Advances in Stem Cell Aging

K. L. Rudolph

• Publisher: S. Karger
• Year: 2012
• ISBN:
  9783318021714
• Topic: Medicine
• Subtopic: Gastroenterology & Hepatology

Adult stem cells are present in most postnatal tissues of mammals. Tissues with high rates of cell turnover depend on the functional capacity of stem cells for lifelong maintenance of tissue homeostasis. Adult stem cells are also required for the regeneration of tissues in response to injury as in, for example, the regeneration of skeletal muscle. In addition to its function in tissue homeostasis and regeneration, adult stem cells can represent the cell type of origin of various types of cancers including leukemia and colorectal cancer. Stem cells are the most long-lived cells in the proliferative compartment of mammalian tissues. Therefore, stem cells have an increased risk of acquiring mutations that could ultimately lead to the transformation of tissue stem cells.This publication presents the current knowledge in the field of stem cell aging, which was discussed at the Else Kröner-Fresenius Symposium on Advances in Stem Cell Aging in 2011. It will be of special interest to scientists working on stem cell research, aging, regeneration, and cancer as well as physicians and scientists specializing in geriatric medicine, internal medicine, and surgery.

Chapter 1

Rudolph KL (ed): Advances in Stem Cell Aging.
Else Kröner-Fresenius Symp. Basel, Karger, 2012, vol 3, pp 2–17

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Speakers at the Symposium

Miwako Morita

Institute of Molecular Medicine and Max Planck Research Group on Stem Cell Aging, University of Ulm, Ulm, Germany

Steven Artandi, MD, PhD

S.A. is an associate professor in the Department of Medicine at Stanford University School of Medicine. He received his MD and PhD degrees from Columbia University and completed residency in internal medicine at Massachusetts General Hospital and a fellowship in oncology at the Dana-Farber Cancer Institute at Harvard Medical School. S.A. completed his postdoctoral studies in the laboratory of Dr. Ron DePinho at Harvard University and joined the faculty at Stanford in 2000. S.A.’s laboratory employs a broad, interdisciplinary approach to understand cancer, stem cell function, and aging, including the use of mouse models, biochemistry, cell biology, proteomics, and genomics. S.A.’s laboratory has pioneered the finding that telomerase has a direct role in stem cell regulation and cancer, independent of its telomere-elongating function. Through the generation and in-depth analysis of inducible telomerase mice, he revealed the unanticipated finding that telomerase activates quiescent stem cells in the skin. This function of telomerase does not involve its reverse transcriptase function; instead, S.A.’s laboratory has found that telomerase associates with promoter chromatin in part to control the Wnt signaling pathway, one of the most important circuits in self-renewal, stem cell regulation, and cancer. S.A. is also a leader in the biochemical dissection of the human telomerase ribonucleoprotein complex purified from human cancer cells. His laboratory has identified novel ATPases in telomerase assembly, as well as a new component of the telomerase holoenzyme, TCAB1, which is critical for the function of telomerase in human cells. His laboratory studies the stem cell disease dyskeratosis congenita using patient-derived induced pluripotent stem cells to understand how telomere shortening affects human stem cell populations.

S.A. was elected as a fellow of the American Association for the Advancement of Science, he was elected member of the American Society for Clinical Investigation, and he serves on the editorial board of Stem Cells and as a senior editor for Molecular Cancer Research. He is the associate director of the Paul F. Glenn Laboratories for the Biology of Aging at Stanford, an institute to support and foster aging research at Stanford.

Cédric Blanpain, MD, PhD

C.B. is an MD/PhD and is studying the role of stem cells (SCs) during development, homeostasis, and cancer. As a postdoc in the laboratory of Elaine Fuchs, The Rockefeller University, he developed a new method to isolate hair follicle SCs and demonstrated their multipotency. He defined the role of Wnt and Notch signaling pathways in regulating epidermal SCs. Since beginning to work in his own lab at the Université Libre de Bruxelles as a researcher of the Belgian FNRS in 2006, he has demonstrated the key role of Mesp1 during the specification of cardiovascular progenitors, identified the cellular origin of Merkel cells as well as the two most frequent skin cancers, and uncovered the mechanisms by which hair follicle SCs resist DNA damage-induced cell death. He also recently identified new SC populations in the mammary epithelium and a new role of VEFG in regulating skin cancer SCs.

C.B. is a member of the editorial board of Stem Cells, The Journal of Cell Biology, and The EMBO Journal. C.B. also received a Career Development Award from the Human Frontier Science Program, as well as a starting grant from the European Research Council, and he is an EMBO Young Investigator.

Helen M. Blau, PhD

H.M.B. received her BA from the University of York (UK) and her MA and PhD from Harvard University. H.M.B. is currently a Donald E. and Delia B. Baxter Professor and director of the Baxter Laboratory for Stem Cell Biology (http://baxterlab.stanford.edu/) in the Microbiology and Immunology Department and the Stanford Institute for Stem Cell Biology and Regenerative Medicine at the Stanford University School of Medicine, Stanford, Calif. (USA).

H.M.B. currently serves on the Ellison Medical Foundation Scientific Advisory Board and the Harvard Board of Overseers and is an elected member of the American Academy of Arts and Sciences and the Institute of Medicine of the National Academy of Sciences and a fellow of the American Association for the Advancement of Science. Awards include: the Senior Career Recognition Award of WICB of the American Society of Cell Biology, the FASEB Excellence in Science Award, an Honorary Doctorate from the University of Nijmegen (Holland), a Nobel Forum Lecture at the Karolinska Institute in Stockholm, a Rolf-Sammet-Fonds Visiting Professorship at the University of Frankfurt, and two Fulbright Senior Specialist awards to study and teach at the Institut Pasteur and then at the Institut Curie in Paris.

H.M.B.’s research area is regenerative medicine with a focus on stem cells. She is world renowned for her research on nuclear reprogramming and demonstrating the plasticity of cell fate using cell fusion. Her laboratory has also pioneered the design of biomaterials to mimic the in vivo microenvironment and direct stem cell fate. Her muscle heterokaryon experiments proved that silent muscle genes can be activated in diverse adult cells and that the differentiated state of a cell requires continuous regulation and is dictated by the balance of regulators present at any given time. Most recently, her lab used this cell fusion approach to define a novel role for the enzyme AID in mammalian DNA demethylation and reprogramming cells toward pluripotency. H.M.B.’s laboratory also engineers artificial in vitro platforms that recapitulate key features of in vivo stem cell microenvironments, or niches. These studies address a major limitation, as most tissue-specific stem cells cannot currently be cultured without loss of stemness. Her findings are leading to more efficient iPS generation, cell-based therapies and the discovery of novel molecules and therapies that will impact muscle-wasting diseases and hematopoietic malignancies. Her laboratory uses a multidisciplinary approach to overcome major clinical hurdles by elucidating the molecular nature of cell-intrinsic regulators and extrinsic niche components that induce adult stem cell self-renewal, pluripotency, and function in mammalian regeneration.

Thomas Braun, MD

T.B. is director of the Department of Cardiac Development and Remodeling at the Max Planck Institute for Heart and Lung Research in Bad Nauheim (Germany) (www.mpi-bn.mpg.de). After finishing his medical studies in Göttingen and his medical thesis at the Institute of Human Genetics in Hamburg, he worked as a postdoc at the Department of Toxicology of the University of Hamburg in Hamburg (Germany), the Institute of Virology in Oxford (UK), the Medical Research Council in Cambridge (UK), and the Whitehead Institute for Biomedical Research in Cambridge (USA) and as a group leader at the Department of Cellular and Molecular Biology, Braunschweig University of Technology, Braun-schweig (Germany). In 1993, he completed his PhD in cellular biochemistry and the German ‘habilitation’. He has been associate professor at the Institute of Medical Radiology and Cell Research, Würzburg (Germany) and full professor and director of the Institute of Physiological Chemistry at the University of Halle-Wittenberg where he also served as vice dean for research in the Medical Faculty. Since 2004, he has been a scientific member and director of the Max Planck Institute in Bad Nauheim and full professor at the Department of Internal Medicine of the University of Giessen (Germany). He is an elected member of the German Academy of Natural Scientists, Leopoldina, and St. Cross College, Oxford (UK).

T.B.’s research has two main focuses. The first is processes that lead to proliferation of organ-typical precursor cells and their coordinated differentiation during organ development and regeneration. The second is the development of preclinical models which can be used to enable, improve, and accelerate tissue regeneration, particularly in the heart. He has made several seminal contributions to the understanding of muscle development and regeneration that have had a major impact on the field. Key findings were the identification of the myogenic factor Myf-5, the analysis of the biological function of Myf-5, Myf-6, and MyoD in vivo, the discovery of the homeobox protein Lbx1 as a regulator of limb muscle precursor cell migration, the analysis of the role of FGFs for muscle cell migration and regeneration, the identification of Pax7 as a crucial regulator of muscle satellite cell survival and maintenance, the identification of new muscle-specific transcriptional co-regulators, and many other discoveries, including the recent identification of miRNAs as regulators of phenotype modulation of smooth muscle cells, which has a major impact on the understanding of the pathogenesis of arteriosclerosis.

Anne Brunet, PhD

A.B. is an associate professor in the Department of Genetics at Stanford University. A.B. obtained her BSc from the Ecole Normale Supérieure in Paris (France) and her PhD from the University of Nice (France). She did her postdoctoral research training in Dr. Michael Greenberg’s lab at Harvard Medical School. A.B. is interested in the molecular mechanisms of aging and longevity, with a particular emphasis on the nervous system. Her lab studies the molecular mechanism of action of known longevity genes, including FOXO transcription factors, in mammalian cells and organisms. A.B. is particularly interested in the role of longevity genes in neural stem cells during aging. Another goal of A.B.’s lab is to discover novel genes and processes regulating longevity using two model systems: the invertebrate Caenorhabditis elegans and an extremely short-lived vertebrate, the African killifish Nothobranchius furzeri. A.B. has received several grants from the National Institute on Aging to study the importance of FOXO transcription factors in aging neural stem cells and the molecular mechanisms of dietary restriction, and to develop genetic tools for the short-lived fish N. furzeri. She has published over 50 peer-reviewed papers, reviews, and book chapters. She has received a number of awards, including the Pfizer/AFAR Innovations in Aging Research Award, a Junior Investigator Award from the California Institute for Regenerative Medicine, a Glenn Foundation Award, and an Ellison Medical Foundation Senior Scholar Award.

David Bryder, PhD

D.B. holds a docent position at the Medical Faculty at Lund University (Sweden) in the section for immunology. After completing PhD studies in Lund, he conducted postdoctoral studies with Irving L. Weissman at Stanford University. He started his own research group in Lund in 2005 aided by a personal research award from the Swedish Strategic Research Foundation.

D.B.’s research focuses on regulation of early stages of blood cell differentiation in the adult. D.B. has made several contributions in the fields of early lymphoid development, leukemogenesis, and erythropoiesis. Lately, his laboratory has specifically worked on characterizing age-associated consequences at the level of hematopoietic stem cells (HSCs). His main contributions include: (1) cellular dissection of early hematopoietic lineage commitment, (2) the demonstration that age-dependent compromise of nuclear genomic maintenance compromises HSC function, and (3) establishment of the consequences of mitochondrial DNA deterioration on blood cell formation.

Gerald de Haan, PhD

G.d.H. is a professor of molecular stem cell biology at the Department of Cell Biology, University Medical Center Groningen (The Netherlands) (www.rug.nl/umcg) and co-director of the European Research Institute on the Biology of Aging (www.eriba.umcg.nl). He received his PhD in 1995 and was a postdoctoral fellow in the lab of Gary Van Zant at the University of Kentucky until 1998. He was awarded a fellowship by the Royal Netherlands Academy of Arts and Sciences to establish his own lab in Groningen and received a VICI grant from the Netherlands Organization for Scientific Research.

G.d.H.’s research interests relate to the molecular understanding of self-renewal of hematopoietic stem cells. This includes the identification of genes that regulate self-renewal, hematopoietic stem cell expansion, development of leukemia, and studies on hematopoietic stem cell aging. In earlier studies, G.d.H.’s group was able to show how hematopoietic stem cell turnover is correlated with mouse lifespan. Genetic studies have identified genomic loci that control these parameters, and more recently genome-wide expression studies have resulted in the construction of gene networks that underlie stem cell turnover and functioning. In addition, his lab studies the involvement of epigenetic modifications during hematopoietic stem cell aging.

James DeGregori, PhD

J.D. received a BA in microbiology from the University of Texas at Austin in 1987 and a PhD in biology from the Massachusetts Institute of Technology in Cambridge in 1993 (under the mentorship of Dr. Earl Ruley). From 1993 to 1997, as a postdoctoral fellow in the lab of Dr. Joe Nevins at Duke University Medical Center, he studied how the E2F transcription factor family controls transcription and cell fate decisions. Since 1997, he has been a faculty member in the Department of Biochemistry and Molecular Genetics at the University of Colorado School of Medicine. He currently serves as the director of the Program in Molecular Biology (a graduate program) and coleader of the Molecular Oncology Program of the University of Colorado Cancer Center.

Studies to better understand the conditions that foster the initiation of leukemias and lymphomas are currently a major thrust of the lab (http://medschool.ucdenver.edu/DeGregoriLab). The J.D. lab has developed an evolutionary based model for cancer development: adaptive oncogenesis. The lab is currently exploring how reduced stem cell fitness resulting from carcinogen exposure, irradiation, inadequate diet, or aging can select for adaptive cancer-causing mutations and thereby promote cancer. Other studies in the lab are geared towards the development of novel therapeutic strategies to treat leukemias and non-small cell lung cancers. The lab performs genome-wide screens to identify genes whose inhibition will synergize with current targeted therapeutics to eliminate cancer cells. These studies could lead to the discovery of novel combination therapies that will more effectively treat or possibly even cure common malignancies.

Kenneth Dorshkind, PhD

K.D., professor and vice chair for research in the Department of Pathology and Laboratory Medicine at the David Geffen School of Medicine at the University of California, Los Angeles, earned his doctorate in biological structure at the University of Washington, Seattle, in 1980 and then completed a postdoctoral fellowship at the Ontario Cancer Institute in Toronto. He serves as director for Shared Resources in the Jonsson Comprehensive Cancer Center (www.cancer.ucla.edu) and as academic associate director of the UCLA Broad Stem Cell Research Center (www.stemcell.ucla.edu). Work in the K.D. laboratory is supported by multiple grants from the National Institutes of Health.

Research in the K.D. laboratory is focused on the analysis of lymphocyte development during embryogenesis and senescence. One aim is to compare and contrast B cell progenitors that emerge during fetal life with those that are generated in postnatal bone marrow. Emerging data from his laboratory indicate that the first wave of B cell development in the fetus generates B-1 B cell progenitors, which are effectors of innate immunity. The other main goal of the laboratory is to determine the basis for declines in lymphocyte development with age. It is known that lymphoid progenitors exhibit severe growth defects during aging while myelopoiesis is relatively unperturbed. Recent data generated in his laboratory have demonstrated that the preferential expression of p16Ink4a and Arf tumor suppressor proteins in aged lymphoid progenitors contributes to their reduced growth and survival and makes the aged progenitors refractory to transformation. Downregulation of p16Ink4a and Arf reversed the senescent phenotype but restored susceptibility to transformation. These data have provided a molecular explanation for lymphoid lineage aging and support the hypothesis that aging and cancer resistance are linked processes.

Daniela Drummond-Barbosa, PhD

D.D.-B. received her BS degree in biochemistry and immunology from the Universidade Federal de Minas Gerais in Belo Horizonte in 1991. She next moved to New Haven, Conn. (USA) to join the genetics graduate program at Yale University. She did her thesis research with Dr. Daniel Di-Maio on the interaction between the bovine papillomavirus E5 protein and the platelet-derived growth factor receptor, obtaining her PhD degree in 1995. In 1996, D.D.-B. joined Dr. Allan Spradling’s laboratory for her postdoctoral training. Her discovery that stem cells and their descendants respond to diet, and that the insulin pathway is a major mediator of this response in the Drosophila ovary, laid the foundation for the establishment of her independent research program on the regulation of stem cells by the physiological/systemic environment. In 2002, D.D.-B. joined the Department of Cell and Developmental Biology at the Vanderbilt University Medical Center as an assistant professor. Her laboratory continued to play a pioneering role in elucidating how germline stem cells are regulated by diet, insulin signals, and other nutrient-sensing pathways, and also initiated a new line of research on the control of meiotic maturation in Drosophila. More recently, D.D.-B. accepted a faculty position as associate professor in the Department of Biochem...