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  Newsletter Issue 8, 4 November 2013

Gold Sponsors

 

STEM CELL SOCIETY SYMPOSIUM 2013

"Early Human Development & Fetal-Maternal Medicine"

18 - 19 November

Matrix Building Level 2 & 2M
30 Biopolis Street, Singapore 138671

Silver Sponsors

 

Bronze Sponsors

Dear Members, Delegates, Friends, and Colleagues,

The Symposium 2013 Newsletter, Issue 8 features abstracts, bios and questionnaires of Hanna Mikkola from UCLA, US, and Ashley Moffett, from the University of Cambridge, UK.

We also present the abstract selected speakers Cheryl Lee, from theUniversity of Cambridge, UK and Kyle Loh from Stanford University School of Medicine, US.

COUNT DOWN: the symposium starts in 13 day and there are only 6 days to submit your online registration.

We'd like to inform you about the most recent publication of Jacob Hanna, one of our pleanry speakers:

Gafni O, Weinberger L, Mansour AA, Manor YS, Chomsky E, Ben-Yosef D, Kalma Y, Viukov S, Maza I, Zviran A, Rais Y, Shipony Z, Mukamel Z, Krupalnik V, Zerbib M, Geula S, Caspi I, Schneir D, Shwartz T, Gilad S, Amann-Zalcenstein D, Benjamin S, Amit I, Tanay A, Massarwa R, Novershtern N, Hanna JH. Derivation of novel human ground state naive pluripotent stem cells. Nature. 2013 Oct 30. doi: 10.1038/nature12745. [Epub ahead of print]

Updates:

Programme: The programme can be viewed here.

Symposium hotel: The Park Avenue Rochester Hotel which is just across the road and in walking distance to the symposium venue is the ideal hotel for your stay during in Singapore. It l is conveniently located close to public transport facilities such as the bus and the MRT networks. Considering staying in this hotel? Click here for more information.

Delegate Networking Event: A networking event open to all delegates of the symposium will take place on the first evening (18th November). Venue will be the Epicentre at Biopolis. Drinks and food should help stimulating interactions and communications among delegates.

DEADLINES:

IMPORTANT: Online Registration closes in 6 days!!

Online registration has been extended to 11 November 2013!

To register, click HERE.

To learn more about the symposium, follow this LINK.

Contact us HERE.

Register today to enjoy excellent science and the networking opportunity with your colleagues and collaborators,

The Organizing Committee Stem Cell Society Singapore Symposium 2013

 

 

Featured Speakers  

Hanna MIKKOLA

UCLA, USA

 
Abstract  
Connecting Placental Stem/progenitor Cell Biology and Fetal Hematopoiesis

 

The placenta provides the interface for gas and nutrient exchange between mother and fetus. It was also recently discovered as a hematopoietic organ that generates hematopoietic stem/progenitor cells (HS/PC) and provides a niche to protect HS/PC from premature differentiation. In mice, placental labyrinth (analogous to the chorionic villi in human) serves as the site for gas and nutrient exchange and HS/PC expansion. However, little is known about the trophoblast stem/progenitor cell hierarchy responsible for placental labyrinth development. As the trophoblast stem (TS) cells disappear by chorio-allantoic fusion, it has been proposed that yet unknown progenitors establish the placental labyrinth. We have identified a novel multipotent labyrinth trophoblast progenitor (LaTP) in midgestation mouse placenta as the missing link. In vitro culture and clonal in vivo fate mapping using the multicolor Rainbow reporter mouse revealed that LaTP generate all labyrinth trophoblast subtypes: syncytiotrophoblasts I and II (SynT-I and II) and sinusoidal trophoblast giant cells (sTGC). Moreover, we discovered that Hgf/c-Met signaling is required for maintaining proliferation of LaTP during midgestation.

Loss of trophoblast c-Met also disrupted terminal differentiation and polarization of syncytiotrophoblasts, leading to placental inflammation, intrauterine fetal growth restriction and demise. In addition, trophoblast specific loss of c-Met compromised fetal liver hematopoiesis, documenting a direct link between placental dysfunction and defective hematopoiesis even in distant sites. While SynT are responsible for fetal-maternal exchange, sTGC secrete cytokines and hormones. Our recent studies revealed that sTGC are important niche cells in placental hematopoietic microenvironment; disruption of PDGF-B signaling was sufficient upregulate Epo production in sTGC, inducing ectopic definitive erythropoiesis in placental labyrinth. These studies provide new insights to how defective development and differentiation of placental stem/progenitor cells (trophoblast and hematopoietic) may cause pregnancy complications.

 

Biography PubMed

 

Dr. Hanna Mikkola is Associate Professor in Molecular, Cell, and Developmental Biology and a member of the UCLA Broad Stem Cell Research Center and Jonsson Comprehensive Cancer Center at University of California, Los Angeles, where she joined as faculty in 2005. Dr. Mikkola got interested in stem cells during post-doctoral training in Lund University, Sweden, working with Dr. Stefan Karlsson and in Harvard Medical School, Boston, working with Dr. Stuart Orkin. She obtained MD PhD degrees in University of Helsinki, Finland, focusing on molecular genetics of blood coagulation disorders. One of the key discoveries from Dr. Mikkola and her colleagues is the identification of the placenta as a source of hematopoietic stem cells during development. Her work now focuses on the regulatory mechanisms that dictate the development of different stem/progenitor cells during mouse and

human embryogenesis. Her recent work on defining the placenta as a hematopoietic organ has also provided new insights to the trophoblast stem/progenitor cell hierarchy that create the placenta, and how the various placental cell types contribute to the hematopoietic niche. Dr. Mikkola is the 2013 recipient of the Mc Culloch and Till award that recognizes early career investigators in the field of experimental hematology and stem cells, and she has also received awards from the Leukemia & Lymphoma Society, American Society of Hematology and V-Foundation for Cancer Research. In addition to her research, Dr. Mikkola teaches about stem cell biology to undergraduate and graduate students at UCLA.

Interview  

What was the first phenomenon you can recall that fascinated you to do science?

In my school biology books, the three most interesting chapters were “DNA”, “RNA”, and “Protein”. They also described the identification of the first mutation explaining a genetic disease, sickle cell anemia. I remember thinking that  “this is amazing, this is exactly what I want to do.

What is your most memorable career achievement?

We had been studying a transcription factor Scl/tal1 that is critical for establishing hemogenic endothelium and hematopoietic stem cells.  When we put Scl deficient yolk sacs in culture in hematopoietic conditions, they started beating! In the absence of Scl, the endothelium in embryonic hematopoietic tissues had become misspecified to cardiac fate, and generated beating cardiomyocytes. Thus, loss of one master regulator was sufficient to convert a hematopoietic organ to a cardiogenic organ.

What attracted you to a career in Science/Research?

Since childhood, I had had this mystical, lofty goal, of “curing leukemia”, so I went to medical school with the goal of becoming a hematologist. However, already in med school, I found clinical work unsatisfactory because so little was known about the diseases (e.g. leukemia) that we were trying to treat, and most of the treatments were “unspecific” and killed anything that divides, rather than being specific for malignant cells. I decided that my place in the “sequence toward curing leukemia” was in basic research, trying to understand how blood cells are regulated in order to decipher why their dysregulation leads to disease. Once I started working in the lab, the decision to stay in science was self-evident.

Who are your scientific heroes/role models and why?

First I have to acknowledge my post-doc mentor, Stuart Orkin, who has been pivotal in mapping the transcriptional and epigenetic regulators that create the hematopoietic hierarchy. I admire his exceptional vision and clarity of thinking, and his ability to translate the experimental results to “the big picture”. I remember when he presented my data in his talk for the first time, I finally understood what my data “really means”! Another outstanding scientist who has influenced my career since I started working on stem cell development, is Gordon Keller. He has stayed exceptionally truthful to his long-standing mission to define how to take embryonic stem cells and differentiate them into various tissues and stem cell types in a culture dish.

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Having had the chance to work with his lab for one week to learn “hemangioblast differentiation” from mouse ES cells, I fully appreciated the precision and thoughtfulness that is necessary to give these cells the chance to recapitulate embryonic development and generate the cell type of interest. Another big bonus was that if you did the differentiation exactly as Gordon said, it always worked!

What influenced you to pursue stem cell research?

I started working on hematopoietic stem cells in Lund during my post-doctoral training with Stefan Karlsson. His lab was focusing to develop gene therapy for blood diseases, and thus it was critical to learn how to identify, isolate, modify, and assays, hematopoietic stem cells. However, at the time, many of these things were difficult to do, as the tools and knowledge was not available. It has been amazing to see how our understanding of hematopoietic stem cells has progressed in these 15 years. However, despite the great advances, many of the old challenges are still there (e.g. the inability to expand HSCs in culture), limiting the clinical applications of HSC. For me, the real heroes are those who are committed to solving the questions they have set for themselves to answer, rather than the opportunists who join the field because of the “cool-factor”.

What's the worst advice you ever had?

Not to pursue a medical or research career because it is “too demanding for women”.

What’s your motto in life?

Never ever give up on something you truly believe in.

What would you tell a student asking you for advice whether to pick up a career in the stem cell field?

Don’t get too discouraged about the prevailing difficult funding situation and jump out from the train. The field is in extremely interesting state right now. The combination of the various high throughput sequencing technologies and reprogramming approaches not only gives us the opportunity to answer how a key regulatory factor acts but also enables us to use these factors modify the cell fate. The rest is up to our creativity and perseverance. This is the time when we can finally start making a difference.

Read the full interview here.

 

Ashley MOFFETT

University of Cambridge, UK

 

 
Abstract  
Maternal NK cell KIR recognition of trophoblast HLA-C regulates placentation  

The mucosal lining of the uterus contains large numbers of NK cells with a distinctive phenotype. These maternal NK cells have receptors known as Killer Immunoglobulin-like receptors (KIR) that bind to trophoblast MHC molecules, HLA-C. Both KIR and HLA-C are highly polymorphic. In genetic studies of women with disorders of pregnancy (e.g. pre-eclampsia) we have shown an increased frequency of KIR AA genotypes when the fetus has a paternal allele of the HLA-C2 group. A recent study has found similar genetic risk associations in women with pre-eclampsia in Uganda, although interestingly, the protective KIR genes on the KIR B haplotype are different than in Europeans. One particular allele of the inhibitory KIR for C2, KIR2DL1, confers most risk. In contrast, in women who have very large babies, the KIR AA genotype is reduced in frequency.

In Europeans, the KIR on the B haplotype that binds HLA-C2 and may be protective in pregnancies with a HLA-C2 fetus is the activating KIR2DS1. We now show how the uNK KIR repertoire is skewed during pregnancy towards recognition of HLA-C2 and, in vitro, KIR2DS1+ cells are activated by HLA-C2+ target cells. We have identified novel responses triggered by KIR2DS1+ on uterine NK cells; these include cytokines capable of regulating trophoblast invasion. This provides a potential mechanism by which KIR2DS1 may extend a protective effect in pregnancy by defining the territorial boundary between mother and baby. In this way the maternal KIR/fetal HLA-C interactions may regulate birth weight.

Biography PubMed  

My scientific career has an unusual trajectory.  I qualified as a doctor in 1973 (MB, Cantab), trained as a physician (MRCP 1975) and a pathologist (MRCPath 1984), eventually working as a reproductive pathologist in Cambridge.  I have pursued the idea that the immune system is responsible for pregnancy disorders that have an underlying defect of placentation (eg pre-eclampsia). In 1987 I went into full time scientific research to investigate this question. I identified a population of Natural Killer (NK) cells that are unique to the site of placentation and these cells were the subject of my MD thesis (1991). I was a Senior Research Fellowship at St John’s College and now work in the Department of Pathology, University of Cambridge. Subsequently I moved to King’s College and was promoted to Professor of Reproductive Immunology in 2008. We have now identified HLA-C on trophoblast as a ligand for uNK cell receptors (NKR).

Using genetic studies, we see that the high degree of genetic polymorphism in both maternal NK cell receptors and fetal HLA-C leads to variation in the demarcation of the maternal/fetal boundary and, in particular NKR/HLA combinations, to disorders such as low birth weight and pre-eclampsia. My current research brings together genetic and functional studies, in an investigation of the cell/cell interactions operating at the maternal/fetal boundary and their functional consequences in terms particularly of access to the maternal blood supply. I hope that a detailed understanding of events at the maternal/fetal interface will lead to the development of predictive tests and effective therapies for women at risk of pregnancy disorders.

Abstract Selected Speakers

Cheryl LEE

University of Cambridge, UK

 

 

 

 
Abstract  
Characterising the trophoblast progenitors within early human placentas  
During human pregnancy, the placenta is key to the growth and development of the fetus. The main hurdle in the investigation of placental development and function is the lack of human trophoblast cells that can be propagated in culture. Although trophoblast stem cells (TSC) have been isolated from a range of species, no human TSC derived from extraembryonic tissue is available. Our aim was to identify and isolate proliferative trophoblast from early human placentas. Using immunohistochemistry, we have explored the location of possible niches for trophoblast progenitors in first trimester placental villi by staining for proliferative markers and transcription factors important in mouse TSC maintenance. We have identified a proliferative niche at the base of the cytotrophoblast cell columns. Using an integrin found on cells within this niche, we have now isolated and characterised them. Our results will be presented.
Biography  
Cheryl did her undergraduate degree in Imperial College in Biomedical Science. She then moved to Cambridge for her PhD, under the co-supervision of Prof Ashley Moffett and Dr Myriam Hemberger, working on characterizing the proliferative trophoblast in human placentas. Cheryl will be pursuing a joint fellowship between the Centre of Trophoblast Research in Cambridge and the Rossant lab in Toronto.
Interview  

What was the first phenomenon you can recall that fascinated you to do science?

When I was eleven, I was one of those irritating kids who actually flipped through the encyclopaedia. I chanced upon the section that talked about proteins, which led me on to amino acids, and then to genes etc, and it just intrigued me that there were building units smaller than cells. Although the fascination in miniscule objects did not extend further (otherwise I would be a physicist now), the interest in science did, leading me down this path.

What would you be if not a scientist/clinician?

Event planner.

What's the best advice you ever had?

“Complacency and pride are the biggest stumbling blocks to greatness.” Additional effort is often spent on overcoming the fear of failure when learning a new skill. There will be less inertia if there is less ego.

What's the worst advice you ever had?

“Finish your PhD in the shortest amount of time possible, to start building your career earlier.” PhD is the best time to fail and learn. Rushing through it is to short-change oneself the chance to be better equipped.

   

Kyle LOH

Stanford University School of Medicine

 
Abstract  
Developmental signaling logic animating lineage bifurcations during endoderm development and patterning from human pluripotent stem cells  
Directed differentiation of human embryonic stem cells (hESC) typically yields heterogeneous developmental outcomes. However, generation of mixed lineages is suboptimal for cell replacement therapy and obscures molecular analysis of lineage commitment events. We have precisely delineated the developmental signaling logic underlying four consecutive cell-fate transitions during the induction and anterior-posterior patterning of the definitive endoderm germ layer (embryonic progenitor to liver, pancreas and other organs). This signaling logic clearly explains how alternate lineages are separated at every developmental branchpoint. Precise knowledge of the underlying signaling logic informed a single, effective strategy to universally differentiate diverse hESC and hiPSC lines into highly-pure (>90%) endodermal populations in fully-defined conditions, superseding previous line-to-line variability in differentiation efficiencies. Definitive endoderm was subsequently anterior-posteriorly patterned into distinct anterior foregut, posterior foregut or midgut/hindgut populations, culminating in formation of either liver or pancreas progenitors from posterior foregut endoderm. This led to hESC-derived liver progeny that engrafted long-term in mouse livers. Detailed understanding of signals controlling endoderm bifurcations permitted highly-efficient differentiation throughout multiple stages by exclusion of mutually-exclusive fates at every step. Critically, this system yielded endoderm populations that were substantially purer than those induced by contemporary schema. To afford mechanistic insight into endoderm commitment, we comprehensively profiled the chromatin and transcriptional state of a hierarchy of six distinct endoderm progenitor populations. This revealed multiple routes whereby endoderm enhancer elements may be activated at the level of chromatin during differentiation. Ultimately, we show a unified signaling roadmap spanning multiple stages of germ-layer formation and patterning avails the universal specification of highly-pure endoderm populations: the necessary forerunner to efficient generation of committed endodermal progeny or molecular analysis of gastrulation.
Biography PubMed  
Kyle Loh is a member of Irving Weissman’s group at Stanford, where he seeks to delineate the precise developmental signaling logic arbitrating germ-layer formation and patterning during human embryonic stem cells (hESC) differentiation. The prevailing model of pluripotency suggests pluripotency transcription factors within ESCs suppress differentiation to maintain an undifferentiated state. By contrast, Kyle proposed that within ESCs, pluripotency factors act as “lineage specifiers” that induce differentiation to particular lineages (Cell Stem Cell 8: 363-9). Coexpression of diverse lineage-specifying pluripotency factors in ESCs (each advocating differentiation to a distinct lineage) permits ESCs to access all germ-layer fates (thus explaining pluripotency) and generates a “precarious balance” in which opposing pluripotency factors neutralize one another to yield an undifferentiated state. Recently, in collaboration with Lay Teng Ang and Bing Lim in Singapore, Kyle has resolved the signaling logic governing definitive endoderm germ-layer formation and anterior-posterior patterning by understanding signals that drive four consecutive lineage bifurcations during endoderm development. Knowledge of how mutually-exclusive lineages are separated at every developmental step culminated in efficient, universal differentiation of diverse hESC/hiPSC lines into highly-pure endoderm populations by systematically inhibiting specification of alternate fates at each juncture. The newfound ability to generate highly-pure endoderm populations provides a powerful system to accurately capture transcriptional and chromatin dynamics during endoderm development, which is currently being explored by Shyam Prabhakar and coworkers. Altogether, the universal establishment of highly-pure endoderm populations from hESCs/hiPSCs is also the necessary first step for cell replacement therapy. Of equal importance, this coherent view of endoderm signaling logic illuminates developmental biology and provides a clear framework forward for highly-efficient in vitro differentiation to a number of lineages. Kyle is supported by the Hertz Foundation, the U.S. National Science Foundation and the Davidson Institute.