A functionally characterized test set of human induced pluripotent stem cells

Boulting, Gabriella L.; Kiskinis, Evangelos; Croft, Gist F.; Amoroso, Mackenzie W.; Oakley, Derek H.; Wainger, Brian J.; Williams, Damian J.; Kahler, David J.; Yamaki, Mariko; Davidow, Lance S.; Rodolfa, Christopher T; Dimos, John; Mikkilineni, Shravani; MacDermott, Amy B.; Woolf, Clifford J.; Henderson, Chris; Wichterle, Hynek; Eggan, Kevin

doi:10.1038/nbt.1783

Cited by 450 publications

(473 citation statements)

References 24 publications

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“…Furthermore, epigenetic differences between mouse iPSC lines diminish, as the cells are passaged [8], consistent with what was shown for gene expression between hiPSCs and hESCs [2,12]. So far, differentiation efficiency appears to be as variable amongst hESC lines as it is for hiPSC lines [5,[13][14][15].…”

Section: Introductionsupporting

confidence: 78%

Defining the nature of human pluripotent stem cell progeny

et al. 2011

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While it is clear that human pluripotent stem cells (hPSCs) can differentiate to generate a panoply of various cell types, it is unknown how closely in vitro development mirrors that which occurs in vivo. To determine whether human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs) make equivalent progeny, and whether either makes cells that are analogous to tissue-derived cells, we performed comprehensive transcriptome profiling of purified PSC derivatives and their tissue-derived counterparts. Expression profiling demonstrated that hESCs and hiPSCs make nearly identical progeny for the neural, hepatic, and mesenchymal lineages, and an absence of re-expression from exogenous reprogramming factors in hiPSC progeny. However, when compared to a tissuederived counterpart, the progeny of both hESCs and hiPSCs maintained expression of a subset of genes normally associated with early mammalian development, regardless of the type of cell generated. While pluripotent genes (OCT4, SOX2, REX1, and NANOG) appeared to be silenced immediately upon differentiation from hPSCs, genes normally unique to early embryos (LIN28A, LIN28B, DPPA4, and others) were not fully silenced in hPSC derivatives. These data and evidence from expression patterns in early human fetal tissue (3-16 weeks of development) suggest that the differentiated progeny of hPSCs are reflective of very early human development (< 6 weeks). These findings provide support for the idea that hPSCs can serve as useful in vitro models of early human development, but also raise important issues for disease modeling and the clinical application of hPSC derivatives.

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Section: Introductionsupporting

confidence: 78%

Defining the nature of human pluripotent stem cell progeny

et al. 2011

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“…Importantly, initiation of RA treatment at day 3 followed by subsequent neuronal maturation also produced a high percentage of HB9 þ cells (60.1 ± 9.5%; n ¼ 8) from H9 hESCs, suggesting conserved responses in hESCs. Next, we determined whether the hESC-derived MNs were functional using established assays 8,[26][27][28] . First, the cells were capable of extending long projections, suggesting neuronal maturation (Fig.…”

Section: Resultsmentioning

confidence: 99%

High-efficiency motor neuron differentiation from human pluripotent stem cells and the function of Islet-1

et al. 2014

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Efficient derivation of large-scale motor neurons (MNs) from human pluripotent stem cells is central to the understanding of MN development, modelling of MN disorders in vitro and development of cell-replacement therapies. Here we develop a method for rapid (20 days) and highly efficient (B70%) differentiation of mature and functional MNs from human pluripotent stem cells by tightly modulating neural patterning temporally at a previously undefined primitive neural progenitor stage. This method also allows high-yield (4250%) MN production in chemically defined adherent cultures. Furthermore, we show that Islet-1 is essential for formation of mature and functional human MNs, but, unlike its mouse counterpart, does not regulate cell survival or suppress the V2a interneuron fate. Together, our discoveries improve the strategy for MN derivation, advance our understanding of human neural specification and MN development, and provide invaluable tools for human developmental studies, drug discovery and regenerative medicine.

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“…Screening of dozens of clones that passed the teratoma assay by in vitro differentiation into a required somatic cell line to find the perfect clone for a specific application has not been effective 36,37 and considering the possible need for multiple somatic cell types. Even the previously developed scorecard approach may be inefficient in the search for iPSC clone that would match with a patient's own isogenic ESC line.…”

Section: Discussionmentioning

confidence: 99%

An integrative analysis of reprogramming in human isogenic system identified a clone selection criterion

et al. 2016

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Kiselev (2016) An integrative analysis of reprogramming in human isogenic system identified a clone selection criterion, Cell Cycle, 15:7, 986-997, DOI: 10.1080/15384101.2016 ABSTRACTThe pluripotency of newly developed human induced pluripotent stem cells (iPSCs) is usually characterized by physiological parameters; i.e., by their ability to maintain the undifferentiated state and to differentiate into derivatives of the 3 germ layers. Nevertheless, a molecular comparison of physiologically normal iPSCs to the "gold standard" of pluripotency, embryonic stem cells (ESCs), often reveals a set of genes with different expression and/or methylation patterns in iPSCs and ESCs. To evaluate the contribution of the reprogramming process, parental cell type, and fortuity in the signature of human iPSCs, we developed a complete isogenic reprogramming system. We performed a genome-wide comparison of the transcriptome and the methylome of human isogenic ESCs, 3 types of ESC-derived somatic cells (fibroblasts, retinal pigment epithelium and neural cells), and 3 pairs of iPSC lines derived from these somatic cells. Our analysis revealed a high input of stochasticity in the iPSC signature that does not retain specific traces of the parental cell type and reprogramming process. We showed that 5 iPSC clones are sufficient to find with 95% confidence at least one iPSC clone indistinguishable from their hypothetical isogenic ESC line. Additionally, on the basis of a small set of genes that are characteristic of all iPSC lines and isogenic ESCs, we formulated an approach of "the best iPSC line" selection and confirmed it on an independent dataset.

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A functionally characterized test set of human induced pluripotent stem cells

Cited by 450 publications

References 24 publications

Defining the nature of human pluripotent stem cell progeny

Defining the nature of human pluripotent stem cell progeny

High-efficiency motor neuron differentiation from human pluripotent stem cells and the function of Islet-1

An integrative analysis of reprogramming in human isogenic system identified a clone selection criterion

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