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September 2010 Issue

Connections in Hematology & Stem Cells is supported by a grant from 

Special 2010 Annual Scientific Meeting Issue

In the September 2010 issue
Meeting Update – Presidential Symposium – Late-breaking abstracts
Next year’s meeting: Vancouver 2011
Young Investigators Eight Melbourne presenters
Society News New leadership – Experimental Hematology
News from the Field ASH honors ISEH members
Member Profiles Ihor Lemischka, Metcalf Award – Bertie Göttgens, McCulloch and Till Award Presidential Symposium Speaker Abstracts

Annual Scientific Meeting Update...

15-18 September, Melbourne, Australia

Presidential Symposium

Be sure to attend Friday’s Presidential Symposium: Stem Cell Niche Interactions beginning at 3:30 pm.

"This session will provide delegates with a state-of-the-art update on HSC-niche biology,” explains Susie Nilsson, CSIRO, local organizing committee co-chair and one of the session’s featured speakers. "Collectively, speakers will describe the current understanding of the cellular and molecular components of the HSC niche and how these act in concert to regulate HSC. In addition we will identify gaps in our understanding and knowledge of HSC/niche interactions, the immediate challenges for future research and how this impacts on clinical hematology.

ISEH offers the Presidential Symposium at annual scientific meetings to focus on a topical area of experimental hematopoiesis that is of fundamental interest to the field. This year's speakers were selected by ISEH president Toshio Suda because they are established, internationally regarded leaders and often present different perspectives on the science.

This year’s topic, Stem Cell Niche Interactions, is a perfect example, with insights into the nature, location and function of the HSC niche in normal and aberrant hematopoiesis as it underpins clinical hematology. Paul Frenette is recognized for his ground-breaking studies on the role of the circadian regulation of bone formation and HSC trafficking and the identity of bone marrow stromal cells. David Scadden, a leader in HSC and niche biology, provides insight into how HSC might be used more effectively for therapy. Susie Nilsson has conducted pioneering studies on the nature and molecular characteristics of HSCs and their niche and describes how distinct regions within the niche critically regulate HSC functions. Kateri Moore’s research focuses on the haemopoietic microenvironment and through recent work with genetic models provides insight into the mechanisms of HSC quiescence and how niches regulate HSC fate.

Click here to view abstracts from these four speakers

Late-Breaking Abstracts Announced

Sixteen presentations featuring new research were selected during the late-breaking abstract submission period. Be sure to attend these sessions!

Thursday, 16 September

  • 243 - The Mechanism of Platelet-Mediated Protection Against Malaria Infection
  • 246 - Hypoxia Inducible Factor Regulation of Stem Cells
  • 248 - The Addition of Anti Apoptotic Compounds to the Expansion Cultures Lead to an Improved Adhesion and Migration Properties of CB Derived Hematopoietic Stem/Progenitor Cells
  • 249 - Overexpression of the Homeobox Gene CDX4 Induces Erythroid Leukemia in the Murine Bone Marrow Transplantation Model
  • 250 - Role of Biallelic C/Ebpalpha Mutations and FLT-3 ITD in Initiation and Maintenance of AML
  • 251 - Quantification and Characterization of a Cardiac-Resident MSC-Like Stem Cells in the Embryonic and Adult Mouse Heart
  • 253 - Regulation of Hematopoietic Stem Cells by their Mature Progeny
  • 254 - CCL28 is a Growth Factor for Human Hematopoietic Stem- and Progenitor Cells
  • 255 - Oxygen Levels Influence the Cytokine Release Profile of AML Cells

Friday, 17 September

  • 220 - Stochastic Switch Model for HSC Fate Decisions Simulates a Critical-Like Pluripotent State
  • 244 - The Identification of Novel Haematopoietic Progenitor Marker APJ During Early Mesendodermal Differentiation of HESC
  • 245 - A Distinct Expression of Various Gene Subsets and Differential Mirna Expression in Patients with Early and Advanced Myelodysplastic Syndrome
  • 247 - Hematopoietic Progenitors are Enriched in GFP-Positive Cells Isolated from Differentiating RUNX1CGFP/W Human Embryonic Stem Cells
  • 252 - Generating Cytotoxic Natural Killer T Cells: Specifically from AML Patients
  • 256 - In Vitro RNA Interference Screen for Regulators of Adhesion in Hematopoietic Stem/Progenitor Cells

Another abstract, FOXO1 is Essential for the Regulation of Pluripotency in Embryonic Stem Cells, was accepted but author was unable to present in Melbourne.

Those not attending the meeting can access session abstracts in the special meeting supplement included with your September issue of Experimental Hematology. The supplement is viewable on the website.

2011 Annual Scientific Meeting
25-28 August, Vancouver, Canada

In 2011, ISEH celebrates its fortieth year of presenting ground-breaking research in hematology and stem cells.

"This international meeting is the ideal mix of intimate size and ground-breaking science,” states David Scadden, MD, Gerald & Darlene Jordan Professor of Medicine, Harvard University, and 2011 chair. "It has a casual, friendly atmosphere that’s just right for exchanging ideas between experienced scientists and young investigators alike.

Peter Lansdorp, PhD, MD, from the Terry Fox Laboratory in Vancouver and 2011 local organizing committee chair, believes this Canadian city is a great place to hold ISEH’s premier event.

"Vancouver offers a stunning setting to think about science, meet friends and have a good time,” adds Lansdorp.

Mark your calendar for this stellar event in 2011.

2011 Scientific Program Committee

  • Gerald de Haan, PhD (chair) – Netherlands
  • Elaine Dzierzak, PhD – Netherlands
  • Tariq Enver, PhD – United Kingdom
  • Anthony Richard Green, PhD – United Kingdom
  • David Haylock, PhD – Australia
  • Peter Lansdorp, PhD, MD – Canada
  • Kelly McNagny, PhD – Canada
  • Susie Nilsson, PhD – Australia
  • David Scadden, MD – United States
  • Toshio Suda, MD – Japan

Young Investigators Session...

Four Ph.D. students and four post-docs have been selected to present Friday afternoon, 17 September, during the New Investigators Session. Partial presentation abstracts are noted below along with some of their insightful comments.

ISEH is committed to helping provide opportunities for young scientists to grow in their careers and become the leaders of the future. We encourage ISEH established scientists to take time to meet these young investigators.

HAS3-Synthesized Hyaluronan Participates in Directing the Preferential Homing of Transplanted Hemopoietic Stem Cells to the Metaphysis During the Initial Stages of Homing
S.L. Ellis, Peter MacCallum Cancer Centre, East Melbourne, Australia

Hemopoietic stem cells (HSC) exist in specialized niches within bone marrow that are responsible for their attraction, retention and regulation. Significant evidence suggests HSC exist in an endosteal niche, but more recently suggestions have been made that HSC also reside in vascular niches. Analysis of the spatial distribution of 2,426 transplanted HSC (Lineage- Sca+Kit+) at the single cell level in 30 nonmyeloablated recipients reveals 71% of HSC preferentially home to the trabecular-rich metaphysis at all time-points from 15min to 15 hour post-transplant.

"Participating in the ISEH meeting provides excellent opportunities to network with other stem cell scientists whose papers I have read and to discuss science in an informal and collegiate setting. Through attending the sessions, I will gain first hand knowledge of current stem cell topics and the questions these topics generate."
    - Sarah Ellis, PhD scholar, Australian Stem Cell Centre, Clayton, Victoria, Australia

The Role of Freshly Isolated Mature Megakaryocytes in Regulating HSC Function in Vitro and in Vivo
J. Neaves, Australian Stem Cell Centre, Clayton, Australia

Interactions between hematopoietic stem cells (HSC) and the cellular and extracellular constituents of the endosteal bone marrow niche are crucial for HSC regulation. However, the precise interactions regulating HSC function remain unclear. Interestingly, we demonstrate that following HSC transplants into non-ablated recipients, 68% of transplanted cells were within two cells of mature megakaryocytes (MM). We therefore conducted studies investigating the role of MM in regulating HSC growth. In vitro studies were performed with purified populations of MM isolated with a novel multi-parameter FACS strategy (CD41high SSC-Ahigh), isolating viable MM of defined ploidy.

"Moving forward, I find that there is a lack of job security, especially in academia. With the recent economic hardship, however, this is also the case in biotechnology. The career structure of a PhD graduate is not clearly defined creating a spectrum of roles and pay scales that outside a university are not regulated or adequately assessed. In addition, career mentorship is scant and funding of career development awards are severely lacking. To foster the next successful generation of medical researchers, more detail is required within the PhD degree itself but most importantly a strong focus is required on the transition path from student to successful member of the scientific workforce."
    - Rebecca Neaves, PhD student, Nilsson Lab, Australian Stem Cell Centre, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia

Overexpression of Polycomb Gene CBX7 in Hematopoietic Cells Induces Distinct Types of Leukemia
K. Klauke, University Medical Centre Groningen, Groningen, Netherlands

Proteins that control chromatin organization, like Polycomb group proteins, have been shown to be one of the key players in cancer pathogenesis. Although Bmi1 has been the most studied polycomb protein in relation to cancer, its interaction partner Cbx7 has also recently been linked to hematological malignancies. We now show that Cbx7 overexpression results in the development of distinct leukemia subtypes with a 100 percent penetrance upon transplanation. In this overexpression model, we have implemented a new 'barcoding' method to study clonal dynamics of these different types of leukemia’s.

"The biggest challenge for a PhD student is to get your priorities straight. As your knowledge in a subject increases, you encounter more and more questions that might seem interesting to investigate. However, which questions do you chase and which questions will you put aside? Fortunately, I work in a lab with inventive and motivating colleagues and discussing my work and ideas with them helps me to pursue the most relevant questions."
    - Karin Klauke, PhD student, Stem Cell Biology lab of Gerald de Haan, Groningen, The Netherlands

Canonical Wnt Signaling Regulates Hematopoiesis in a Dosage-Dependent Fashion
T.C. Luis, Leiden University Medical Center, Leiden, Netherlands

The canonical Wnt signaling pathway has been implicated in regulation of hematopoiesis through studies from many different laboratories. However, different inducible gain-of-function approaches retrieved controversial results. Making use of different targeted hypomorphic mutations in the negative Wnt signaling regulator Apc a gradient of canonical Wnt activation was obtained. We show that there is a differential, lineage specific, optimum Wnt dosage in the hematopoietic system that differs between HSC, myeloid precursors and T lymphoid precursors. This provides a unifying concept that explains the differences reported among inducible gain-of-function approaches.

"It will be a great opportunity to present my work during the New Investigators Session at the ISEH meeting in Melbourne. It is very pleasing to be selected for oral presentation in such a big and important meeting. Besides bringing more visibility to the work I have been doing, I think this will allow me to discuss my data with top scientists from all over the world."
    - Tiago Cunha Luis, PhD student at Leiden University Medical Centre and Erasmus University Medical Centre, Rotterdam, The Netherlands

Diabetes Impairs Hematopoietic Stem Cell Trafficking
F. Ferraro, Harvard Stem Cell Institute, Massachusetts General Hospital, CRM, Boston, United States of America

Peripheral blood stem cells (PBSC) collected after mobilization by granulocyte colony-stimulating factor (G-CSF) represent the major source for hematopoietic reconstitution. However, 15-20 percent of patients fail to reach adequate number of HSCs (poor mobilizers), a severe therapeutic limitation that is only partially overcome by new mobilizing agents. Reviewing a 4-year caseload of PBSC mobilization, we found an overall 17.35% incidence of mobilization failure. 85.7% of poor mobilizers were affected by diabete mellitus (DM) while the incidence of disease was 14.3% in the good mobilizers group.

"I think science has become too much of a business and I think the main challenge is to remind ourselves daily that science and progress are primary meant for the service of human beings."
    - Francesca Ferraro, post-doc, Center for Regenerative Medicine, MGH, Harvard Stem Cell Institute, Boston, MA, USA.

Prevention of Chemotherapy-Induced Damage in the Hematopoietic Microenvironment by Neuroprotection
D. Lucas-Alcaraz, Mount Sinai School of Medicine, New York, USA

Transplantation of mobilized hematopoietic stem cells (HSC) is the only curative therapy for many malignancies. However, patients that have previously received chemotherapy treatment often fail to mobilize sufficient HSC numbers and show reduced survival after transplantation. The reasons for these deficits remain unclear. Since signals from the sympathetic nervous system (SNS) are necessary for mobilization and because many chemotherapy agents induce peripheral neuropathy, we hypothesized that SNS denervation induced by chemotherapy altered HSC engraftment and mobilization.

"It is an honor to be chosen for the New Investigator Session. It means the opportunity to make my research known by other investigators in the field with similar interests and to get feedback and suggestions that will improve the quality of my research. It also offers a unique opportunity to get much needed exposure at this stage of my career."
    - Daniel Lucas, instructor in the laboratory of Dr. Paul S. Frenette, Albert Einstein Medical College in the Bronx, New York USA

Commitment of Endothelial Cells to a Hematopoietic Fate in the AGM Occurs Before E10.5
G.L. Swiers, University of Oxford, Oxford, United Kingdom

The identity of the cell that gives rise to the hematopoietic stem cell (HSC) during embryogenesis has been a topic of intense study. Recent lineage tracing experiments supported the long-held notion that definitive hematopoietic cells, including HSCs, are derived from a subset of endothelium known as hemogenic endothelium. However, the developmental time point at which endothelial cells commit to the hematopoietic lineage remains unclear. To begin to establish this point of commitment, we made use of a transgenic mouse line carrying a Runx1 +23 enhancer-GFP reporter construct (+23-GFP), which marks a subset of endothelial cells at hematopoietic sites, in addition to marking all emerging hematopoietic cells.

"I am really excited about the opportunity to present my work, and represent the lab I work in at an international conference. It has given me a huge confidence boost to know that my peers are interested in hearing what I have been working on."
    - Gemma Swiers, MRC Career Development Fellow, University of Oxford, United Kingdom

Changes in the Epigenome Associated With Meis1 Induced Leukemic Transformation
E.S. Yung, BC Cancer Agency, Vancouver, Canada

Meis1, a TALE homeodomain protein family member and a Hox transcription factor co-factor, is overexpressed in AML and is a potent, rate-limiting collaborating gene in numerous murine leukemia models. While likely a transcription factor that affects the expression of a wide spectrum of genes, the full range of target genes and mechanisms of Meis1-induced changes in gene expression and their impact on leukemic stem cell function remain poorly resolved. To gain a more comprehensive understanding of the role of Meis1 in leukemia, we have exploited next-generation sequencing (Illumina platform) to perform genomewide analysis of Meis1-induced changes in key histone marks associated with activation (H3K4me3), priming (H3K4me3 and H3K27me3) or silencing chromatin states (H3K9 and/or H3K27me3).

"I hope to gain valuable networking contacts at the conference, as collaborations always occur and it helps to put faces and personalities to the names and publications we’re all aware of."
    - Eric Yung, research fellow, Terry Fox Laboratory, British Columbia Cancer Agency, Canada

Society News...

ISEH Elects New Leadership

Congratulations to the 2010-2011 ISEH Board of Directors, who were elected by their peers in August. The Society looks forward to their leadership. We extend our thanks to outgoing board members Thalia Papayannopoulou (Past-President), Reuben Kapur (Treasurer), Dominique Bonne (Director) and Gay Crooks.

Vice president: Elaine Dzierzak, PhD
Elaine Dzierzak studied biology at the University of Illinois, (USA) and received her PhD in biology from Yale University. She did her postdoctoral training at the Whitehead Institute for Biomedical Research (MIT) and was the first to demonstrate the expression of a retrovially transduced therapeutic gene in hematopoietic cells after bone marrow stem cell transplantation. At the National Institute for Medical Research (London), she changed the long-held textbook dogma of the yolk sac origins of the adult hematopoietic system, showing that adult-type HSCs are generated from the embryonic aorta. In 1996 she moved her research group to Erasmus Medical Center (Rotterdam), Dept. of Cell Biology where she is a professor of developmental biology and director of the Erasmus Stem Cell Institute. She is co-director and founder of the master of science program in molecular medicine, a VICI and NIG merit award winner, a member of EMBO and director of the BSIK SCDD consortium. She aims to identify the molecules involved in the generation and expansion of hematopoietic stem cells with long term goals to improve clinical cell replacement therapies for blood-related genetic diseases and leukemias.

Director: David Traver, PhD
David Traver is associate professor in the Section of Cell and Developmental Biology, Department of Cellular and Molecular Medicine at the University of California San Diego in La Jolla, Calif. His undergraduate degree in cell and molecular biology is from the University of Washington. He earned his doctoral degree in immunology from Stanford University followed by a post doctoral assignment at Harvard University. Dr. Traver is an associate editor for Experimental Hematology. His research interests and expertise include use of model organisms (zebrafish) to understand hematopietic stem cell biology.

Director: Emmanuelle Passegué, PhD
Emmanuelle Passegué is associate professor in the Department of Medicine, Division of Hematology Oncology with the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at the University of California San Francisco (UCSF). Her research focus is deciphering the mechanisms controlling hematopoietic stem cell (HSC) and progenitor cell functions during normal hematopoiesis and in hematological malignancies. Dr. Passegué earned her doctoral degree from the University Paris XI, France. She trained at the Institute for Molecular Pathology in Vienna, Austria and at Stanford University.

Director: Louise Purton, PhD
Louise Purton is senior research fellow at St. Vincent’s Institute of Medical Research and the University of Melbourne. She is also an associate director at St. Vincent’s. Research in her laboratory is focused on understanding how HSCs are regulated, and determining the roles of the bone marrow microenvironment in regulating haemopoietic diseases, including leukaemia. Dr. Purton received her bachelor’s and doctoral degrees in physiology from the University of Melbourne and did a post doc in hematology/oncology at the Fred Hutchinson Cancer Research Center, Seattle, Washington USA.

Following the elections, Tao Cheng was appointed treasurer.

Treasurer: Tao Cheng, MD
Professor Tao Cheng is the scientific director at the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, director of the State Key Laboratory for Experimental Hematology and the founding director of the Center for Stem Cell Medicine at CAMS in China. He received his medical degree from the Second Military Medical University in Shanghai, China, followed by his residency in internal medicine and clinical fellowship in hematology at Changhai Hospital, Shanghai. Dr. Cheng did his postdoctoral research training at the Hipple Cancer Research Center, Dayton, Ohio and Massachusetts General Hospital, Boston before moving to Harvard University and the University of Pittsburgh to teach.

Your 2011 ISEH Board of Directors:

  • President: David Scadden, MD (USA)
  • President-Elect: Gerald de Haan, PhD (The Netherlands)
  • Vice President: Elaine Dzierzak, PhD (The Netherlands)
  • Treasurer: Tao Cheng, MD (China)
  • Immediate Past President: Toshio Suda, MD (Jqpan)
  • Mitchell Cairo, MD (USA) - Director
  • Margaret Goodell, PhD (USA) - Director
  • Toshio Kitamura, PhD (Japan) - Director
  • Hanna Mikkola, MD, PhD (USA) - Director
  • Susie Nilsson, PhD (Australia) - Director
  • Emmanuelle Passegué, PhD (USA) - Director
  • Louise Purton, PhD (Australia) - Director
  • Timm Schroeder, PhD (Germany) - Director
  • David Traver, PhD (USA) - Director
  • R. Keith Humphries, MD, PhD (Canada) - Ex-Officio as Editor-In-Chief

New Associate Editors – Experimental Hematology

R. Keith Humphries, MD, PhD, senior scientist in the Terry Fox Laboratory at the British Columbia Cancer Agency takes on the role of editor-in-chief beginning with the January 2011 issue of Experimental Hematology. The society thanks Esmail Zanjani, PhD, for his years of dedicated service as editor-in-chief, as well as all of the outoing associate editors. He will continue to contribute as an associate editor.

"We have a strong team that will help attract articles and further define the scope and emphasis of the journal on hematopoietic stem cells, hematologic malignancies and the exciting emerging areas of model organisms and genomics as applied to normal and malignant hematopoiesis,” explains Dr. Humphries.

Dr. Humphries is proud to name his associate editors:

Koichi Akashi, MD, PhD
Dept. of Medicine and Biosystemic Science, Kyushu University, Japan
Research interests/expertise: leukemia, stem cell biology, transcriptional control of early hematopoiesis

Gerald de Haan, PhD
Department of Stem Cell Biology, University Medical Centre, Groningen, The Netherlands
Research interests/expertise: molecular genetic control of stem cell function including self-renewal, homing, engraftment

Bertie Göttgens, PhD
Cambridge Institute for Medical Research, Cambridge University, United Kingdom
Research interests/expertise: hematopoietic development, stem cell biology, transcription factor networks, systems biology

Toshio Kitamura, PhD
The Institute of Medical Science, University of Tokyo, Japan
Research interests/expertise: hematopoietic signal transduction, transcription factors, cellular therapy

Susie Nilsson, PhD
Commonwealth Scientific and Industrial Research Organisation, Material Science and Engineering, Melbourne, Australia
Research interests/expertise: hematopoietic stem cell biology, bone marrow transplantation, hematopoietic niche

David Traver, PhD
Division of Biological Science, UC San Diego, USA
Research interests/expertise: use of model organisms (zebrafish) to understand hematopietic stem cell biology

Mervin Yoder, MD
Dept. of Pediatrics and Dept. of Biochemistry and Molecular Biology, Indiana University, USA
Research interests/expertise: hematopoietic stem cell ontogeny, role of endothelial cells in hematopoiesis, microenvironment

Axel Zander, MD
Bone Marrow Transplantation Center, University Hospital Hamburg-Eppendorf / Germany
Research interests/expertise: bone marrow transplantation, clinical trials

Esmail Zanjani, PhD - outgoing editor-in-chief
Department of Animal Biotechnology, University of Nevada, USA
Research interests/expertise: Large animal models (sheep) to study hematopietic stem cells, ontogeny

News from the Field...

ASH Recognizes Two ISEH Members

The American Society of Hematology (ASH) will honor six scientists who have made significant contributions to the understanding and treatment of hematologic diseases. Two of the six are ISEH members. These awards will be presented at the 52nd ASH Annual Meeting December 4-7 in Orlando.

David T. Scadden, MD, of the Massachusetts General Hospital and the Harvard Stem Cell Institute, Boston, MA, will be presented with the 2010 Dameshek Prize for his landmark contributions to stem cell biology. Dr. Scadden increased the fundamental understanding of the stem cell niche and how cells engage it. His laboratory was the first to show that modifying CXCR4 can lead to stem cell mobilization and more recently defined two new molecular regulators of stem cell homing and engraftment. These, combined with real-time imaging of individual stem cells engrafting in their niche, provide new opportunities for understanding and manipulating the processes critical for stem cell transplantation. His contributions have altered thinking in the field and given direction for interventions to improve transplantation. The award is named after the late Dr. William Dameshek, a past president of the Society and first editor of its journal, Blood.

Leonard I. Zon, MD, of Children’s Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, will be recognized with the E. Donnall Thomas Lecture and Prize for his pioneering research into the development and regulation of hematopoietic stem cells. Dr. Zon is internationally recognized for his pioneering research in the new fields of stem cell biology and cancer genetics. His laboratory has used the zebrafish as a model for finding novel genes involved in blood development and stem cell formation. Several of these genes have predicted new human disease genes, and he has found signal transduction pathways and transcription factors that regulate hematopoiesis. Some of these pathways may help marrow and cord blood transplantation in humans. This prize, named after a Nobel Prize laureate and past Society president, recognizes pioneering research achievements in hematology.

ISEH members also were honored in 2009. The 2009 Henry M. Stratton Medal was awarded to Connie Eaves, PhD, of BC Cancer Agency at the University of British Columbia in Vancouver, Canada, for her remarkable achievements in the area of stem cell biology. The 2009 E. Donnall Thomas award was given to John Dick, PhD, of University HealthNetwork in Toronto, Canada, for his groundbreaking research into the development of human leukemia.

Member Profiles...

Ihor Lemischka, PhD
The Mount Sinai Medical Center
2010 Metcalf Award Winner

"I am greatly honored to have been selected for this award," says Ihor Lemischka, PhD, The Mount Sinai Medical Center. "ISEH has always been a very special organization for me. I’ve been involved for a long time and at one point, it was the only place where we could go every year to discuss stem cell biology."

Dr. Lemischka is the Lillian and Henry M. Stratton professor of gene and cell medicine and professor of developmental and regenerative biology at the Mount Sinai School of Medicine. He also serves as director of the Black Family Stem Cell Institute, Mount Sinai’s foundation for both basic and disease-oriented research on embryonic and adult stem cells.

Prior to Mount Sinai, Dr. Lemischka spent 21 years at the forefront of stem cell research as a professor of molecular biology at Princeton University. He earned his doctoral degree in the Center for Cancer Research at Massachusetts Institute of Technology and went on to become a postdoctoral research associate there, followed by an additional postdoctoral fellowship at MIT’s Whitehead Institute for Biomedical Research.

The move to Mount Sinai has allowed him to do things in a bigger way to further advance his research on the molecular and cellular nature of the undifferentiated stem cell "states" and how such states are altered during a change in cell fate.

"Princeton did not have a medical school," Dr. Lemischka notes. "In order to transition to drug therapy and translational study related to human disease, I wanted to be at a research-based medical center."

The Black Family Stem Cell Institute website states: "Progress in understanding the implications of stem cell research has been swift. Studies show that it is possible to reprogram adult skin cells into cells that are very similar to embryonic stem cells. Once stem cells can be grown and differentiated in a controlled way to replace degenerated cells and repair tissues, medical science may then be able to diagnose and cure many intractable diseases at their earliest stages, such as type 1 diabetes, Parkinson’s disease, various cardiovascular diseases, liver disease, and cancer.

"My Metcalf address in Melbourne will be a combination of several things," Dr. Lemischka says. "I’d like to give a historical perspective on how the field has moved along during my career and how my research has helped address important questions. I’ll talk about qualitative and systems biology, touch on my recently published and yet-to-be-published work, as well as share my very strong personal viewpoint of where we need to go to achieve clinical breakthroughs."

Among his research published recently was "Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome," which was featured on the cover of Nature 465, 808-812 (10 June 2010). Dr. Lemischka is happy leading a team working to identify how and when things go wrong at the cellular level in order to learn to interfere with the process or block it to prevent these diseases

"I come from a family heavily loaded with physicians, including my father," he recalls. "When I decided to go into the PhD world vs. becoming an MD, it caused considerable consternation with my father and mother. There came the time, however, when my father said to me ‘son, I’m glad you didn’t take my advice and go to medical school. Now I see what an impact your research has for medicine of the future.’ That was truly a special moment for me."

Bertie Göttgens, DPhil
University of Cambridge
McCulloch and Till Award Winner

Dr. Bertie Göttgens, too, is thrilled and also humbled to receive this ISEH honor.

"The McCulloch and Till Award is a highlight of my career to date," Göttgens expresses. "I studied biochemistry for my first degree at the University of Tübingen in Germany. My degree course was very traditional with a strong emphasis on classical biochemistry such as having to learn by heart the famous Boehringer Biochemical Pathways Map. However, I was more interested into the then still emerging field of molecular biology, in particular gene regulation. I therefore chose to do a PhD with Prof. Lorna Casselton in Oxford, where my goal was to identify and functionally characterize homeobox transcription factors that control mating in mushrooms. The subsequent jump from studying sex in fungi to blood stem cells was by chance. I was looking for an exciting lab working on gene regulation in the Cambridge area and was offered a postdoc position in the lab of Tony Green. This turned out to have been an excellent choice, particularly as I was very quickly given the opportunity to establish my own research theme which ever since has been to combine state of the art transgenic assays with bioinformatic and genomic approaches to study transcriptional control mechanisms in blood stem and progenitor cells."

Today, Dr. Göttgens is reader in molecular haematology on a permanent position within the Department of Haematology, University of Cambridge. He runs an 11-strong research group funded through grants won competitively from a variety of funding agencies. The group is based in the Cambridge Institute for Medical Research, a multi-disciplinary centre of excellence within the Medical School of Cambridge University.

The long-term research goal of the Göttgens group is to decipher the molecular hierarchy of transcriptional networks responsible for blood stem cell development. To this end, the group uses complementary state-of-the-art approaches including transgenic mice, bioinformatics, ChIP-Seq assays and mathematical modelling of stem cell regulatory networks. In particular, the group has been at the forefront of using new techniques for the analysis of gene regulatory elements such as long-range genomic sequence comparisons (Nature Biotech 2000), transgenic characterisation of blood stem cell enhancers (EMBO J 2002), genome wide computational screens for gene regulatory elements with predicted in vivo activity (Proc Natl Acad Sci U S A. 2004; Hum Mol Genet 2005; Bioinformatics 2005; Dev Cell 2009), chip-on-chip assays (Genome Research 2006; Blood 2008; Blood 2009; Mol Cell Biol 2010), regulatory network reconstruction (Proc Natl Acad Sci U S A. 2007; PLoS Comp Biol 2010), the first ChIP-Seq analysis of any key blood stem cell regulator (Blood 2009), and the first multi-factor ChIP-Seq analysis of any adult stem/progenitor cell type (Cell Stem Cell 2010). The cumulative output of more than 50 research papers over the last five years has been the development of the most comprehensive transcriptional dataset for any adult stem/progenitor cell type with more than 100 in vivo validated direct functional interactions.

When asked about the biggest challenge facing him in his professional life today, he cites the need of maintaining the right balance between regular interaction with his team to keep everybody motivated and focused on addressing important biological questions on the one hand against the constant temptation to be distracted by answering the many e-mails in his inbox marked urgent.

When not "doing science," Dr. Göttgens enjoys spending time with his family.

"Given that my older daughter will finish school in three years, this family time is becoming ever more precious," he states.

Presidential Symposium Speaker Abstracts...

Presidential Symposium
Stem Cell Niche Interactions

Chair: Toshio Suda (Tokyo, Japan)

Neural Regulation of the Stem Cell Niche

P. Frenette
Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, New York. United States of America

Hematopoiesis in the bone marrow is regulated in situ by a complex array of soluble and contact factors. In addition, the bona marrow microenvironment receives long-distance cues from hormones or nerves that affect the biological function of hematopoietic stem cells (HSCs). Our recent studies have suggested that innervation from the sympathetic nervous system (SNS) plays a key role in the trafficking of HSCs and more committed progenitors. Indeed, HSC/progenitors are released in a circadian manner through rhythmic oscillation of noradrenergic signals which are locally delivered by nerves in the bone marrow microenvironment. These signals are transmitted by the b3 adrenergic receptor, leading to the regulation in the expression of the chemokine Cxcl12 which retains HSCs in the marrow. These adrenergic signals play key role in hematopoietic regeneration after cytotoxic chemotherapy. Stromal cell targeted by the SNS is a bona fide self-renewing mesenchymal stem cell (MSC) which express the b3 adrenergic receptor and high levels of key cytokines involved in HSC maintenance. These results argue that the hematopoietic niche is made of stem cell pairs, mesenchymal and hematopoietic, located adjacent to the bone marrow vasculature.

Understanding the HSC Niche

S.K. Nilsson
CSIRO, Melbourne, Australia

The ability of adult mammals to sustain and control the number of blood cells within the peripheral circulation is a remarkable physiological process underpinned by the regulation of the hemopoietic stem cell (HSC) pool and ultimately HSC fate. The concept of a bone marrow (BM) stem cell "niche” was first proposed by Schofield, who suggested that the hemopoietic potential of residing stem cells was due to a complex interaction of, signals between HSC themselves and their immediate microenvironment. Our research demonstrates that the specific anatomical location of phenotypically distinct HSC within the BM defines their functional properties.

Cells with identical CD150CD48LSK characteristics residing close to the bone-BM interface, the endosteal region, have enhanced biological function and hemopoietic potential compared to those from other BM areas. To begin to understand these differences, we have conducted a detailed characterisation of the vasculature throughout the BM, molecular and cellular interactions within specific BM regions as well as transcriptional profiling of phenotypically identical HSC and progenitors isolated from distinct BM areas. This analysis demonstrated an extensive and continuous vascular network throughout the cavity with all cells in close proximity of vasculature. These data also demonstrated high expression of specific adhesion molecules on vasculature within metaphyseal BM, resulting in enhanced trans-endothelial migration of transplanted stem/progenitor cells. Analysis of molecular and cellular interactions revealed self regulation of previously identified key regulators of HSC. Transcriptional profiling of stem/progenitors with identical CD150CD48LSK characteristics from different BM regions identified candidate genes with differential expression. These are currently being investigated to define potential roles in the functional differences between cells in different regions. Understanding the interactions of the BM microenvironment and HSC in steady state hemopoiesis is essential to enable investigations of how BM responds to perturbation and injury and what happens during aging, inflammatory and autoimmune conditions and malignancy.

Model Systems to Elucidate Molecular Mechanisms in Stem Cell Niches

K. Moore
Mount Sinai School of Medicine, New York, United States of America

How stem cells maintain normal tissue homeostasis and respond to systemic physiological stimuli are questions of central importance in stem cell biology. All stem cells have the ability to self-renew and to differentiate to produce functional mature cells. These decisions have to be balanced and carefully regulated in order to ensure a life-long source and supply of differentiated cells. Stem cell microenvironments or niches play important, though poorly understood, roles in regulating the properties of stem cells.

We suggest that hematopoietic stem cells (HSC) are maintained in a state of relative quiescence within a specific cellular architecture and are infrequently utilized during steady-state hematopoietic homeostasis. Within the niche there is a unique molecular dialog that normally maintains quiescence but can mediate rapid HSC activation and cell fate decisions in response to systemic stimuli. We propose that niche mediated quiescence is central to the maintenance of HSC with robust self-renewal capability and that this property is progressively depleted as a function of proliferative history. We have addressed these questions by utilizing mouse genetic models. One model allows stem cell specific and controllable dynamic chromosomal labeling with GFP through which viable label-retaining cells (LRC) can be isolated for functional and molecular studies. We have developed a molecular profile of the LRC on the basis of their divisional history and also show that the ability of LRC to repopulate decreases as cells divide and dilute the GFP-label irrespective of canonical stem cell phenotypic markers. Another transgenic mouse system perturbs signaling from niche specific cells and has detrimental effects on the maintenance of the resident stem cells after systemic insult. These mice constitutively overexpress a Wnt-inhibitor, Wif1, specifically in osteoblasts. Using this model we have shown that stem cells appear to proliferate at the expense of self-renewal via a dysregulation of niche signaling impacting on unexpected pathways. Ultimately, we hope to develop a precise portrait of the molecular and cellular interactions characteristic to HSC and niche cells. This information will inform strategies that target the niche as a therapeutic entity.

Niche Initiated Oncogenesis

D.T. Scadden
Massachusetts General Hospital/Harvard Stem Cell Institute, Boston, United States of America

The microenvironment in which tumor cells reside is a recognized modulator of tumor cell behavior. Whether that environment can participate in the induction of cancer is less clear and difficult to investigate in part because of our limited understanding of the specific cell types comprising ‘stroma.’ The hematopoietic system has been informative in exploring multiple aspects of tissue homeostasis and malignant transformation. Among these is defining heterologous cells in the microenvironment that can serve a regulatory role including the regulation of hematopoietic stem cells. Specific mesenchymal cells in bone have been shown to serve as niche components for stem cells in the bone marrow stroma. By genetically modifying subsets of osteolineage cells we induced perturbation of stem cell function and caused disordered hematopoiesis. The resulting myelodysplasia was microenvironment dependent and resulted in the emergence of a frank leukemia with distinctive secondary genetic abnormalities. These genetic abnormalities did not include the gene deletion we induced in the microenvironment. The multi-step process of oncogenesis may then include an initiating step in heterologous cells that comprise ‘stroma.’ To test whether a dependence on stroma was retained, we transplanted the leukemic cells and found that the leukemia could only engraft in recipients who had the genetically altered osteolineage cells. Therefore the interaction between the microenvironmental cells and the hematopoietic cells was capable of initiating malignancy and appeared to be necessary for its maintenance. The dependence on interaction between cell types offers the potential for intervention at the points of cell-cell interaction in treatment and prevention strategies.

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