The 15th Colloque Médecine et Recherche of the Fondation IPSEN in the Endocrinology Series: “Stem Cells in Neuroendocrinology”
Stem cells in adults are the source of the body’s regenerative potential. Dividing and differentiating to replace dying or damaged cells. Discovering the specific signals that activate stem cells holds substantial promise for repairing damaged organs. Recently developed techniques for producing large numbers of stem cells in the laboratory are enabling the investigation of basic stem-cell biology and the creation in vitro models of diseases. Cells are being prepared for transplantation into the body and the relationship between healthy and cancer-forming stem cells is being examined. At the Fondation IPSEN’s annual Colloque Médecine et Recherche in the Endocrine Interactions series, an international panel of speakers reviewed how these potent new techniques are being applied to the control of hormone production by the hypothalamus and pituitary gland, the master neuro-endocrine organs that regulate processes ranging from growth, metabolic control and appetite to sleep, stress and aging. Advancing understanding of this system and our ability to repair it will substantially benefit human health and well-being. This meeting, was held in Paris on December 7th , 2015, was organised by Donald Pfaff (The Rockefeller University, New York, USA ) and Yves Christen (Fondation IPSEN, Paris, France ).
Many of the body’s functions are regulated by endocrine hormones, secreted by glands such as the thyroid, pancreas and adrenals. These are controlled by the pituitary gland, located just below the brain, which in turn is governed by the hypothalamus, in the base of the brain, in response to signals it receives from other parts of the brain. This complex neuro-endocrine regulatory system ensures homeostasis by integrating different body functions and their responses to environmental signals. For example, the response to stressful situations involves the central nervous system, the neuro-endocrine and the immune system. Failure either to activate or terminate these responses may result in anxiety, depression and eating disorders (Alon Chen, Max Planck Institute, Munich, Germany ).
Damage to the hypothalamus and pituitary can result from accident, radiation or tumour growth, with profound consequences that include sleep disturbances, weight gain, abnormal stress responses and age-related conditions. Current hormone replacement treatment is costly and has side effects. Stem-cell therapy, whether by transplanting stem cells grown in vitro or activating intrinsic stem cells offers a much more satisfactory alternative (Pfaff; Karine Rizzoti, MRC National Institute for Medical Research, London, UK ).
Many adult tissues contain nests of stem cells, which are undifferentiated and retain the capacity to proliferate. Each cell division creates one offspring with stem-cell properties and the other, known as a progenitor cell, that can differentiate into a variety of cell types. Studying stem and progenitor cells is providing the information needed for using stem cells to repair damaged human tissues (Inna Tabansky, The Rockefeller University, New York, USA ). This includes understanding the molecular pathways that determine the fate of each cell, how tissues maintain and repair themselves, and the role of cell turnover in organ function. Another important aspect is to discover how tissues are organised in three dimensions, so that transplanted cells can be successfully integrated into living tissue (Tabansky; Rizzoti).
Proliferation and differentiation are triggered by chemical signals from within or outside the tissue, few of which have been identified. Recently discovered stem cells in the pituitary seem to be activated mainly in pathological states: in mice that lack a certain type of hormone-producing cell, functional replacement cells were generated by stimulating this stem-cell population (Hugo Vankelekom, University of Leuven, Leuven, Belgium ). A complex of local signals, some secreted by the stem cells themselves, and environmental influences yet to be identified determine whether stem cells remain quiescent or divide. A signaling pathway well-known in developmental biology promotes proliferation in vitro in a subset of stem cells that give rise to hormone-producing cells (Cynthia Andoniadou, King’s College, London, London, UK ). Differentiation of progenitor cells depends on epigenetic mechanisms, such as chromatin remodeling, that activate genes specific to each type of cell. The choice of differentiation pathway determines the fate of the pituitary-cell progenitors, in this case whether they become cells that secrete melanocyte-stimulating hormone or ones producing adrenocorticotropic hormone (Jacques Drouin, Institut de Recherches Cliniques de Montréal, Montréal, Canada ).
In one part of the hypothalamus, cells known as tanycytes have the properties of neural stem cells and progenitors. In response to a high-fat diet and low levels of the hormone leptin, which signals satiety, they differentiate into neurons. Learning more about these signals may contribute to the treatment of diabetes and obesity (Seth Blackshaw, Johns Hopkins University School of Medicine Baltimore, USA ).
Like all things in life, stem cells have their dark side: under certain conditions, they can seed tumour formation. Various animal models are being used to establish what causes this potential and to understanding why and how tumours form in the pituitary. This is essential to safeguard against stem cells used for transplantation developing into tumours (Vankelekom; Andoniadou; Rizzoti).
Stem cells in culture are also offering new opportunities for unravelling the cellular mechanisms of disease an approach being successfully applied to the study of depression (Patricia Zunszain, Institute of Psychiatry, London, UK ). Stem-cells from the human hippocampus, a part of the brain involved in memory formation, differentiate in response to anti-depressant drugs. On the other hand, the birth of new neurons is suppressed by inflammatory molecules, which are an integral part of depression resulting from stress, and the stress hormone cortisol. In time, it should be possible to tailor treatment for individual patients by determining their inflammatory status.
But perhaps the ultimate goal of stem-cell research is to transplant well-defined cells into humans to replace cells that malfunction as a result of genetic mutation, accident or degenerative processes. The recent discovery that skin fibroblasts taken from a patient can be reprogrammed in vitro, so that they revert to stem or progenitor cells, has been a huge step forward. These induced pluripotent stem cells (iPSC) can be produced in large numbers and because they match the patient’s genotype, complications of graft rejection are avoided. Signal molecules and transcription factors are being identified that can reliably direct these cells to differentiate into the required cell types (Tabansky).
One exciting approach is to grow three-dimensional ‘organoids’ in culture for studying the complex of positional signals involved in generating organ structure. They also be used as models for disease and drug screening, as well as providing tissue for transplantation (Hidetaka Suga, Nagoya Univesrity Hospital, Nagoya, Japan ; Rizzoti). Floating three-dimensional aggregates have been created: one has properties of specific areas of the hypothalamus, including hormone release, and another of pituitary cells releasing adrenocorticotropic hormone. When this cultured tissue is transplanted into mice lacking pituitaries, their hormone levels, physical activity and survival are restored (Suga).
Most promising of all, human mid-brain dopamine neurons, which degenerate in Parkinson’s disease, have successfully been generated in vitro. They are functionally integrated when transplanted into animal models of the disease and regulatory approval for testing in human patients is awaited (Lorenz Studer, Memorial Sloan Kettering Cancer Centre, New York, USA ). The methods employed provide a blueprint for generating progenitor cells for the pituitary and hypothalamic neurons that release corticotrophin-releasing hormone and thyroid-stimulating hormone (Studer; Viviane Tabar, Memorial Sloan Kettering Cancer Centre, New York, USA ). Progenitors for myelin-producing oligodendrocytes also are being created, for repairing the diffuse demyelination that results from radiation damage and causes motor and cognitive deficits (Tabar).
About the Fondation Ipsen
Established in 1983 under the aegis of the Fondation de France, the mission of the Fondation Ipsen is to contribute to the development and dissemination of scientific knowledge. The long-standing action of the Fondation Ipsen aims at fostering the interaction between researchers and clinical practitioners, which is indispensable due to the extreme specialization of these professions. The ambition of the Fondation Ipsen is to initiate a reflection about the major scientific issues of the forthcoming years. It has developed an important international network of scientific experts who meet regularly at meetings known as Colloques Médecine et Recherche , dedicated to six main themes: Alzheimer's disease, neurosciences, longevity, endocrinology, the vascular system and cancer science. Moreover the Fondation Ipsen has started since 2007 several meetings in partnership with the Salk Institute, the Karolinska Institutet, the Massachusetts General Hospital, the Days of Molecular Medicine Global Foundation as well as with the science journals Nature, Cell and Science. The Fondation Ipsen produced several hundred publications; more than 250 scientists and biomedical researchers have been awarded prizes and research grants.
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