Direct Reprogramming of Terminally Differentiated Mature B Lymphocytes to Pluripotency

Hanna, Jacob; Markoulaki, Styliani; Schorderet, Patrick; Carey, Bryce W.; Beard, Caroline; Wernig, Marius; Creyghton, Menno P.; Steine, Eveline J.; Cassady, John P.; Foreman, Ruth K.; Lengner, Christopher J.; Dausman, Jessica; Jaenisch, Rudolf

doi:10.1016/j.cell.2008.07.013

Cited by 254 publications

(348 citation statements)

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“…This is clear in iPS studies, where Oct4, Klf4 and Sox2 are critical to the maintenance of ES cell pluripotency [103], but also applies in other contexts, such as the reprogramming of exocrine cells to β cells in the pancreas, and the progressive reprogramming of B cells into macrophages, and later, into iPS cells [90,91,93]. Pdx1, used in the in vivo pancreas reprogramming and the liver to pancreas cell reprogramming, is critical for pancreas development and islet β cell specification [104,105].…”

Section: Nuclear Reprogrammingmentioning

confidence: 99%

“…We know that adult fibroblasts can be reprogrammed [88] and since this landmark study other adult cell types, including those from the stomach and liver, have been shown to be amenable to nuclear reprogramming as well [89]. Most recently, Hanna et al [90] demonstrated that reprogramming of mature B cells from adult spleen to iPS cells required an additional factor, C/EBPα, in combination with the established Oct4, Sox2, Klf4 and c-myc reprogramming factors. This shows that not all adult cells can be similarly reprogrammed and suggests that critical factors for nuclear reprogramming are context-dependant.…”

Section: Nuclear Reprogrammingmentioning

confidence: 99%

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Stem cell options for kidney disease

Hopkins

Rae

et al. 2008

The Journal of Pathology

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Chronic kidney disease (CKD) is increasing at the rate of 6-8% per annum in the US alone. At present, dialysis and transplantation remain the only treatment options. However, there is hope that stem cells and regenerative medicine may provide additional regenerative options for kidney disease. Such new treatments might involve induction of repair using endogenous or exogenous stem cells or the reprogramming of the organ to reinitiate development. This review addresses the current state of understanding with respect to the ability of non-renal stem cell sources to influence renal repair, the existence of endogenous renal stem cells and the biology of normal renal repair in response to damage. Understanding repair options via an understanding of renal developmentThe prevalence and incidence of chronic kidney disease (CKD) is increasing at 6-8% per annum in the USA alone, largely as a result of increased prevalence of diabetes and obesity [1]. To understand what might be possible with respect to cellular therapies or regenerative medicine for the kidney, one first needs to consider what is understood about normal renal development and response to injury. The kidney has been classically regarded as an organ with minimal cellular turnover and no capacity for regeneration. The subsequent identification of stem cells in a number of such organs, including the brain, has challenged this view. However, the dogma remains that the kidney reaches a maximal complement of nephrons and then loses these over time [2]. This dogma is drawn from our understanding of the development of this organ. The progenitor population during developmentThe kidney is mesodermal in origin and develops from two populations derived from intermediate mesoderm, the ureteric bud (UB) and the metanephric mesenchyme (MM). While an even broader potential had been proposed [3], genetic and lineage analyses have confirmed that the MM gives rise to all portions of the nephron other than the collecting ducts and also gives rise to elements of the renal interstitium [4][5][6]. The UB gives rise to the ureter and collecting ducts only. The MM is apparently not homogeneous but forms condensed mesenchyme around the tips of the branching UB. This cap mesenchyme (CM) contains self-renewing progenitors capable of generating all cells of the nephron other than the collecting ducts via an initial mesenchyme-epithelial transition (MET) event throughout the prenatal developmental period [6]. The continued expression of the transcription factor Six2 in CM is required for maintenance of this stem cell population during kidney development [5]. As the UB branches and extends through the MM, individual MET events occur at the underside of each tip to form a new nephron [2]. This nephron endowment therefore proceeds from the centre of the kidney out to the periphery, with the CM stem cell field remaining on the outer edge of the expanding organ. Endowment of new nephrons is restricted to prenatal development in humans, while in rodents it persists only until the imm...

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Section: Nuclear Reprogrammingmentioning

confidence: 99%

Section: Nuclear Reprogrammingmentioning

confidence: 99%

Stem cell options for kidney disease

Hopkins

Rae

et al. 2008

The Journal of Pathology

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“…In general, the more differentiated a cell is, the more resistant it is to the reprogramming process 10,12,[66][67][68] . What is responsible for this resistance to reprogramming?…”

Section: Box 1 Combinatorial Control Of Gene Status and Resistance Tomentioning

confidence: 99%

Mechanisms of nuclear reprogramming by eggs and oocytes: a deterministic process?

Jullien

Pasque²,

Halley-Stott³

et al. 2011

Nat Rev Mol Cell Biol

106

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Differentiated cells can be experimentally reprogrammed back to pluripotency by nuclear transfer, cell fusion or induced pluripotent stem cell technology. Nuclear transfer and cell fusion can lead to efficient reprogramming of gene expression. The egg and oocyte reprogramming process includes the exchange of somatic proteins for oocyte proteins, the post-translational modification of histones and the demethylation of DNA. These events occur in an ordered manner and on a defined timescale, indicating that reprogramming by nuclear transfer and by cell fusion rely on deterministic processes.The remarkable stability of cell differentiation under normal conditions can be reversed experimentally by nuclear transfer, cell fusion and induced pluripotent stem (iPS) cell technology [1][2][3][4][5] . This provides an opportunity to generate pluripotent embryonic cells from adult cells of the same individual and hence opens the possibilit y of cell replacement without the need for immunosuppression.iPS cell technology makes use of the overexpression of transcription factors (FIG. 1a) and has been extensively reviewed, so it is not discussed in detail [6][7][8][9] . To generate entirely unrelated cell types by iPS cell technology, treated cells must be grown for multiple cell divisions over a long period of time (up to 3 weeks). By contrast, nuclear transfer and cell fusion do not involve the overexpression of new genes, and instead make use of natura components present in eggs and some early embryos to initiate new transcription.There are two kinds of nuclear transfer experiments: egg-NT involves the transfer of a single somatic nucleus to an unfertilize d enucleated egg (in both mammals and amphibians) 1 (FIG. 1b); and ooc-NT involves the transplantation of multiple somatic cell nuclei into the germinal vesicle (the nucleus) of a growing meiotic prophase amphibian oocyte (an immature egg) 10 (FIG. 1c). Note that the terms egg and oocyte refer to different developmental stages in amphibians and mammals: amphibian eggs are in metaphase II of meiosis, which is equivalent to mouse metaphase II stage oocytes, whereas their immediate precursors, oocytes, are blocked in meiotic prophase I, which is equivalent to mouse germinal vesicle stage oocytes.© 2011 Macmillan Publishers Limited. All rights reserved Correspondence to J.B.G.j.gurdon@gurdon.cam.ac.uk. Competing interests statementThe authors declare no competing financial interests. There are important differences between the two types of nuclear transfer experimen t. Extensive cell division takes place in egg-NT experiments, and functional new cell types appear as the nuclear transplant embryo develops. By contrast, in ooc-NT experiments, no new cell types are formed, and neither the oocyte nor the introduced nuclei divide, but there is a direct transition from nuclei of differentiated cells to reprogrammed nuclei that transcribe pluripotency genes. Analysis of the mechanism of reprogramming (which involves transcription of pluripotency and other genes) in egg-NT expe...

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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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Direct Reprogramming of Terminally Differentiated Mature B Lymphocytes to Pluripotency

Cited by 254 publications

References 0 publications

Stem cell options for kidney disease

Stem cell options for kidney disease

Mechanisms of nuclear reprogramming by eggs and oocytes: a deterministic process?

Reprogramming to pluripotency: stepwise resetting of the epigenetic landscape

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