I. Introduction to Stem Cells
II. Tapping the Potential of Adult Stem Cells, and Summary
Part II: Tapping the Potential of Adult Stem Cells, and Summary
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During embryogenesis, a single fertilized oocyte gives rise to a multicellular organism whose cells and tissues have adopted differentiated characteristics or fates to perform the specified functions of each organ of the body. As embryos develop, cells that have acquired their particular fate proliferate, enabling tissues and organs to grow. Even after an animal is fully grown, however, many tissues and organs maintain a process known as homeostasis, where as cells die, either by natural death or by injury, they are replenished. This remarkable feature has ancient origins, dating back to the most primitive animals, such as sponges and hydrozoans. The fabulous ability of an embryo to diversify and of certain adult tissues to regenerate throughout life is a direct result of stem cells, nature's gift to multicellular organisms.
Stem cells have both the capacity to self-renew, that is, to divide and create additional stem cells, and also to differentiate along a specified molecular pathway. Embryonic stem cells are very nearly totipotent, reserving the elite privileges of choosing among most if not all of the differentiation pathways that specify the animal. In contrast, stem cells that reside within an adult organ or tissue have more restricted options, often able to select a differentiation program from only a few possible pathways, which still can make them valuable for tissue regeneration in a clinical setting. Long-standing examples of such successes include bone marrow transplants in immune disorders, including cancers, and skin culture grafts to replace epidermis damaged from burns.
My laboratory studies the stem cells of the skin that can make epidermis, sebaceous glands and hair follicles. Although only the thickness of cellophane, the epidermis of the skin is responsible for providing protection against harmful microbes and for preventing the evaporation of our essential body fluids. Being at the skin surface, epidermal cells are constantly exposed to wear and tear. Yet they keep regenerating, due to a supply of active stem cells, which create a new epidermis every 4 weeks throughout the course of a lifetime. Skin stem cells also account for why our hairs fall out but regrow, and why our body surface is lubricated with fresh oils and sweat. In this lecture, I discuss the differences between embryonic and adult stem cells, the controversies involved, and their potential for regenerative medicine. Using skin as a model system, I explore the fascinating features of adult stem cells, how they choose among different lineages and how they repair tissues damaged during injury.
Elaine Fuchs is a world leader in skin biology and its human genetic disorders, which include skin cancers and life-threatening genetic syndromes such as blistering skin disorders. Fuchs focuses on the molecular mechanisms that underlie the development and differentiation of the epidermis and its appendages from multipotent stem cells. Throughout her studies, she has used the basic biology that she uncovers to elucidate how perturbations of these mechanisms result in disease. She has systematically applied molecular and genetic approaches to these problems. In doing so, Fuchs pioneered the use of "reverse genetics," an unconventional and now textbook approach to start with understanding how proteins function and then work up to the human diseases they cause when defective. She initially conceived and applied this strategy to elucidate the functions and genetic basis of the first intermediate filament disorder, now a group of nearly 20 related but distinct human disorders that affect not only skin, but also muscle, the nervous system, liver and other tissues and organs of the body. More recently, she has applied her findings to devise approaches for identifying, isolating and characterizing the multipotent stem cells from skin and determine how they respond to various external cues to select their fates to become hair follicles, sebaceous glands or epidermis. In facing the problem of progressing from a stem cell to a tissue, Fuchs' laboratory now tackles how cells coordinate changes in transcription, cell polarity, adhesion and cytoskeletal dynamics. She has greatly accelerated the transition of dermatology into a modern day science, and takes an active interest in how her research can be used in a clinical setting. She has published over 250 papers, mostly in high profile scientific and medical journals.
Fuchs received her Ph.D. in Biochemistry from Princeton University in 1977. She conducted postdoctoral research at the Massachusetts Institute of Technology in the laboratory of Howard Green. In 1980, she joined the faculty at the University of Chicago. When she left Chicago to accept a position at The Rockefeller University in 2002, Fuchs was the Amgen Professor of Basic Sciences and an Investigator of the Howard Hughes Medical Institute. Fuchs’ many awards and honors include the Presidential Young Investigator Award, the Richard Lounsbery Award from the National Academy of Sciences, the Novartis-Drew Award for Biomedical Research, the Dickson Prize in Medicine, the FASEB Award for Scientific Excellence and the Beering Award. She is a member of the National Academy of Sciences, the Institute of Medicine of the National Academy of Sciences, the American Academy of Arts and Sciences and the American Philosophical Society, and she holds honorary doctorates from Mt. Sinai/New York University School of Medicine and from the University of Illinois, Champaign-Urbana. Fuchs is also a past President of the American Society of Cell Biology.
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Scratching the surface of skin development. Fuchs E. Nature 445, 834-842 (2007).
Reik, W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 447:425-32 (2007).
Turning over new leaves: epithelial stem cells. Blanpain C, Horsley V and Fuchs E. Cell 128, 445-458 (2007).
Lindvall O, Kokaia Z. Stem cells for the treatment of neurological disorders. Nature 441:1094-6 (2007).
Epidermal stem cells of the skin. Blanpain C, Fuchs E. Ann Rev Cell Dev Biol 22, 339-373 (2006).
Intermediate filaments in morphogenesis & disease. Cleveland DW, Fuchs E. Science 279, 514-19 (1998).
Mice cloned from skin cells. Li J, Greco V, Guasch G, Fuchs E, Mombaerts P. PNAS USA 104, 2738-44 (2007).
Blimp1 defines a novel progenitor population that governs cellular input to the sebaceous gland, Horsley V, O’Carroll D, Tooze R, Ohinata Y, Saitou M, Obukhanych T, Nussenzweig M, Tarakhovsky A, Fuchs E. Cell 126, 597-609 (2006).
Lhx2 maintains stem cell character in hair follicles. Rhee H, Polak L, Fuchs E. Science 312,1946-49 (2006).
Asymmetric cell divisions promote stratification and differentiation of mammalian skin, Lechler T & Fuchs E. Nature 437, 275-280 (2005).
Molecular dissection of mesenchymal-epithelial interactions in the hair follicle, Rendl M, Lewis L & Fuchs E. PLoS Biology 3, 1910-1924 (2005).
Defining the impact of ß-catenin/Tcf transactivation on epithelial stem cells Lowry WE, Blanpain C, Nowak J, Guasch G, Lewis L, Fuchs E. Genes Dev 19, 1596-1611 (2005).
Self renewal, multipotency and the existence of two cell populations within an epithelial stem cell niche. Blanpain, C, Lowry W.E, Geoghegan A, Polak, L, Fuchs E. Cell 118, 635-648 (2004).
Socializing with the neighbors: stem cells & their niches. Fuchs E, Tumbar T, Guasch G. Cell 116 769-78 (2004).
Defining the epithelial stem cell niche of the skin. Tumbar T, Guasch G, Greco V, Blanpain C, Lowry WE, Rendl M, Polak L, Fuchs E. [Science Express Dec 11, 2003] Science 303, 359-363 (2004).
At the roots of a never-ending cycle. Fuchs E, Merrill B, DasGupta R. Dev Cell 1,13-26 (2001).
A common human skin tumor is caused by activating mutations in beta-catenin, Chan EF, Gat U, McNiff J, Fuchs E. Nature Genetics 21, 410-413, 1999.
De novo hair follicle morphogenesis and hair tumors in mice expressing a truncated ß-catenin in skin. Gat U, DasGupta R, Degenstein L, Fuchs E. Cell, 95, 605-614 (1998).