Differentiation stage determines potential of hematopoietic cells for reprogramming into induced pluripotent stem cells

Eminli, Sarah; Foudi, Adlen; Stadtfeld, Matthias; Maherali, Nimet; Ahfeldt, Tim; Mostoslavsky, Gustavo; Hock, Hanno; Hochedlinger, Konrad

doi:10.1038/ng.428

Cited by 393 publications

(353 citation statements)

References 55 publications

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“…Eminli and colleagues discovered that in the hematopoietic lineage, stem and progenitor cells can be converted to iPSCs much more easily than terminally differentiated B and T cells (Eminli et al, 2009). This implies that the relatively flexible epigenetic state of tissue-specific stem cells makes them more amenable for reprogramming.…”

Section: Change Of Epigenetic Landscapementioning

confidence: 99%

Mechanism and methods to induce pluripotency

Wang

2011

Protein Cell

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Pluripotent stem cells are able to self-renew indefinitely and differentiate into all types of cells in the body. They can thus be an inexhaustible source for future cell transplantation therapy to treat degenerative diseases which currently have no cure. However, non-autologous cells will cause immune rejection. Induced pluripotent stem cell (iPSC) technology can convert somatic cells to the pluripotent state, and therefore offers a solution to this problem. Since the first generation of iPSCs, there has been an explosion of relevant research, from which we have learned much about the genetic networks and epigenetic landscape of pluripotency, as well as how to manipulate genes, epigenetics, and microRNAs to obtain iPSCs. In this review, we focus on the mechanism of cellular reprogramming and current methods to induce pluripotency. We also highlight new problems emerging from iPSCs. Better understanding of the fundamental mechanisms underlying pluripotenty and refining the methodology of iPSC generation will have a significant impact on future development of regenerative medicine.

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Section: Change Of Epigenetic Landscapementioning

confidence: 99%

Mechanism and methods to induce pluripotency

Wang

2011

Protein Cell

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“…The stochastic nature of the reprogramming process suggests that Oct4, Sox2, Klf4 and c-Myc must encounter epigenetic barriers that can be seen as roadblocks in the journey to pluripotency. Furthermore, many different cell types reprogram with similar kinetics under almost identical reprogramming conditions [1,31,[46][47][48][49][50][51]. One might predict that the more characteristics the starting cell type and iPS cell end product share, the less roadblocks reprogramming faces and the more efficient the process will be.…”

Section: (Not) All Roads Lead To Romementioning

confidence: 99%

Reprogramming to pluripotency: stepwise resetting of the epigenetic landscape

2011

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In 2006, the "wall came down" that limited the experimental conversion of differentiated cells into the pluripotent state. In a landmark report, Shinya Yamanaka's group described that a handful of transcription factors (Oct4, Sox2, Klf4 and c-Myc) can convert a differentiated cell back to pluripotency over the course of a few weeks, thus reprograming them into induced pluripotent stem (iPS) cells. The birth of iPS cells started off a rush among researchers to increase the efficiency of the reprogramming process, to reveal the underlying mechanistic events, and allowed the generation of patient-and disease-specific human iPS cells, which have the potential to be converted into relevant specialized cell types for replacement therapies and disease modeling. This review addresses the steps involved in resetting the epigenetic landscape during reprogramming. Apparently, defined events occur during the course of the reprogramming process. Immediately, upon expression of the reprogramming factors, some cells start to divide faster and quickly begin to lose their differentiated cell characteristics with robust downregulation of somatic genes. Only a subset of cells continue to upregulate the embryonic expression program, and finally, pluripotency genes are upregulated establishing an embryonic stem cell-like transcriptome and epigenome with pluripotent capabilities. Understanding reprogramming to pluripotency will inform mechanistic studies of lineage switching, in which differentiated cells from one lineage can be directly reprogrammed into another without going through a pluripotent intermediate.

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“…Claims that the differentiation state of a somatic cell acts as a barrier to efficient reprogramming into iPS [36] can be addressed by measuring the susceptibility of progressive differentiation stages to pluripotent conversion in ES-somatic heterkaryons, for example by comparing the reprogramming success of purified human pro-B, pre-B, immature, mature B and plasma cell targets (figure 3), as well as the effects of chromatin-modifying drugs that may weaken epigenetic memory. Perhaps the most significant future advances are likely to come from technologies that enable high-throughput heterokaryon and hybrid analysis to be established.…”

Section: Optimizing Reprogramming: Future Directions and Technologiesmentioning

confidence: 99%

Using heterokaryons to understand pluripotency and reprogramming

Piccolo

Pereira

Cantone

et al. 2011

Phil. Trans. R. Soc. B

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Reprogramming differentiated cells towards pluripotency can be achieved by different experimental strategies including the forced expression of specific 'inducers' and nuclear transfer. While these offer unparalleled opportunities to generate stem cells and advance disease modelling, the relatively low levels of successful reprogramming achieved (1 -2%) makes a direct analysis of the molecular events associated with productive reprogramming very challenging. The generation of transient heterokaryons between human differentiated cells (such as lymphocytes or fibroblasts) and mouse pluripotent stem cell lines results in a much higher frequency of successful conversion (15% SSEA4 expressing cells) and provides an alternative approach to study early events during reprogramming. Under these conditions, differentiated nuclei undergo a series of remodelling events before initiating human pluripotent gene expression and silencing differentiation-associated genes. When combined with genetic or RNAi-based approaches and high-throughput screens, heterokaryon studies can provide important new insights into the factors and mechanisms required to reprogramme unipotent cells towards pluripotency.

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Differentiation stage determines potential of hematopoietic cells for reprogramming into induced pluripotent stem cells

Cited by 393 publications

References 55 publications

Mechanism and methods to induce pluripotency

Mechanism and methods to induce pluripotency

Reprogramming to pluripotency: stepwise resetting of the epigenetic landscape

Using heterokaryons to understand pluripotency and reprogramming

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