinc finger protein that functions both as an activator and repressor of transcription (Kim et al) and which is enriched in oocytes and 1-cell embryos, can effectively replace MYC in the reprogramming of mouse and human fibroblasts when used alongside OCT4, SOX2 and KLF4 (OSK), resulting in enhanced generation of fully pluripotent iPSCs. This study is published in Nature.

A Motherly Gift to Reprogrammers : Direct reprogramming of somatic cells is promoted by maternal transcription factor Glis1

From Nature
By Stuart P. Atkinson

Of the most widely used transcription factors in reprogramming experiments, MYC is often considered the “problem child”. Although MYC boosts the efficiency of induced pluripotent stem cell (iPSC) generation, it also increases the tumorigenic nature of the resultant cells thereby presenting clear cautionary implications for clinical use (Nakagawa et al). It is for this reason that studies have attempted to describe protocols for iPSC generation which remove MYC from the reprogramming cocktail or attempt to replace it with alternative reprogramming factors or small-molecules in order to generate “safer” iPSCs. Maekawa et al from the lab of Shinya Yamanaka now show that GLIS1, a GLI-related Kruppel-like zinc finger protein that functions both as an activator and repressor of transcription (Kim et al) and which is enriched in oocytes and 1-cell embryos, can effectively replace MYC in the reprogramming of mouse and human fibroblasts when used alongside OCT4, SOX2 and KLF4 (OSK), resulting in enhanced generation of fully pluripotent iPSCs. This study is published in Nature.

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.

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.

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.

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