the Node » stem cells

Smart signaling in the developing brain

Erin M Campbell — Thu, 10 May 2012 20:02:36 +0000

The WNT pathway functions in so many processes during development that it is easy to be jealous of its multi-tasking abilities. A recent paper in Development describes the role of WNT signaling in neural stem cell proliferation.

WNT signaling plays an important role in neural development, axon guidance, cell polarity, and stem cell biology. WNT pathway mutations are linked to several different cancers, including medulloblastomas. Medulloblastomas are malignant tumors found in the cerebellum of the brain and are more commonly found in children. Recently, Pei and colleagues asked which cells in the developing cerebellum were responsive to canonical WNT signaling and found that WNT signaling promotes proliferation of neural stem cells (NSCs), the major source of neurons on the cerebellum. WNT signaling, however, did not induce proliferation in granule neuron precursors, the other major class of progenitors in the cerebellum. In addition, Pei and colleagues used transgenic mice with an inducible allele of β-catenin to find that constitutive activation of WNT signaling induced NSC proliferation in vivo. This increase in proliferation, however, caused NSCs to lose the ability to undergo self-renewal or differentiation. The images above show cerebellum tissue from a control mouse (left) and a transgenic mouse with activated β-catenin (right). Constitutively active WNT signaling caused an increase in the population of NSCs (G-FAP, Sox1), which were also actively proliferating (BrdU, bottom).

For a more general description of this image, see my imaging blog within EuroStemCell, the European stem cell portal.

Pei, Y., Brun, S., Markant, S., Lento, W., Gibson, P., Taketo, M., Giovannini, M., Gilbertson, R., & Wechsler-Reya, R. (2012). WNT signaling increases proliferation and impairs differentiation of stem cells in the developing cerebellum Development, 139 (10), 1724-1733 DOI: 10.1242/dev.050104

Stem cells at home

Erin M Campbell — Thu, 12 Apr 2012 18:23:11 +0000

We depend on our own comfort zones to keep us grounded, and stem cells are no different. A recent paper in Development describes how the adhesion that keeps a stem cell in its niche is regulated.

A stem cell’s niche is important in maintaining its long-term undifferentiated state. A great model of stem cell niche biology is the Drosophila testes, in which germline stem cells (GSCs) reside next to somatic hub cells within their niche. GSCs maintain proximity to the “hub” through the use of E-cadherin-based adherens junctions. A recent paper identifies a new player in adhesion of GSCs to the hub. Srinivasan and colleagues found that the receptor tyrosine phosphatase Lar (Leukocyte-antigen-related-like) promotes GSC-hub adhesion through E-cadherin. Lar, typically associated with axonal migration and synapse formation, is also required for proper localization of Apc2 and E-cadherin localization, in turn regulating centrosome positioning and asymmetric division. Without Lar, fewer GSCs were found at the hub. Images above show localization of Lar (red in merged, white in right image) at the GSC-hub interface (arrowheads) in Drosophila testes (early germ cells are green). Lar is also seen between sister cells of early spermatogonial cysts (arrows), which have the ability to later replace lost GSCs.

For a more general description of this image, see my imaging blog within EuroStemCell, the European stem cell portal.

Srinivasan, S., Mahowald, A., & Fuller, M. (2012). The receptor tyrosine phosphatase Lar regulates adhesion between Drosophila male germline stem cells and the niche Development, 139 (8), 1381-1390 DOI: 10.1242/dev.070052

Postdoctoral Research Associate CSCR Wellcome Trust (Hendrich Lab)

cscrjobs — Wed, 07 Mar 2012 13:09:03 +0000

The Wellcome Trust Centre for Stem Cell Research provides outstanding scientists with the opportunity and resources to undertake ground-breaking research into the fundamental properties of mammalian stem cells.

Postdoctoral Research Associate in Transcriptional control of embryonic stem cell differentiation PS14181

Salary £ 27,578 - £35,938

Applications are invited for a postdoctoral position to investigate the molecular control of embryonic stem cell lineage commitment and differentiation. As part of the European Commission 7thFramework Programme Project “4DCellFate,” you will spearhead the lab’s effort to elucidate how cells use the biochemical complexity of transcriptional silencing complexes to derive cellular diversity from pluripotency.

For this position demonstrated experience in the analysis of transcriptional and developmental mechanisms will be required. The candidate is expected to have considerable expertise in molecular biological and biochemical techniques and in mammalian embryonic stem cell culture and manipulation. Previous experience in early mammalian embryogenesis and gene targeting is highly desired. The position will be in the Transcriptional Control of Stem Cell Fate Group and is available immediately. The funds for this post are available for 2 years in the first instance.

You should have been awarded a PhD degree or equivalent and have substantial laboratory experience.
Informal enquiries are welcome via email to: Dr Brian Hendrich Brian.Hendrich@cscr.cam.ac.uk or to cscrjobs@cscr.cam.ac.uk
To apply, please visit our vacancies webpage: http://www.cscr.cam.ac.uk/careers-study/vacancies/
Applications must be submitted by 17:00 on April 16th 2012.
Interviews will be held week commencing 23rd April 2012
If you have not been invited for interview by the shortlisting deadline on 19th April 2012, you have not been successful on this occasion.

05 March 2012 - 16th April 2012

Stem cells on the Slovenian slopes

Katherine Brown — Mon, 06 Feb 2012 11:39:30 +0000

A couple of weeks ago, around 70 stem cell scientists gathered in the beautiful ski resort of Kranjska Gora, Slovenia, for the sixth meeting organised by the European Stem Cell consortium EuroSyStem. Although the snow wasn’t up to much (as the photo proves – just take a look at the opposite side of the valley!), the lack of fresh powder left more time for the science. And there was a lot of great science to be discussed…

Hans Clevers (Hubrecht Institute) kicked things off in the first of two outstanding plenary talks, with the latest developments on intestinal stem cell homeostasis, including beautiful demonstrations of how two innovative technologies – in vitro organoid culture, and the “Brainbow” cell labelling technique – have provided insights into the life of the Lgr5+ crypt stem cell. The name of Charles Leblond came up often in his talk: neither I nor many in the audience had ever heard of him, but his insights into stem cell self renewal, as well as his development of autoradiography, definitely earn him a place in the stem cell Hall of Fame (see here for a summary of his achievements).

The following day took us on a whistle-stop tour of model organisms, with planaria, flies, zebrafish, salamanders and Arabidopsis all taking their turn in the spotlight. After that, mammals took centre stage, with talks covering the whole spectrum of the stem cell field, from lineage determination and ES cell reprogramming, to aging and cancer. Prize for “Unsettling Animal Photo of the Week” (with apologies to the Guardian newspaper for blatant plagiarism of their feature) goes to Tom Rando (Stanford), whose lab has provided striking insights into systemic effects of aging from heterochronic parabiosis experiments – essentially grafting two mice together. Take home message: if you need a blood transfusion, you really want a young person’s blood! Other highlights included a lively debate on the Immortal Strand hypothesis following talks from Shahragim Tajbakhsh (Institut Pasteur) and Peter Lansdorp (Terry Fox Laboratory), and a detour into the molecular mechanisms regulating autophagy from Paul Coffer (University Medical Centre Utrecht).

Finally, the scientific program ended with an impressive demonstration of what money and technical resources can achieve, when coupled with hard work and – most importantly – a sharp nose for sniffing out an interesting story. The second plenary speaker, Huck Hui Ng (Genome Institute of Singapore), presented a tour-de-force analysis of the transcriptional and post-transcriptional networks underlying reprogramming, self-renewal and differentiation.

But the real talking point of the meeting came on the Wednesday evening, when we were fortunate enough to be joined by Arnd Hoeveler from the European Commission, who came to talk about future funding from the EC for stem cell research. While the direction the EC’s framework program is taking – towards funding mainly translational research – may not have gone down universally well with the audience of mostly basic researchers, we were given a fantastic forum to discuss science funding and politics with someone who clearly cares deeply about advancing science in Europe, and who faces a tough challenge to convince the political elite of the importance of the kind of research that this meeting was all about.

I’ve only had the chance to mention a few of the great talks, but all in all this was a fantastic conference, seamlessly organised by the EuroSyStem team. So thanks to them, the speakers and the rest of the participants for putting on an eye-opening and stimulating meeting. Now, if only they could have arranged for better piste conditions, it would have been just perfect!

Shaggy hairs and stem cells

Erin M Campbell — Tue, 10 Jan 2012 20:28:01 +0000

Our intestinal tissue doesn’t need a New Year’s resolution to keep up its amazing productivity. Our intestinal epithelium is replenished at breakneck speed in an assembly line that begins with stem cells. Today’s image is from a recent Development paper that discusses the importance of Notch signaling in stem cell self-renewal and intestinal homeostasis.

Our intestinal epithelium is folded and shaped into finger-like villi (“shaggy hair” in Latin) that increase the surface area of the tissue for more nutrient absorption. Each villus has several populations of cells in homeostasis in order to maintain function and constant replenishment. This production of epithelium starts with the actively-dividing crypt base columnar (CBC) stem cells that sit in the crypts. Although the identity of these cells has been known for a while, the factors regulating CBC stem cell self-renewal and differentiation were not well understood. A recent Development paper discusses the role for Notch signaling in CBC stem cell function. According to VanDussen and colleagues, Notch signaling is required for CBC stem cell self-renewal and survival. Notch inhibition caused a decrease in the number CBC cells, as well as precocious differentiation of more specialized intestinal cell types. VanDussen and colleagues showed that Notch regulates CBC cell self-renewal and cell fate choice through different pathways and by targeting different cell populations. In the images above, intestinal tissue was stained for a marker of CBC stem cells (Lgr5, green) and for proliferating cells (Ki67, red). In normal tissue (left), CBC stem cells were found at the base of the crypts, some of which were also actively dividing (arrows). Notch inhibition (right) resulted in a misshapen morphology of CBC stem cells, a decrease in the CBC cell marker, and a drop in the number of CBC cells that were actively dividing (arrowheads on left).

For a more general description of this image, see my imaging blog within EuroStemCell, the European stem cell portal.

VanDussen, K., Carulli, A., Keeley, T., Patel, S., Puthoff, B., Magness, S., Tran, I., Maillard, I., Siebel, C., Kolterud, A., Grosse, A., Gumucio, D., Ernst, S., Tsai, Y., Dempsey, P., & Samuelson, L. (2011). Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells Development, 139 (3), 488-497 DOI: 10.1242/dev.070763

Four Year International PhD Programme in Stem Cell Biology at the University of Cambridge

cscrjobs — Thu, 05 Jan 2012 15:07:05 +0000

Studentships starting October 2012
Application deadline 13 January 2012
Interviews to be held 30-31 January 2012

Stem Cell Biology

Stem cells are defined by the dual capacity to self-renew and to differentiate. These properties sustain homeostatic cell turnover in adult tissues and enable repair and regeneration throughout the lifetime of the organism. In contrast, pluripotent stem cells are generated in the laboratory from early embryos or by molecular reprogramming. They have the capacity to make any somatic cell type, including tissue stem cells.

Stem cell biology aims to identify and characterise which cells are true stem cells, and to elucidate the physiological, cellular and molecular mechanisms that govern self-renewal, fate specification and differentiation. This research should provide new foundations for biomedical discovery, biotechnological and biopharmaceutical exploitation, and clinical applications in regenerative medicine.

Cambridge Stem Cell Community

The University of Cambridge is exceptional in the depth and diversity of its research in Stem Cell Biology, and has a dynamic and interactive research community that is ranked amongst the foremost in the world. By bringing together members of both the Schools of Biology and Medicine, this four year PhD programme will enable you to take advantage of the strength and breadth of stem cell research available in Cambridge. Choose from over 30 participating host laboratories using a range of experimental approaches and organisms.

Programme Outline

During the first year students will:
• perform laboratory rotations in three different participating groups working on both basic and translational stem cell biology;
• study fundamental aspects of Stem Cell Biology through a series of teaching modules led by leaders in the field;
• learn a variety of techniques, such as advanced imaging, flow cytometry, and management of complex data sets.

Students are expected to choose a laboratory for their thesis research by June 2013, and will then write a research proposal which will be assessed for the MRes Degree in Stem Cell Biology. Students will then normally commence a three year PhD.
Visit http://www.stemcells.cam.ac.uk/careers-study/studentships/ for full details.

Modeling stem cell population dynamics

Hillel Kugler — Fri, 23 Dec 2011 22:01:21 +0000

Many tissues and organs contain self-renewing stem cell populations that are crucial for their maintenance. Synthesizing the relative effects of anatomical constraints, cell proliferation dynamics and cell fate specification on the overall stem cell population dynamics is challenging, and so we reasoned that dynamic computational models that have the potential to systematically manipulate different influences might facilitate an understanding of experimental studies on self-renewing cell populations.

In our study published in Development [1] we have built a computational model of germline development in C. elegans. In this model, germ cells move, divide, respond to signals, progress through mitosis and meiosis, and differentiate according to a developmental program specified for a “cell”. This developmental program incorporates cellular decision-making that influences germ cell behavior, as defined by a subset of cell components and their dynamic interactions. Simulations driven by the model recapitulate C. elegans germline development and the effects of various genetic manipulations, as shown in supplementary movies, also available at [2].

Our analyses of model simulations and laboratory studies suggest that: (1) when the ligand interaction occurs over a short distance (that is, reaching only the distal-most germ cells), small differences in this distance destabilize the system and introduce unexpected variability; (2) inherent differences between progenitor cell types need not necessarily be invoked to explain complex differentiation dynamics upon reduction of receptor activity; (3) population dynamics and anatomical constraints influence niche residence; and (4) the germ cell proliferation rate during larval stages influences the differentiation pattern in the adult.

The computational modeling in this project has been carried out in the computational science laboratory at Microsoft Research in Cambridge, in close collaboration with the Hubbard lab. We are applying and developing modeling methods that were originally introduced for building and understanding engineering and software systems. Since biological systems are far more complex and robust than man-made engineering systems, a long term goal of this research is to challenge the ways engineering and software systems are currently constructed and understood.

[1] Y. Setty, D. Dalfo, D.Z. Korta, E.J. Albert Hubbard, and H. Kugler, A model of stem cell population dynamics: in-silico analysis and in-vivo validation, in Development, vol. 139, 47-56, 2012.

[2] http://research.microsoft.com/celegans

Book review: A practical guide to human stem cell biology

Development Book Reviews — Thu, 22 Dec 2011 09:07:25 +0000

This book review originally appeared in Development. Neil Singh and Ludovic Vallier review “Human Stem Cell Technology and Biology” (Edited by Gary S. Stein, Maria Borowski, Mai X. Luong, Meng-Jiao Shi, Kelly P. Smith and Priscilla Vasquez).

Book info:
Human Stem Cell Technology and Biology: A Research Guide and Laboratory Manual Edited by Gary S. Stein, Maria Borowski, Mai X. Luong, Meng-Jiao Shi, Kelly P. Smith, Priscilla Vasquez Wiley-Blackwell (2011) 419 pages ISBN 978-0-470-59545-9 £93.50/€112.20 (hardback)

Do we need another book on human stem cell biology? The field is fairly long in the tooth now, thirteen years after Thomson first derived human embryonic stem (ES) cells (Thomson et al., 1998). There are many books that cover the theoretical aspects of the discipline (Oderico et al., 2004) and others that attempt to collate protocols useful to human stem cell biologists (Sullivan et al., 2007). Nevertheless, the new book Human Stem Cell Technology and Biology succeeds in combining both of these characteristics, providing not only a clear account of the scientific discoveries underpinning human stem cell biology, but also a useful range of laboratory protocols. The end product may be less comprehensive than Lanza’s classic text (Lanza et al., 2009), but it is perhaps more manageable and appropriate for a newcomer to the field or for an early career scientist working with human pluripotent cell lines for the first time.

The editors are all based at the Center for Stem Cell Biology & Regenerative Medicine at the University of Massachusetts Medical School. The individual chapters are written predominantly by scientists from institutes on the East coast of the United States, although some contributors are based in Australia, Canada and China. The book is divided broadly into five sections: an introduction; two sections on the culture and characterisation of human pluripotent stem cells; and two sections covering more recent technologies and applications relevant to human ES cells.

In the introduction, the authors have managed to distill over 50 years of stem cell advances in just a few pages of text. Although this may be too short for experienced scientists hoping for a colourful narrative history of each breakthrough, we think it does well to bring even novice readers up to speed with current thinking in stem cell biology, from the bottom up.

The sections containing protocols are excellent and provide the perfect framework for experimental work on human stem cells. Each chapter is devoted to a separate technique and begins with an extremely helpful overview that underlines the basic steps, and importance, of each protocol. The layout has been well thought out, supplementing the customary ‘equipment’ and ‘procedure’ sections with helpful tables, log sheets with blanks to be filled in and space for the reader to make their own notes in the margin. These protocols have been used as part of practical courses in stem cell biology at the University of Massachusetts Medical School for several years, and this is evident by the careful explanation of each technique in the book and the thoughtful addition of pros and cons of each technique.

Later sections of the book will appeal to established stem cell investigators as they summarise the latest in bioinformatic, genomic, epigenetic and proteomic analyses of human stem cells. These chapters provide a brief account of the logic and application of these various techniques, and feature tables and pictorial representations of the scientific basis of the techniques. This is most notable in the chapter on epigenetics.

Four years after Yamanaka’s group first successfully reprogrammed differentiated adult human dermal fibroblasts into pluripotent cells (Takahashi et al., 2007), much attention should be paid to the chapter devoted to reprogramming and induced pluripotent stem cells. It outlines the differences between reprogramming during fertilisation and during somatic cell nuclear transfer. The chapter describes the major developments in reprogramming, such as the use both of cell extracts and of transcription factors, most notably the Yamanaka factors: Oct4, Sox2, c-myc and Klf4. The chapter does well to highlight the limitations of the current protocols, as well as recent attempts to improve the efficiency and safety of classical directed reprogramming using the Yamanaka factors.

Much has been made of the potential applications of human stem cell biology. The final section deals with these applications. These include the use of stem cells in drug screening (testing various types and doses of medications to streamline the drug development process); stem cells as in vitro models of disease (to further understanding of aetiology and pathogenesis); and stem cells in cell therapy (using stem cells or insights into growth conditions to help repopulate and regenerate degenerative and diseased organs). Although brief, the final chapter manages to encapsulate the major recent breakthroughs and future prospects for cell replacement therapies in ectodermal, mesodermal and endodermal tissues.

One of the book’s major strengths is the accompanying DVD. It provides printable copies of the protocols from the book, and even has a helpful search tool, which we found extremely useful. The DVD also contains six videos, which demonstrate good laboratory practice, aseptic technique and how to harvest, passage and thaw cells. We would strongly recommend that laboratories use these videos as part of the induction of new members to stem cell labs, as few laboratory members have the time or training to offer such a clear and standardised tutelage on the basics of laboratory practice and stem cell culture. The lead editor, Professor Gary Stein, provides much of the training in these videos himself. The book also boasts a student companion website (http://www.wiley.com/go/stein/human) which is supposed to collate updates, amendments and additional resources. However, we were disappointed to discover that at the time of writing there were no additional resources available.

We would recommend this readable and well-organised book to all laboratories dealing with human ES cells. We envisage that a laboratory copy will prove to be invaluable as a reference text for all new members of your laboratory, and the later sections will be of benefit to more senior investigators. Although not the most energetic nor the most exhaustive book of this type on the market, this volume succeeds by summarising the historic and recent research breakthroughs in human ES cell science and combining this with excellent and reliable laboratory protocols. To the beginner, the field of stem cell biology – with a burgeoning number of principles, terms and techniques to master – can seem impossible to navigate. This book will act as an excellent guide.

References:
* Lanza R., Gearhart J., Hogan B., Melton D., Pedersen R. A., Thomas E. D., Thomson J. A., Wilmut I. (2009). Essentials of Stem Cell Biology. Maryland Heights: Academic Press.
Odorico J., Pedersen R. A., Zhang S. (2004). Human Embryonic Stem Cells. Abingdon: Taylor & Francis.
* Sullivan S., Cowan C. A., Eggan K. (2007). Human Embryonic Stem Cells: The Practical Handbook. Hoboken: Wiley-Blackwell.
* Takahashi K., Tanabe K., Ohnuki M., Narita M., Ichisaka T., Tomoda K., Yamanaka S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872.
* Thomson J. A., Itskovitz-Eldor J., Shapiro S. S., Waknitz M. A., Swiergiel J. J., Marshall V. S., Jones J. M. (1998). Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147.

Repulsive signals: bad breath, rude manners, and ephrin ligands

Erin M Campbell — Wed, 07 Dec 2011 19:50:58 +0000

Satellite cells are muscle stem cells that regenerate injured muscle (remember this earlier post?). They are highly motile cells that may be able to travel in order to repair injured muscle far away, and a recent paper in Development describes the role of Eph/ephrin signaling in satellite cell motility and patterning.

One of the most well-understood guidance pathways is the Eph/ephrin pathway, which has major roles in cell migration and axon guidance throughout development. In this pathway, Eph receptors on one cell interact with ephrin ligands bound to another cell’s membrane. This interaction typically causes rapid changes in the Eph-expressing cell’s adhesion and cytoskeletal organization, and frequently causes the cells to repel each other. A recent paper describes the role of Eph/ephrin signaling in satellite cell motility and patterning. Stark and colleagues showed that ephrin ligands are differentially localized to healthy and regenerating muscle tissue, and used a well-established “stripe assay” to show that ephrins can repel mouse satellite cells. As seen in the images above (increasing magnification from left to right), stripes of ephrin-B1 ligand (bottom row, blue stripes) repulsed the satellite cells, compared to the distribution of cells on control stripes (top row). In addition, Stark and colleagues explanted mouse satellite cells into the hindbrain of developing quail embryos, from which neural crest cells emigrate using Eph/ephrin signaling. Some satellite cells migrated along with the neural crest cells and conformed to the same boundaries.

For a more general description of this image, see my imaging blog within EuroStemCell, the European stem cell portal.

Stark, D., Karvas, R., Siegel, A., & Cornelison, D. (2011). Eph/ephrin interactions modulate muscle satellite cell motility and patterning Development, 138 (24), 5279-5289 DOI: 10.1242/dev.068411

Further strides in ES cell organogenesis

Paul O'Neill — Sun, 13 Nov 2011 01:19:15 +0000

A new Nature study has again demonstrated the power of ES cells as a model system for recapitulating developmental processes in vitro. Following on from the amazing self-assembly of differentiated optic-cups reported earlier this year, Yoshiki Sasai’s latest work has resulted in the generation of functional pituitary gland tissue from mouse ES cells.

Using a modification of their 3D floating aggregate culture protocol (which can generate complex patterned neural structures), Sasai’s group, from RIKEN CDB in Kobe, Japan, observed the generation of small ectodermal pouches, which expressed markers typical of adenohypophysis (anterior pituitary) maturation.

During embryogenesis, adenohypophysis development is dependent on the interaction of two distinct neural tissues: Pitx1-positive rostral head ectoderm, and Rx-positive rostral hypothalamic neuroectoderm. By using greater cell numbers to establish ES-cell aggregates than in their previous reports, both of these tissue types were generated together. Pitx1-positive ectoderm formed an outer layer, with sheets of Rx-positive tissues within. Regions of Pitx1-positive ectoderm were then observed to express the adenohypophysis marker Lim3, invaginate, and bud, forming vesicles in a manner consistent with normal pituitary development.

Reprinted by permission from Macmillan Publishers Ltd: Nature doi:10.1038/nature10637, copyright (2011)

By manipulating the culture conditions, the immature pituitary vesicles were encouraged to differentiate each of the mature cell types associated with the mature adenohypophysis. Blocking Notch signalling for example, promoted production of ACTH synthesising cells, whereas activating the Wnt pathway resulted in GH and prolactin precursor cells. The efficacy of the ES-cell-derived glands was also confirmed by transplantation of the tissues into mice in which the pituitary had been surgically removed. This resulted in a rise of blood glucocorticoid levels, an increase in locomotor activity, and prolonged life expectancy in the treated animals.

The mechanisms underlying adenohypophysis induction by the neuroectoderm remain unclear, but this methodology provides an excellent system to address this issue. Moreover, the generation of inductive and responsive tissues in the same dish is an exciting progression in the quest to accurately emulate complex tissue formation in vitro.

Reference:
Suga, H., Kadoshima, T., Minaguchi, M., Ohgushi, M., Soen, M., Nakano, T., Takata, N., Wataya, T., Muguruma, K., Miyoshi, H., Yonemura, S., Oiso, Y., & Sasai, Y. (2011). Self-formation of functional adenohypophysis in three-dimensional culture Nature, 480 (7375), 57-62 DOI: 10.1038/nature10637