The Niche

Induced pluripotent stem cells, reading list

In a testament to the pace of the field, on the very day two features on induced pluripotent stem cells publish, so does a new paper showing how to reprogram without DNA, perhaps the most obvious milestone in the reprogramming race.. (See the previous blog post)

Here are related stories on Nature Reports. The links are divided into four sections. The first lists overarching stories, including my two features and lovely Q&As with Tom Graf and James Thomson. The others key off the specific research publications noted. They are grouped according to 1) reprogramming techniques 2) understanding pluripotency 3) embryonic stem cell behavior in culture.

Such lists are always incomplete. Send comments to theniche[at]nature.com

Related Nature Reports features, Q&As and commentaries

What does reprogramming do?

Researchers grapple with the factors that make cells pluripotent

Stem cells: fast and furious (Subscription required)

The field of induced pluripotent stem cells has gone from standing start to headlong rush in less than three years.


In a testament to the pace of the field, on the very day two features on induced pluripotent stem cells publish, so does a new paper showing how to reprogram without DNA, perhaps the most obvious milestone in the reprogramming race.. (See the previous blog post)

Here are related stories on Nature Reports. The links are divided into four sections. The first lists overarching stories, including my two features and lovely Q&As with Tom Graf and James Thomson. The others key off the specific research publications noted. They are grouped according to 1) reprogramming techniques 2) understanding pluripotency 3) embryonic stem cell behavior in culture.

Such lists are always incomplete. Send comments to theniche[at]nature.com

Related Nature Reports features, Q&As and commentaries

What does reprogramming do?

Researchers grapple with the factors that make cells pluripotent

Stem cells: fast and furious (Subscription required)

The field of induced pluripotent stem cells has gone from standing start to headlong rush in less than three years.

Thomas Graf: Cellular identity and transdifferentiation

James Thomson: shifts from embryonic stem cells to induced pluripotency

Smash the (Cell) State!

A new quest for short cuts between specialized states could lay bare the machinery governing cell fate

Zhou, Q., Brown, J., Kanarek, A., Rajagopal, J. & Melton, D. A. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. <>Nature 455, 627–32 (2008)

How to assess a stem cell genome by Mike Teitell

To pick the best line for the job, genetic variation should be better understood

What comes after iPS? by Tom Zwaka

Though applications of reprogrammed cells will be valuable, the questions they engender will be just as important

Embryonic Stem Cells 2.0

Scientists’ enthusiasm grows for induced pluripotent cells

From skin cell to stem cell

Mouse skin cells made pluripotent by genetic modification can give rise to all types of tissue

Fertilized eggs reprogram adult-cell genomes

Findings that fertilized eggs can be used to clone mice raise an old question: how can a single cell manipulate DNA to support an entire organism’s development?

Man or beast? Man and beast! by Ian Wilmut

Why scientists should try putting human nuclei into animal eggs.

Reprogramming tools, techniques, and alternatives

Reprogramming to pluripotency without genetic engineering

Researchers finally make iPS cells without DNA at all

Zhou et al., Generation of induced pluripotent stem cells using recombinant proteins, Cell Stem Cell

doi:10.1016/j.stem.2009.04.005 (23 April 2009)

Look now! Human iPS cells with no genetic integration

Six reprogramming factors in a plasmid reach a holy grail

Yu, J. et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science doi:10.1126/science.1172482 (published online 26 March 2009).

Test tube disease models one step closer

Skin cells from Parkinson’s patients transformed into tailor-made neurons

Soldner, F. et al. Cell 136, 964–977 (2009).

Virus-free pluripotency for human cells

Stem-cell advance could bring tailored treatments closer.

Cells reprogrammed using only one gene

Taking neural stem cells to pluripotency with Oct4 alone

Kim, J. B. et al. Oct4-induced pluripotency in adult neural stem cells. Cell 136, 411–419 (2009).

Hybrid embryos fail to live up to stem-cell hopes

Strategy for creating pluripotent cells called into question

Chung, Y. et al. Reprogramming of human somatic cells using human and animal oocytes. Cloning Stem Cells doi:10.1089/clo.2009.0004 (published online 2 February 2009).

Big potential in rat pluripotent stem cells

Rat pluripotent stem cells could bring knock-out rats, reprogramming insights, and a larger menagerie of stem cells

Buehr, M. et al. Capture of authentic embryonic stem cells from rat blastocysts. Cell 135, 1287–1298 (2008).

Li, P. et al. Germline competent embryonic stem cells derived from rat blastocysts. Cell 135, 1299–1310 (2008).

Li, W. et al. Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors. Cell Stem Cell doi:10.1016/j.stem.2008.11.014 (published online 18 December 2008).

Liao, J. et al. Generation of induced pluripotent stem cell lines from adult rat cells. Cell Stem Cell doi:10.1016/j.stem.2008.11.013 (published onling 18 December 2008).

Authentic rat embryonic stem cells

Genetically engineered rats should follow soon, providing new models of human disease

Buehr, M. et al. Capture of authentic embryonic stem cells from rat blastocysts. Cell 135, 1287–1298 (2008).

Li, P. et al. Germline competent embryonic stem cells derived from rat blastocysts. Cell 135, 1299–1310 (2008).

Reprogrammed skin cells provide testing ground for new drugs

Induced pluripotent stem cells pass key milestone

Ebert, E.D. et al. Induced pluripotent stem cells from a spinal muscular atrophy patient Nature. 457, 277-80. (2009)

Adult monkey cells reprogrammed

Mouse, human and monkey cells can be induced to pluripotency

Liu, H. et al. Generation of induced pluripotent stem cells from adult Rhesus monkey fibroblasts. Cell Stem Cell 3, 587–590 (2008).

Exogenous aids to reprogramming and self-renewal

Small molecules replace pluripotency gene and Wnt boosts self-renewal and reprogramming

Shi, Y. et al. Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. Cell Stem Cell 3, 568–574 (2008).

Kalani, M. Y. S. Wnt-mediated self-renewal of neural stem/progenitor cells. Proc. Natl Acad. Sci. USA 105, 16970–16975 (2008).

Lluis, F., Pedone, E., Pepe, S. & Cosma, M. P. Periodic activation of Wnt/-catenin signaling enhances somatic cell reprogramming mediated by cell fusion. Cell Stem Cell 3, 493–507 (2008).

Embryonic-like stem cells from a single human hair

Compared to fibroblasts, keratinocytes generate a hundred times more iPS cells in half the time

Huangfu, D. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nature Biotechnol. advance online publication, doi:10.1038/nbt.1502 (12 October 2008).

Aasen, T. et al. Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nature Biotechnol. advance online publication, doi:10.1038/nbt.1503 (17 October 2008).

Integration-free iPS cells

Reprogramming does not require permanent genetic modification

Stadtfield, M. et al. Induced pluripotent stem cell generated without viral integration. Science doi:10.1126/science.1162494 (published online 25 September 2008).

Okita, K. Generation of mouse induced pluripotent stem cells without viral vectors. Science doi:10.1126/science.1164270 (published online 9 October 2008).

Ten diseases in a dish

Disease-specific cell lines will help the study and treatment of medical conditions.

Park, IH, et al. Disease-specific induced pluripotent stem cells. Cell 134, 877-86 (2008)

New routes to pluripotency

Human testis cells become pluripotent in culture

Conrad, S. et al. Generation of pluripotent stem cells from adult human testis. Nature advance online publication, doi:10.1038/nature07404 (8 October 2008).

Cell ‘rebooting’ technique sidesteps risks

Virus reprograms cells without disrupting genome

Stadtfeld, M. et al. Induced pluripotent stem cells generated without viral integration. Science doi:10.1126/science.1162494 (2008).

Nerve cells made from elderly patient’s skin cells

Reprogrammed cells may offer insight into neurodegenerative disease

Dimos, J. T. et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science doi:10.1126/science.1158799 (published online 31 July 2008).

‘Reprogramming-ready’ mice

Transgenic mice mice offer a source of genetically identically induced pluripotent stem cells

Wernig, M. et al. A drug-inducible transgenic system for direct reprogramming of multiple somatic cell types. Nature Biotechnol. advance online publication, doi:10.1038/nbt1483 (1 July 2008).

Small molecules boost reprogramming rates

Induced pluripotent stem cells edge away from viruses

Shi, Y. et al. A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell 2, 525–528 (2008).

Huangfu, D. et al. Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nature Biotechnol. advance online publication, doi:10.1038/nbt1418 (22 June 2008).

How do you know a reprogrammed cell is reprogrammed?

Scientists consider minimum standards for induced pluripotent stem cells

Unlocking reprogramming

New strategies could lead to changes in the quality, quantity of induced pluripotent cells

Mikkelsen, T. S. et al. Dissecting direct reprogramming through integrative genomic analysis. Nature advance online publication, doi:10.1038/nature07056 (28 May 2008).

Mali, P. et al. Improved efficiency and pace of generating induced pluripotent stem cells from human adult and fetal fibroblasts. Stem Cells doi:10.1634/stemcells.2008-0346 (published online 29 May 2008).

Stem cells improve Parkinson’s disease symptoms

Reprogrammed mice cells show promise as a cell replacement therapy but safety issues need to be addressed

Wernig, M. et al. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proc. Natl. Acad. Sci. USA doi: 10.1073/pnas.0801677105 (published online 7 April 2008).

Personalizing pluripotency

A simple skin biopsy can yield stem cells specific to an individual patient

Park, I. H. et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature advance online publication, doi: 10.1038/nature06534 (23 December 2007).

Adult cells reprogrammed to pluripotency, without tumors

Just a trio of introduced genes can send cells back in development

Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell doi:10.1016/j.cell.2007.11.019 (published online 20 November 2007).

Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science doi:10.1126/science.1151526 (published online 20 November 2007).

Nakagawa, M. et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotechnol. advance online publication, doi:10.1038/nbt1374 (30 November 2007).

Primate cells cloned by nuclear transfer

304 monkey oocytes yield 35 blastocysts, 2 cell lines

Byrne, J. A. et al. Producing primate embryonic stem cells by somatic cell nuclear transfer. Nature 450, 497–502 (2007).

New genetic engineering tools for human embryonic stem cells

Phage and zinc fingers allow precise genetic tinkering

Lombardo, A. et al. Gene editing in human stem cells using zinc finger nucleases and integrase-defective lentiviral vector delivery. Nature Biotechnol. advance online publication, doi:10.1038/nbt1353 (28 October 2007).

Thyagarajan, B. et al. Creation of engineered human embryonic stem cell lines using phiC31 integrase. Stem Cells doi:10.1634/stemcells.2007-0283 (published online 25 October 2007).

Stem cells treat anaemia in mice

Results provide proof of principle for therapeutic promise of induced pluripotent stem cells.

Hanna, J. et al. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318, 1920–1923 (2008).

Understanding pluripotency

MicroRNAs boost reprogramming, boot out cMyc

MicroRNAs, along with other transcription factors, produce homogenous iPS cell colonies from mouse fibroblasts

Judson, R. L., Babia, J. E., Venere, M. & Blelloch, R. Embryonic stem cell–specific microRNAs promote induced pluripotency. Nature Biotechnol. advance online publication, doi:doi:10.1038/nbt.1535 (12 April 2009).

Why hES cells make teratomas

Inhibitors of the protein survivin might lower tumour risk

Blum, B. et al. The anti-apoptotic gene survivin contributes to teratoma formation by human embryonic stem cells. Nature Biotechnol. advance online publication, doi:10.1038/nbt.1527 (1 March 2009).

Characterizing the human embryonic stem cell phosphoproteome

Study finds new phosphorylation sites on pluripotency factors Oct4 and Sox2

Swaney, D. L., Wenger, C. D., Thomson, J. A. & Coon, J. J. Human embryonic stem cell phosphoproteome revealed by electron transfer dissociation tandem mass spectrometry. Proc. Natl Acad. Sci. USA 106, 995–1000 (2009).

How the four factors reprogram

An analysis of when and where pluripotency factors bind indicate that c-Myc shuts down specialization and the remaining three turn on pluripotency

Sridharan, R. et al. Role of the murine reprogramming factors in the induction of pluripotency. Cell 136, 364–377 (2009).

A new pluripotency factor can stand in for two others

No need for Klf4 and c-Myc when you reprogramme with Esrrb

Feng, B. et al. Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb. Nature Cell Biol. advanced online publication, doi:10.1038/ncb1827 (11 January 2009).

MicroRNAs help embryonic stem cells grow fast

A new screening technique identifies molecules that control the cell cycle

Wang, Y. Embryonic stem cell-specific microRNAs regulate the G1–S transition and promote rapid proliferation. Nature Genet. advanced online publication, doi:10.1038.ng250 (2 November 2008).

Multitasking methyltransferase

G9a silences gene expression two ways

Epsztejn-Litman, S. et al. De novo DNA methylation promoted by G9a prevents reprogramming of embryonically silenced genes. Nature Struct. Mol. Biol. advance online publication, doi:10.1038/nsmb.1476 (26 October 2008).

Plasticity of the pluripotent

Two genes modulate commitment of embryonic cells to embryo proper or outer tissues

Toyooka, Y. et al. Identification and characterization of subpopulations in undifferentiated ES cell culture. Development 135, 909–918 (2008).

Chambers, I. et al. Nanog safeguards pluripotency and mediates germline development. Nature 450, 1230–1234 (2007).

Versatile microRNAs, two-faced transcription factors and embryonic stem cells

Two studies describe the sophistication within the gene regulation systems of stem cells

Tay, Y., Zhang, J., Thomson, A., Lim, B. & Rigoutsos, I. MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature advance online publication, doi:10.1038/nature07299 (21 September 2008).

Lim, B. et al. Sall4 regulates distinct transcription circuitries in different blastocyst-derived stem cell lineages. Cell Stem Cell doi:10.1016/j.stem.2008.08.004 (published online 18 September 2008).

Packaging DNA for pluripotency

An RNAi screen reveals a surprising player

Fazzio, T. G., Huff, J.T. & Panning, B. An RNAi screen of chromatin proteins identifies tip60-p400 as a regulator of embryonic stem cell identity. Cell 134, 162–174 (2008).

The latest pluripotency factor is a lone warrior

Ronin takes a place beside Oct4, Nanog and Sox2

Dejosez, M. et al. Ronin is essential for embryogenesis and the pluripotency of mouse embryonic stem cells. Cell 133, 1162–1174 (2008).

Two networks of pluripotency

An analysis of transcription factor binding sites finds clusters that clarify cooperative binding

Chen, X. et al. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133, 1106–1117 (2008).

Reprogramming turns an end into a beginning

Mature B cells from reprogramming-ready mice become pluripotent

Hanna, J. et al. Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell 133, 250–264 (2008).

Crazy Xs

X chromosome inactivation is fluid and variable in human embryonic stem cells

Silva, S. et al. X-chromosome inactivation and epigenetic fluidity in human embryonic stem cells. Proc. Natl. Acad. Sci. USA doi:10.1073/pnas.0712136105 (published online 13 March 2008).

Shen, Y. et al. X-inactivation in female human embryonic stem cells is in a nonrandom pattern and prone to epigenetic alterations. Proc. Natl. Acad. Sci. USA doi:10.1073/pnas.0712018105 (published online 13 March 2008).

Repressing microRNAs for pluripotency

The protein REST supports renewal by repressing microRNAs

Singh, S. et al. REST/NRSF maintains self-renewal and pluripotency of embryonic stem cells. Nature advance online publication, doi:10.1038/nature06863 (23 March 2008).

Reprogramming kinetics

Virally introduced genes must be active for several days to induce pluripotency

Stadtfeld, M. et al. Defining molecular cornerstones during fibroblast to iPS cell reprogramming in mouse. Cell Stem Cell doi:10.1016/j.stem.2008.02.001 (published online 14 February 2008).

Brambrink, T. et al. Sequential expression of pluripotency markers during direct reprogramming of mouse somatic cells. Cell Stem Cell 2, 151–159 (2008).

More reprogramming tips

A gene used to reprogram differentiated cells blocks microRNA processing

Viswanathan, S., Daley, G. & Gregory, R. Selective blockade of microRNA processing by Lin-28. Science doi:10.1126/science.1154040 (published online 21 February 2008).

Stomach and liver cells reprogrammed

Cells need fewer extra gene copies to become pluripotent, and the resulting mice don’t get tumours

Aoi, T. et al. Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science doi:10.1126/science.1154884 (published online 14 February 2008).

More induced pluripotency

Yamanaka’s quartet reprograms human skin cells in another lab

Lowry, W. E. et al. Generation of human-induced pluripotent cells from dermal fibroblasts. Proc. Natl. Acad. Sci. USA doi:10.1073/pnas.0711983105 (published online 11 February 2008).

Nanog’s new trick

Nanog inhibits NFB signaling and cooperates with Stat3 to maintain pluripotency

Torres, J. & Watt, F. Nanog maintains pluripotency of mouse embryonic stem cells by inhibiting NFB and cooperating with Stat3. Nature Cell Biol. advance online publication, doi:10.1038/ncb1680 (27 January 2008).

Histones preserve cell memories

How nuclei reprogrammed by eggs recall previous lives for dozens of divisions

Ng, R. K. & Gurdon, J. B. Epigenetic memory of an active gene state depends on histone H3.3 incorporation into chromatin in the absence of transcription. Nature Cell Biol. advance online publication, doi:10.1038/ncb1674 (9 December 2007).

Cancer and embryonic stem cells share genetic fingerprints

At least two modules of genes promote stemness

Wong, D. J. et al. Module map of stem cell genes guides creation of epithelial cancer stem cells. Cell Stem Cell 2, 333–344 (2008).

Monkey embryonic stem cells cloned

Attempts in humans already under way

Byrne, J. A. et al. Producing primate embryonic stem cells by somatic cell nuclear transfer. Nature 450, 497–502 (2007).

No role for Oct4 in regenerating adult tissues

Tissues lacking the gene heal just fine

Lenger, C. J. et al. Oct4 is dispensable for somatic stem cell self-renewal. Cell Stem Cell 1, 403–415 (2007).

Cooperative study of 59 human embryonic stem cell lines finds reassuring similarity

Seventeen labs from eleven countries find that embryonic stem cells have lots, but not everything, in common

International Stem Cell Initiative, et al. Characterization of human embryonic stem cell lines by the International Stem Cell Initiative. Nature Biotechnol. advance online publication, doi:10.1038/nbt1318 (17 June 2007).

Parsing pluripotency: the role of Sox2

Sox2, a protein known to be necessary to keep embryonic stem cells from differentiating, does so by an unexpected mechanism

Masui, S. et al. Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nature Cell Biol. advance online publication, doi:10.1038/ncb1589 (21 May 2007).

Embryonic stem cell behaviour in culture

Robust embryonic stem cells may harbor precancerous surprises

Particularly easy-to-culture ES cells resist differentiation

Werbowetski-Ogilvie, T. E. et al. Characterization of human embryonic stem cells with features of neoplastic progression. Nature Biotechnol. 27, 91–97 (2009).

Stem cell lines accrue cancer mutations

Chromosome instability is a problem for long-term culture of human embryonic stem cells

Lefort, N. et al. Human embryonic stem cells reveal recurrent genomic instability at 20q11.21 Nature Biotechnol. advance online publication, doi:10.1038/nbt.1509 (23 November 2008 ).

Spits, C. et al. Recurrent chromosomal abnormalities in human embryonic stem cells. Nature Biotechnol. advance online publication, doi:10.1038/nbt.1510 (23 November 2008).

From one, many genetically different embryonic stem cells

Copy number variants crop up in routine ES cell culture

Liang, Q., Conte, N., Skarnes, W. C. & Bradley, A. Extensive genomic copy number variation in embryonic stem cells. Proc. Natl. Acad. Sci. USA 105, 17453–17456 (2008).

Some human embryonic stem cells have more gene copies than others

Researchers should consider a new layer of genetic variability

Wu, H. et al. Copy number variant analysis of human embryonic stem cells. Stem Cells doi:10.1634/stemcells.2007-0993 (published online 27 March 2008).

Stem cell lines make the grade

Clinical-grade human embryonic stem cell lines generated

Crook, J. et al. The generation of six clinical-grade human embryonic stem cell lines. Cell Stem Cell 1, 490–494 (2007).

Embryonic stem cells make their own niche

Niches-in-dishes may yield clues to differentiation

Bendall, S.C. et al. IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro. Nature 448, 1015–1021 (2007).

Cultured ES Cells Come Unstuck

A clinically approved kinase inhibitor can stop human ES cells from clumping, and should make them easier to grow.

Watanabe, K. et al. Rho-associated kinase inhibitor (ROCK) promotes survival of dissociated human ES cells. Nature Biotechnol. 25, 681–686 (2007).

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