MEETING REVIEW

A symphony of stem cells in Vienna – looking to the futureEnzo R. Porrello1,2,* and Agnete Kirkeby3,4,*

ABSTRACTThe inaugural ‘Symposium for the Next Generation of StemCell Research’ (SY-Stem) was held on February 22-24 at theVienna BioCenter in Austria. The meeting focused on havingyoung researchers as speakers, and the program was of animpressively high quality. Here, we summarise key findings fromthis meeting, which brought together emerging leaders to discussvarious topics, including pluripotency, organoids, endogenousregeneration, transcriptional regulation, clinical applications andemerging technologies.

KEY WORDS: Stem cells, Organoids, Pluripotency, Single-cellanalysis, RNA sequencing, Reprogramming

IntroductionIn Vienna, the home of Mozart and the historical capital of one of theworld’s great empires, 292 researchers from 26 different countriesmet to participate in the first ever SY-Stem meeting. The meetingrevolved around the topic ‘Advances in Stem Cell Biology’ (depictedin the meeting poster through a reworking of the famous Klimtpainting Danaë, Fig. 1), and was organised and hosted by researchersfrom the Institute of Molecular Biotechnology (IMBA) and Instituteof Molecular Pathology (IMP) – Elly Tanaka, Juergen Knoblich,Ulrich Elling, Sasha Mendjan and Chukwuma Agu – in theimpressive and vibrant research facilities of the Vienna BioCenter.The vision for the meeting was to create an environment for the ‘freeexchange of ideas and results’, and the speaker programwas thereforedeliberately composed of primarily young talented researchers (ofwhom 15 out of 31 were female), who were encouraged to share theirunpublished data on the podium. Reflecting the theme of the meeting,the coffee breaks were vibrant, not only with young researchersplanning new collaborations across borders, but also with smallchildren and babies who were welcomed to come along with theirparents to the meeting. We congratulate the organisers for puttingtogether a gender-balanced 3-day program of impressively high-quality stem cell biology, and we look forward to this meetinghopefully being a recurring event. For those who missed it, thisMeeting Review summarises the main findings presented.

PluripotencySeveral talks at the meeting focussed on cell state transitions in stemcell cultures, and on the mechanisms driving or blocking these

transitions. Joerg Betschinger (Friedrich Miescher Institute forBiomedical Research, Basel, Switzerland) opened the meeting witha powerful demonstration of how functional genomic screens canreveal novel biological mechanisms that control stem celldifferentiation. In contrast to the factors that sustain self-renewal ofembryonic stem cells (ESCs), the machinery that regulates exit frompluripotency is not well defined. Building on a recent large-scalesiRNA screen that identified the bHLH transcription factor Tfe3 as agate-keeper of the exit from pluripotency (Betschinger et al., 2013),Betschinger screened for factors that regulate differentiation and Tfe3subcellular localisation in mouse ESCs (mESCs). This identifiedcomponents of the lysosomal amino acid sensing machinery(folliculin and lamtor), and Betschinger showed that a componentof this machinery can phosphorylate and inactivate Tfe3 in mESCs.Mutations that render Tfe3 non-phosphorylatable block mESCdifferentiation and cause a human developmental syndrome. Thesefindings reveal a previously unappreciated requirement for lysosomalsignaling in developmental progression and suggest that ESCdifferentiation is controlled by a check point that senses themetabolic environment prior to exiting pluripotency.

Jacob Hanna (Weizmann Institute, Israel) presented ongoingefforts to identify epigenetic regulators that are important for controlof naïve versus primed pluripotency in mESCs. He reminded us thatnaïve pluripotency is a unique state that, in contrast to primedpluripotency, largely tolerates the loss of epigenetic repression andis characterized by a conspicuous absence of the nucleosomeremodeling complex NuRD under certain growth conditions. Hannahas previously shown that partial depletion of the NuRD complexcomponent Mbd3, when combined with the Yamanaka factors, canincrease reprogramming efficiency into naïve state to >95%, therebymaking the reprogramming process deterministic (Rais et al., 2013).At this meeting, Hanna underpinned this finding by showing thatdepletion of another NuRD component, Gatad2a, showed a similarphenotype in relieving a roadblock in the reprogramming processand making the route towards pluripotency deterministic (Mor et al.,2018preprint).

Naïve pluripotency was also the focus of Hannah Stuart’s talk(José Silva’s group, Cambridge Stem Cell Institute, UK), whopresented evidence that state transitions can occur through multipleroutes. Using single-cell RNA sequencing (scRNAseq), Stuartshowed how the reprogramming of primed epiSCs to naïve ESCsfollowed distinct transcriptional trajectories depending on theinducing transgene, even though the final naïve cell productappeared identical. Interestingly, these different routes exhibiteddifferent requirements for both signalling and genetic factors. Thisprovided evidence that cellular identity can be conceptualised as amultidimensional attractor state, with distinct routes of approachin terms of both transcriptional trajectories and the underlyingfunctional attributes.

Organoids and tissue engineeringHaving set the scene of pluripotent network regulation, the meetingmoved on to cover a diverse range of stem cell topics, with several

1Murdoch Children’s Research Institute, The Royal Children’s Hospital, Parkville,Victoria 3052, Australia. 2Department of Physiology, School of BiomedicalSciences, The University of Melbourne, Parkville, Victoria 3010, Australia. 3HumanNeural Development, Novo Nordisk Foundation Center for Stem Cell Biology(DanStem), University of Copenhagen, 2200 Copenhagen, Denmark. 4WallenbergNeuroscience Center, Department Experimental Medical Science, Lund University,22184 Lund, Sweden.

*Authors for correspondence (agnete.kirkeby@sund.ku.dk;enzo.porrello@mcri.edu.au)

A.K., 0000-0001-8203-6901

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focussing on three-dimensional (3D) culture of stem cells.Starting with the earliest morphogenetic events orchestratedduring development, Magdalena Zernicka-Goetz (University ofCambridge, UK) delivered a breathtaking keynote presentation onthe newest advances in engineering stem cell-derived ‘syntheticembryos’ by co-culturing mouse trophoblast stem cells (TS) andepiblast ESCs (EPI) in 3D (Harrison et al., 2017). Despite theabsence of anterior visceral endoderm (AVE), a spontaneous breakin symmetry is observed in about half of these synthetic embryos,with formation of mesoderm and primordial germ cells (PGCs) ononly one side of the tissue. In Vienna, Zernicka-Goetz showed howher team was able to refine the model further by coating the TS/EPIsynthetic embryos with a layer of extraembryonic visceral endodermcells to achieve embryo structures that proceeded all the way togastrulation. Remarkably, these triple cell-type synthetic embryos

could generate both the anterior and posterior primitive streak, AVEand endothelial-to-mesenchymal transition. This model, whichcircumvents the need for animal-derived embryos, may prove highlyvaluable in enabling large-scale studies of blastocyst developmentand gastrulation.

A symphony of subsequent talks during the meetingdemonstrated the power of organoid systems for modellingvarious developing tissues in normal and diseased state.Focussing on the pancreas, Anne Grapin-Botton (University ofCopenhagen, Denmark) revealed that pancreatic organoids(Greggio et al., 2013) could not be formed from single mousepancreatic progenitors, but required a minimum of four startingcells. Interestingly, organoid formation appeared to depend onparacrine interaction between Notch ligand and its receptor onneighbouring cells, as organoids only grew where there was at leastone Hes+ and one Hes− cell in the starting population. Grapin-Botton also showed progress in generating human pancreaticorganoids from hESC-derived PDX1+ pancreatic progenitors.Unlike the equivalent mouse ESC-derived organoids, the humanorganoids did not display spontaneous endocrine differentiation, butcould be patterned by exogenous factors to produce either endocrineor ductal organoids separately.

On the hepatic side, Barbara Treutlein (Max Planck Institute,Leipzig, Germany) presented recently published work oncharacterising liver organoids as a model for studying liver buddevelopment (Camp et al., 2017). These organoids were generatedfrom hPSC-derived hepatic progenitors mixed with humanendothelial cells (HUVECs) and mesenchymal stem cells, andscRNAseq showed that the transcriptome of the organoidhepatocytes resembled foetal, rather than adult, liver cells and thatthey were more similar to primary liver cells than to hepatocytesgrown in 2D. The organoids (but not equivalent 2D cultures)displayed an angiogenic signature, which could possibly be aresponse to the hypoxia-related gene expression profile observed.Innovative means of analysing the transcriptomic dataset forreceptor-ligand partners on different cell types revealed thathepatocytes in the organoids were more likely to interact withendothelial cells and stromal cells rather than with other hepatocytes,thereby presenting a new way of using transcriptomics to studyorganogenesis in complex systems.

Moving to the gut, Joep Beumer (Hans Clevers’ group, HubrechtInstitute, The Netherlands) showed how intestinal organoids can beused to study the rare population of enteroendocrine cells (EECs),which constitute less than 1% of the epithelial population in theintestine. Beumer found that EECs located in crypts versus villiexpressed different sets of hormones, where they reside in differentBMP niches. Stimulation of BMP signalling in the organoidsinduced hormone switching in some subtypes of EECs, allowingthem to produce villus-associated hormones such as secretin,thereby revealing some degree of endocrine plasticity in the EECpopulation. He also showed that EECs do not necessarily follow thesame crypt-to-villus translocation observed for enterocytes,indicating that EECs are replenished in situ.

Giorgia Quadrato (Paola Arlotta’s group, Harvard University,Boston, MA, USA; shortly starting her own group at the Universityof Southern California, Los Angeles, USA) summarised herimpressive work using hPSC-derived neural organoids and large-scale scRNAseq for studying brain development and neural subtypespecification (Quadrato et al., 2017). Quadrato went on to show thatorganoids generated from hPSCs heterozygous for a mutation inCHD8, a strong risk factor for autism and macrocephaly, grewmuchlarger than organoids from control cells, thereby mimicking the

Fig. 1. Art and science in Vienna. The SY-Stem meeting poster beautifullyadapted the work Danae of the Austrian painter Gustav Klimt and merged itwith the scientific content of the meeting. In the painting, the mythical figureDanae is fertilised by the Greek god Zeus (symbolised as a golden stream),as she is wrapped in a purple veil ornamented with golden figures that areremarkably reminiscent of blastocysts. In the poster, these blastocyst-likefigures evolve into embryos giving rise to different cell types. Reproduced withthe permission of the Research Institute of Molecular Pathology (IMP)/Instituteof Molecular Biotechnology (IMBA) Graphics Department, Vienna, Austria.

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human disease phenotype. Analysis of over 60,0000 single cells byRNAseq further revealed reproducible patterns of genotype-specificdifferential gene expression between the control and CHD8 mutantin both progenitor and neuronal subtypes.Extending the theme of 3D tissue reconstruction, Agnete Kirkeby

(University of Copenhagen, Denmark) presented an alternative toneural organoid models involving a microfluidic system forproducing controlled morphogenic gradients in vitro. By exposingdifferentiating hPSCs to a gradient of WNT signaling, the cellsin this microfluidic system produced a coherent neural tissuecomprising forebrain-, midbrain- and hindbrain-patterned cellslocated in a spatially ordered manner. The system therefore mimicsin a human context the WNT-dependent rostrocaudal patterning ofthe early neural tube, which has been shown to take place in modelorganisms . Kirkeby further showed how the system could be usedto assess region-specific responses of neural cells to genes andgrowth factors.

Transcriptional regulation during differentiation andreprogrammingPrecise regulation of transcription, and concomitant changes inchromatin architecture, are crucial for the acquisition of geneexpression programs that govern cell identity. Chromatinremodelling is a defining feature of fertilisation, which generatesthe zygote – the ultimate totipotent stem cell. Kikuë Tachibana(Institute of Molecular Biotechnology, Vienna, Austria) providedan elegant view of chromatin reorganisation during the oocyte-to-zygote transition in mice, using a recently developed method forsingle cell chromosome conformation capture (Flyamer et al.,2017). Interestingly, global chromatin organisation of zygote nucleiis fundamentally different from that of other interphase cells.Moreover, Tachibana’s work demonstrates a key role for cohesin-dependent loop extrusion in organising the genome during theoocyte-to-zygote transition (Gassler et al., 2017).Epigenetic mechanisms, such as DNAmethylation dynamics, are

not only a defining feature of the earliest stages of organismaldevelopment but also a crucial hallmark of tissue specification.Judith Kraiczy (Matthias Zilbauer’s group, School of ClinicalMedicine, University of Cambridge, UK) demonstrated theimportance of analysing epigenetic marks to determine theregional identity of human organoids derived from intestinal stemcells. Analysis of human biopsy-derived paediatric intestinalorganoids showed that they retained gut segment-specific DNAmethylation marks even after long-term culture. Similarly,organoids derived from individuals with Crohn’s disease retaineddisease-specific alterations in methylation patterns. In contrast,foetal-derived organoids underwent drastic methylation changesin vitro, suggesting an in vitro maturation that could be used tomodel epithelial development.One of the most striking examples of plasticity is the

reprogramming of cellular identity by transcription factors. MarisaKarow (Ludwig Maximilians University, Munich, Germany)showed heterogeneity in the ability of human brain pericytes toreprogram into induced neurons. Interestingly, neuronalreprogramming of pericytes with Ascl1 and Sox2 involved theactivation of certain ‘switch genes’, which displayed a peak inexpression around the time of cell fate decision. These ‘switchgenes’ were enriched for components of the BMP and NOTCHpathways, and modulation of BMP and NOTCH signalling had aprofound effect on reprogramming efficiency.A major highlight of the meeting was the stunning keynote

presentation from Marius Wernig (Stanford University, CA, USA),

providing evidence for a carefully orchestrated synergy betweentranscription factors during neuronal reprogramming. Contrary towhat seems logical for reprogramming factors, Wernig showed thatMYT1L – one of the factors required for reprogramming to neuronalfate - does not act as a transcriptional activator, but instead as arepressor. MYT1L repression targets a multitude of non-neuronalgenes, reflecting the fact that MYT1L is a neuronal-specifictranscription factor. Accordingly, a construct that fused the DNA-binding domain of MYT1L with a transcriptional activator domaincould not induce neuronal reprogramming (Mall et al., 2017).Wernig further presented evidence of a surprisingly high degree ofoverlap in the DNA-binding sites of ASCL1 and MYOD, despitethe fact that ASCL1 directs neural fates and MYOD directs musclefates. This finding could explain why a fraction of cells expressingASCL1 could go towards the muscle, rather than neural, lineage.ASCL1 displayed higher binding affinity to neural loci andMYOD tomuscle loci, but substituting small domains of the MYOD proteinwith the corresponding domains from ASCL1 could convert MYODinto a neuronal reprogramming factor. Moreover, upon combiningwild-type MYOD with MYT1L to repress all non-neuronal fates,MYOD now induced reprogramming into neurons instead of muscle.The work of Wernig therefore beautifully illustrates the importantsynergy between transcriptional activators and repressors in inducingefficient and lineage-specific reprogramming.

Regeneration and homeostasisThe meeting also provided a platform to discuss the remarkableregenerative feats of a menagerie of model organisms, includingaxolotls, newts, zebrafish and mice. Prayag Murawala (EllyTanaka’s group, Research Institute of Molecular Pathology,Vienna, Austria) revisited several long-standing questions aboutthe source of blastemal cells in axolotl limb regeneration usingsophisticated genetic lineage tracing and single cell sequencingtechnologies. Lineage reconstruction from scRNAseq data suggeststhat pre-existing blastemal precursors probably do not exist.Moreover, cells from the mature limb appear to de-differentiateand enter a transitional state, during which there is a loss of cellularheterogeneity, before initiating the regeneration program. Theseelegant technologies are set to transform our molecular understandingof tissue regeneration in the axolotl.

Nadia Mercader Huber (University of Berne, Switzerland)provided insights into the role of cardiac progenitor populations inheart regeneration by developing new tools for genetic lineagetracing in zebrafish (Sánchez-Iranzo et al., 2018). Remarkably,ablation of tbx5a-derived cardiomyocytes (the first heart-fieldpopulation) in the embryo was compensated for by expansion of atbx5a-negative population, suggesting that second heart-fieldprogenitors can substitute for first heart-field progenitors duringembryonic heart development. Moreover, lineage tracing of tbx5a-positive cardiomyocytes following cryoinjury in zebrafish suggeststhat trabecular cardiomyocytes can switch their fate and differentiateinto cortical myocardium during adult heart regeneration. Thesefindings indicate a high degree of cardiomyocyte cell fate plasticityin zebrafish, which may contribute to the regenerative capacity ofthis species.

Also looking at cardiac tissue, Enzo Porrello (MurdochChildren’s Research Institute, Melbourne, Australia) built on arecently developed human cardiac organoid screening platform(Mills et al., 2017) to provide new insights into signalling pathwaysgoverning cardiac regeneration. Through combinatorial screening ofsmall molecules, novel drug interactions were revealed, whichuncovered crosstalk between the MST1 and GSK3 pathways

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in proliferating cardiomyocytes. High-throughput quantitativeproteomics and loss-of-function experiments revealed that themevalonate pathway was required for cardiomyocyte proliferation.This study highlights the power of combining drug screening andhigh-throughput proteomics in cardiac organoids to identify novelpathways and drug targets for cardiac regeneration.In contrast to axolotls, newts and zebrafish, most adult

mammalian tissues have a much more restricted regenerativepotential. One exception is skeletal muscle, which harbours aresident stem cell population that can mediate efficient regenerationfollowing injury. Tom H. Cheung (Hong Kong University ofScience and Technology, China) highlighted the potentialimportance of RNA processing in the regulation of stem cellquiescence. Transcriptional profiling of highly purified muscle stemcell populations revealed a surprising prevalence of intron-retainingtranscripts in quiescent versus activated stem cell populations.Bioinformatic analysis of publicly available datasets suggests thatintron retention might be a general feature of a variety of quiescentstem cell populations, not only specific to muscle. Cheungspeculated that the accumulation of pre-mRNA transcripts inquiescent stem cells could reflect a ‘poised’ state that is primed forrapid activation following muscle injury.In a beautiful demonstration of the power of in vivo imaging,

Sven Falk (Magdalena Götz’s group, Hemholtz Center Munich,Germany) used two-photon microscopy to study in real-time theprogeny of dividing radial glial cells (RGCs) in the lateralganglionic eminence (LGE). With this technique, Falk couldshow that the quiescent neural stem cells (NSCs) in thesubependymal zone of adult mice are derived from RGCs in theLGE at an early time point during development. He further showedthat when genetically manipulating the mitotic spindle assembly toinduce random orientation of the cleavage plane in these RGCs, thecells now generated new RGC daughter cells only infrequently, andinstead gave rise to more differentiating progeny.

Clinical translationTo relate the many basic science findings to the clinic, the meetingalso included a number of clinically-relevant talks. On the diseasemodelling side, Patricia Garcez (University of Rio de Janeiro,Brazil) discussed her pioneering efforts using human neuralorganoids infected with Zika virus to demonstrate a causative linkbetween the South American Zika virus epidemic and the highsimultaneous incidence of microcephaly in newborns (Garcezet al., 2016). Curiously, Garcez revealed that the African strain ofZika virus caused much more severe impairment of neuralorganoid growth than the Brazilian strain, indicating that themicrocephaly epidemic observed in South America may be linkedto strain-dependent differences in crossing the placenta or that theAfrican Zika virus (where infection has not been associated withmicrocephaly) may cause undetected early embryonic lethality.As an additional mechanism of pathogenesis, Garcez presentedevidence that the virus can also impair blood vessel formation inthe developing mouse brain.Going into stem cell-based drug screening platforms, Jerome

Chal (Coyne Scientific, Atlanta, GA, USA) presented an update onrecent commercial applications of stem cell technologies, buildingon protocols that he developed for directed differentiation of skeletalmyocytes from hPSCs (Chal et al., 2015). These protocols arenow being used by Anagenesis Biotechnologies, a company heco-founded with Olivier Pourquié, to identify compounds thatenhance myogenic differentiation. Chal recently joined CoyneScientific, where he is now using a genetically diverse cohort

of hPSC-derived cardiomyocytes as a potential drug toxicityassay, including identification of compounds with potentialarrhythmogenic side-effects.

In the same realm, Meritxell Huch (The Gurdon Institute,Cambridge, UK) built on her groundbreaking work on thederivation of liver organoids (Huch et al., 2013, 2015) to unveilthe power of this platform for biological discovery and drugscreening. For example, Huch has recently developed methods forgrowing human liver tumour organoids, which closely recapitulatethe tumour of origin and can be used to screen for known and noveldrug sensitivities. This approach was recently used to identify anERK inhibitor as a potential therapeutic target for primary livercancer (Broutier et al., 2017).

On the cell therapy side, Frank Edenhofer (University ofInnsbruck, Austria) presented an alternative regenerative functionof transplanted NSCs in offering immune-modulatory properties inneuroinflammatory conditions (Peruzzotti-Jametti et al., 2018).When transplanting induced NSCs (iNSCs) into a mouse model ofmultiple sclerosis, the cells dampened macrophage-inducedinflammation by converting activated macrophages to resting stateand inducing PGE2 release. This anti-inflammatory activity wasdependent on scavenging of extracellular succinate through thesuccinate receptor Sucnr1 on the iNSCs, thereby opening thepotential for an autologous transplantation in humans employingpatient-specific iNSCs. Future research will show whether suchimmune modulatory effects might also be obtained with other typesof transplanted cells or by drug treatment.

Moving from cell replacement in the brain to cell replacement inthe pancreas, Barbara Ludwig (University of Dresden, Germany)showed how transplantation of whole islets derived from dissociatedpancreas tissue can efficiently stabilise blood glucose levels ofpatients and prevent severe hypoglycaemic events. For individualsundergoing pancreatic resection, auto-transplantation of isolatedislets is furthermore a successful strategy in preventing surgery-induced diabetes. Ludwig’s own group is currently working ondeveloping a cassette for protection of transplanted islet cells fromimmune rejection to enable allogeneic transplantation in patientswithout the need for immunosuppressive treatment. Ludwigprojected that future sources of islet cells for transplantation mighteven involve xenografts from pigs or, eventually, human isletsderived from chimeric humanised pigs.

Fotios Sampaziotis (University of Cambridge, UK) gave astunning presentation on the generation of cholangiocyte organoids,including potential clinical applications of bioengineered bile ducts.Recent efforts have focussed on the potential applications ofcholangiocyte organoids to treat common bile duct disorderssuch as biliary atresia. Protocols have been developed for theisolation of primary cholangiocytes from human bile ducts, whichcan be expanded in vitro, thus allowing for scalable production ofcholangiocytes for tissue engineering. After seeding cholangiocytesonto a biodegradable scaffold, cells self-organise to form abioengineered tissue with biliary characteristics. Remarkably, thebioengineered bile duct could repair the gallbladder wall and biliaryepithelium following implantation in vivo in a mouse model(Sampaziotis et al., 2017).

New technologiesIn addition to these exciting biological discoveries and translationalapplications of stem cells, the meeting alsowitnessed the emergenceof a number of innovative technologies. Gabsang Lee (JohnsHopkins University, Baltimore, MD, USA) presented unpublisheddata on an optogenetic system that could be used to control FGFR

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activation to maintain proliferating pluripotent hESCs in theabsence of exogenous FGF2. The optogentically modified hESCscould be maintained in culture with only once-weekly media changeby applying blue-light stimulation of the opto-FGFR cells for 1 minevery 2 h.Moreover, the resulting cells showed less heterogeneity ingene expression profiles compared with conventionally culturedhESCs in the presence of FGF2.A common thread of the meeting was the use of single cell

sequencing technologies to provide new insights into cellularheterogeneity during reprogramming, organoid differentiation,endogenous regeneration and development. Charles Chan(Stanford University, CA, USA) described a new approach todissect the HSC niche with unprecedented resolution using anelaborate in vivo system based on transplantation of membranedye-labelled HSCs from a wild-type donor into recipient mice. Thecellular composition of the homing niche for the transplanted HSCswas subsequently deconstructed by purifying dye-labelledaggregates of cells from the bone marrow and dissecting thecomposition of these aggregates (i.e. niches) through index sortingand scRNAseq.One limitation of current single-cell sequencing approaches

is the high cost of sequencing large numbers of cells. Fatma Uzbas(Micha Drukker’s group, Helmholtz Zentrum Munchen,Munich, Germany) described a new method termed barcode

assembly for targeted sequencing (BART-seq), which enablesanalysis of thousands of samples using a small panel of knowngenes, with high coverage. She suggested that BART-seq couldoffer a relatively cheap solution for high-throughput analysis ofbulk and single-cell samples (e.g. for drug screening applicationsor analysis of stem cell differentiation).

Adding to a growing repertoire of available tools for stem cellresearchers, Malkiel Cohen (Rudolf Jaenisch’s group, RudolfWhitehead Institute, Cambridge, MA, USA) summarised recentadvances in the generation of mouse-human chimaeras. Previouswork from the group showed that human neural crest cells cancontribute chimerically to melanocyte formation in the mouse(Cohen et al., 2016). Cohen reported that transplantation of cellsmodified to overexpress the neuroblastoma-associated oncogenesMYCN and ALKF1174L resulted in chimeric mice that developedneuroblastomas with phenotypic resemblance to tumours frompatients. He speculated that the human tumour cells in the chimericmouse model make use of an immune evasion strategy to avoidxenograft rejection.

Concluding remarksMuch like the classical compositions of Mozart, the inauguralSY-Stem meeting in Vienna was lively and invigorating.By bringing together emerging leaders in stem cell research, the

Fig. 2. Emerging leaders and attendees from26 different countries. TheSY-Stemmeeting assembled 292 attendees from 26 different countries at the ViennaBioCenter. Reproduced with the permission of the Institute of Molecular Biotechnology (IMBA)/pov.at, Vienna, Austria.

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organisers succeeded in creating a high-quality, open and collegialmeeting that lays the foundations for a vibrant and dynamic stem cellcommunity in the future (Fig. 2). The meeting covered enormousterritory over 3 days, spanning a diverse range of topics from thenature of primed versus naïve pluripotency to transcriptionalmechanisms governing endogenous regeneration and cellularreprogramming, as well as clinical applications of stem cell andorganoid technologies. The rapid pace of development in theseexciting fields promises a bright future for regenerative medicine,although with every discovery new questions arise that warrantfurther investigation. Some of these discoveries, such as thegeneration of human organs in a dish, go to the very heart of whatmakes us human and raise important biological and ethicalquestions for the scientific community and society. There is nodoubt that these questions will fuel this vibrant field for many yearsto come and ensure that the next SY-Stem meeting is as stimulatingas the first.

AcknowledgementsWe thank the IMP/IMBA Graphics Department for permission to use the SY-Stemmeeting poster illustration in this publication and the IMBA/pov.at for the photographof meeting attendees.

Competing interestsThe authors declare no competing or financial interests.

FundingE.R.P. is supported by the National Health and Medical Research Council ofAustralia, the Heart Foundation of Australia and Stem Cells Australia. The MurdochChildren’s Research Institute is supported by the Victorian Government’sOperational Infrastructure Support Program. A.K. is supported by funding from theNovo Nordisk Foundation (NNF17CC0027852).

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MEETING REVIEW Development (2018) 145, dev163501. doi:10.1242/dev.163501

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