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Hermann, Andreas,Kim, Jeong Beom,Srimasorn, Sumitra,Zaehres, Holm,Reinhardt, Peter,Schö,ler, Hans R.,Storch, Alexander Hindawi Publishing Corporation 2016 Stem cells international Vol.2016 No.-
<P>Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) by overexpression of the transcription factors OCT4, SOX2, KLF4, and c-Myc holds great promise for the development of personalized cell replacement therapies. In an attempt to minimize the risk of chromosomal disruption and to simplify reprogramming, several studies demonstrated that a reduced set of reprogramming factors is sufficient to generate iPSC. We recently showed that a reduction of reprogramming factors in murine cells not only reduces reprogramming efficiency but also may worsen subsequent differentiation. To prove whether this is also true for human cells, we compared the efficiency of neuronal differentiation of iPSC generated from fetal human neural stem cells with either one (OCT4; hiPSC<SUB>1F-NSC</SUB>) or two (OCT4, KLF4; hiPSC<SUB>2F-NSC</SUB>) reprogramming factors with iPSC produced from human fibroblasts using three (hiPSC<SUB>3F-FIB</SUB>) or four reprogramming factors (hiPSC<SUB>4F-FIB</SUB>). After four weeks of coculture with PA6 stromal cells, neuronal differentiation of hiPSC<SUB>1F-NSC</SUB> and hiPSC<SUB>2F-NSC</SUB> was as efficient as iPSC<SUB>3F-FIB</SUB> or iPSC<SUB>4F-FIB</SUB>. We conclude that a reduction of reprogramming factors in human cells does reduce reprogramming efficiency but does not alter subsequent differentiation into neural lineages. This is of importance for the development of future application of iPSC in cell replacement therapies.</P>
Kim, Jeong Beom,Lee, Hyunah,Araú,zo‐,Bravo, Marcos J,Hwang, Kyujin,Nam, Donggyu,Park, Myung Rae,Zaehres, Holm,Park, Kook In,Lee, Seok‐,Jin EMBO 2015 The EMBO journal Vol.34 No.23
<P>The generation of patient-specific oligodendrocyte progenitor cells (OPCs) holds great potential as an expandable cell source for cell replacement therapy as well as drug screening in spinal cord injury or demyelinating diseases. Here, we demonstrate that induced OPCs (iOPCs) can be directly derived from adult mouse fibroblasts by Oct4-mediated direct reprogramming, using anchorage-independent growth to ensure high purity. Homogeneous iOPCs exhibit typical small-bipolar morphology, maintain their self-renewal capacity and OPC marker expression for more than 31 passages, share high similarity in the global gene expression profile to wild-type OPCs, and give rise to mature oligodendrocytes and astrocytes in vitro and in vivo. Notably, transplanted iOPCs contribute to functional recovery in a spinal cord injury (SCI) model without tumor formation. This study provides a simple strategy to generate functional self-renewing iOPCs and yields insights for the in-depth study of demyelination and regenerative medicine.</P>
Direct reprogramming of human neural stem cells by OCT4
Kim, Jeong Beom,Greber, Boris,Araú,zo-Bravo, Marcos J.,Meyer, Johann,Park, Kook In,Zaehres, Holm,Schö,ler, Hans R. Macmillan Publishers Limited. All rights reserved 2009 Nature Vol.461 No.7264
Induced pluripotent stem (iPS) cells have been generated from mouse and human somatic cells by ectopic expression of four transcription factors (OCT4 (also called POU5F1), SOX2, c-Myc and KLF4). We previously reported that Oct4 alone is sufficient to reprogram directly adult mouse neural stem cells to iPS cells. Here we report the generation of one-factor human iPS cells from human fetal neural stem cells (one-factor (1F) human NiPS cells) by ectopic expression of OCT4 alone. One-factor human NiPS cells resemble human embryonic stem cells in global gene expression profiles, epigenetic status, as well as pluripotency in vitro and in vivo. These findings demonstrate that the transcription factor OCT4 is sufficient to reprogram human neural stem cells to pluripotency. One-factor iPS cell generation will advance the field further towards understanding reprogramming and generating patient-specific pluripotent stem cells.
Direct Reprogramming of Fibroblasts into Neural Stem Cells by Defined Factors
Han, D.,Tapia, N.,Hermann, A.,Hemmer, K.,Hoing, S.,Arauzo-Bravo, Marcos J.,Zaehres, H.,Wu, G.,Frank, S.,Moritz, S.,Greber, B.,Yang, J.,Lee, H.,Schwamborn, Jens C.,Storch, A.,Scholer, Hans R. Cell Press 2012 Cell stem cell Vol.10 No.4
Recent studies have shown that defined sets of transcription factors can directly reprogram differentiated somatic cells to a different differentiated cell type without passing through a pluripotent state, but the restricted proliferative and lineage potential of the resulting cells limits the scope of their potential applications. Here we show that a combination of transcription factors (Brn4/Pou3f4, Sox2, Klf4, c-Myc, plus E47/Tcf3) induces mouse fibroblasts to directly acquire a neural stem cell identity-which we term as induced neural stem cells (iNSCs). Direct reprogramming of fibroblasts into iNSCs is a gradual process in which the donor transcriptional program is silenced over time. iNSCs exhibit cell morphology, gene expression, epigenetic features, differentiation potential, and self-renewing capacity, as well as in vitro and in vivo functionality similar to those of wild-type NSCs. We conclude that differentiated cells can be reprogrammed directly into specific somatic stem cell types by defined sets of specific transcription factors.