Center for Regenerative Therapies Dresden

Dresden, Germany

Center for Regenerative Therapies Dresden

Dresden, Germany
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Klempin F.,Max Delbrück Center for Molecular Medicine | Beis D.,Max Delbrück Center for Molecular Medicine | Mosienko V.,Max Delbrück Center for Molecular Medicine | Kempermann G.,Center for Regenerative Therapies Dresden | And 3 more authors.
Journal of Neuroscience | Year: 2013

Voluntary wheel running has long been known to induce precursor cell proliferation in adult hippocampal neurogenesis in rodents. However, mechanisms that couple activity with the promitotic effect are not yet fully understood. Using tryptophan hydroxylase (TPH) 2 deficient (Tph2-deficient) mice that lack brain serotonin, we explored the relationship between serotonin signaling and exercise-induced neurogenesis. Surprisingly, Tph2-deficient mice exhibit normal baseline hippocampal neurogenesis but impaired activity-induced proliferation. Our data demonstrate that the proproliferative effect of running requires the release of central serotonin in young-adult and aged mice. Lack of brain serotonin further results in alterations at the stage of Sox2-positive precursor cells, suggesting physiological adaptations to changes in serotonin supply to maintain homeostasis in the neurogenic niche. We conclude that serotonin plays a direct and acute regulatory role in activity-dependent hippocampal neurogenesis. The understanding of exercise-induced neurogenesis might offer preventive but also therapeutic opportunities in depression and age-related cognitive decline. © 2013 the authors.

Rueger M.A.,University of Cologne | Androutsellis-Theotokis A.,TU Dresden | Androutsellis-Theotokis A.,Center for Regenerative Therapies Dresden
Current Pharmaceutical Design | Year: 2013

In the 1960s, Joseph Altman reported that the adult mammalian brain is capable of generating new neurons. Today it is understood that some of these neurons are derived from uncommitted cells in the subventricular zone lining the lateral ventricles, and the dentate gyrus of the hippocampus. The first area generates new neuroblasts which migrate to the olfactory bulb, whereas hippocampal neurogenesis seems to play roles in particular types of learning and memory. A part of these uncommitted (immature) cells is able to divide and their progeny can generate all three major cell types of the nervous system: neurons, astrocytes, and oligodendrocytes; these properties define such cells as neural stem cells. Although the roles of these cells are not yet clear, it is accepted that they affect functions including olfaction and learning/memory. Experiments with insults to the central nervous system also show that neural stem cells are quickly mobilized due to injury and in various disorders by proliferating, and migrating to injury sites. This suggests a role of endogenous neural stem cells in disease. New pools of stem cells are being discovered, suggesting an even more important role for these cells. To understand these cells and to coax them to contribute to tissue repair it would be very useful to be able to image them in the living organism. Here we discuss advances in imaging approaches as well as new concepts that emerge from stem cell biology with emphasis on the interface between imaging and stem cells. © 2013 Bentham Science Publishers.

Rachner T.D.,TU Dresden | Hadji P.,University of Marburg | Hofbauer L.C.,TU Dresden | Hofbauer L.C.,Center for Regenerative Therapies Dresden
Pharmacology and Therapeutics | Year: 2012

With an ageing population and improving cancer therapies, the two most common benign and malignant bone diseases, osteoporosis and bone metastases, will continue to affect an increasing number of patients. Our expanding knowledge of the molecular processes underlying these conditions has resulted in novel bone targets that are currently being explored in clinical trials. Clearly, the approval of denosumab, a monoclonal antibody directed against RANKL, has just marked the beginning of a new era for bone therapy with several additional new therapies lining up for clinical approval in the coming years. Potential agents targeting the osteoclast include cathepsin K, currently in phase 3 trials, and src inhibitors. Amongst anabolic agents, inhibitors of the Wnt-inhibitor sclerostin and dickkopf-1 are promising in clinical trials. Here, we will provide a comprehensive overview of the most promising agents currently explored for the treatment of bone diseases. © 2012 Elsevier Inc. All rights reserved.

Santos A.C.,Novartis | Carlos V.,Center for Regenerative Therapies Dresden | Jacinto A.,University of Lisbon
Genetics | Year: 2010

The wound healing response is an essential mechanism to maintain the integrity of epithelia and protect all organisms from the surrounding milieu. In the "purse-string" mechanism of wound closure, an injured epithelial sheet cinches its hole closed via an intercellular contractile actomyosin cable. This process is conserved across species and utilized by both embryonic as well as adult tissues, but remains poorly understood at the cellular level. In an effort to identify new players involved in purse-string wound closure we developed a wounding strategy suitable for screening large numbers of Drosophila embryos. Using this methodology, we observe wound healing defects in Jun-related antigen (encoding DJUN) and scab (encoding Drosophila aPS3 integrin) mutants and performed a forward genetics screen on the basis of insertional mutagenesis by transposons that led to the identification of 30 lethal insertional mutants with defects in embryonic epithelia repair. One of the mutants identified is an insertion in the karst locus, which encodes Drosophila βHeavy-spectrin. We show βHeavy-spectrin (βH) localization to the wound edges where it presumably exerts an essential function to bring the wound to normal closure. Copyright © 2010 by the Genetics Society of America.

Diogo R.,Howard University | Tanaka E.M.,Center for Regenerative Therapies Dresden
Journal of Experimental Zoology Part B: Molecular and Developmental Evolution | Year: 2014

The axolotl is becoming one of the most used model organisms in developmental and regenerative studies but no publication has described in detail the development of its forelimb and hindlimb muscles. We describe and illustrate the ontogeny of these muscles in transgenic axolotls that express GFP in muscle fibers and discuss our results and data previously obtained by us and by other authors about limb regeneration in axolotls and ontogeny in frogs and other tetrapods. Our observations and comparisons: (1) demonstrate radio-ulnar and ventro-dorsal morphogenetic gradients in the order of axolotl forelimb muscle formation and differentiation, while in axolotl hindlimb ontogeny there are only proximo-distal and tibio-fibular gradients; some of the axolotl gradients are therefore different from the ulno-radial/fibulo-tibial fore- and hindlimb and the dorso-ventral hindimb ontogenetic morphogenetic gradients seen in frogs and amniotes such as chickens; (2) provide a potential explanation for the usual presence, in both limbs of taxa from all major tetrapod groups, of more radial/tibial muscles than ulnar/fibular muscles; (3) support the "in-out" developmental mechanism of appendicular muscle formation; (4) offer new insights about the ancestral Bauplan of tetrapod limbs, including the striking similarity of the zeugopodial (forearm/leg) and autopodial (hand/foot) muscles of the two limbs and the ventro-dorsal symmetry of the zeugopodial muscles of a same limb; and (5) provide further evidence to corroborate the hypothesis that these similarities are due to derived homoplastic events that occurred during the fins-limbs transition and not due to forelimb-hindlimb serial homology. © 2013 Wiley Periodicals, Inc.

Rachner T.D.,TU Dresden | Khosla S.,Mayo Medical School | Hofbauer L.C.,TU Dresden | Hofbauer L.C.,Center for Regenerative Therapies Dresden
The Lancet | Year: 2011

Osteoporosis is a common disease characterised by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. With an ageing population, the medical and socioeconomic effect of osteoporosis, particularly postmenopausal osteoporosis, will increase further. A detailed knowledge of bone biology with molecular insights into the communication between bone-forming osteoblasts and bone-resorbing osteoclasts and the orchestrating signalling network has led to the identification of novel therapeutic targets. Novel treatment strategies have been developed that aim to inhibit excessive bone resorption and increase bone formation. The most promising novel treatments include: denosumab, a monoclonal antibody for receptor activator of NF-κB ligand, a key osteoclast cytokine; odanacatib, a specific inhibitor of the osteoclast protease cathepsin K; and antibodies against the proteins sclerostin and dickkopf-1, two endogenous inhibitors of bone formation. This overview discusses these novel therapies and explains their underlying physiology. © 2011 Elsevier Ltd.

Chara O.,TU Dresden | Tanaka E.M.,Center for Regenerative Therapies Dresden | Brusch L.,TU Dresden
Current Topics in Developmental Biology | Year: 2014

In many animals, regenerative processes can replace lost body parts. Organ and tissue regeneration consequently also hold great medical promise. The regulation of regenerative processes is achieved through concerted actions of multiple organizational levels of the organism, from diffusing molecules and cellular gene expression patterns up to tissue mechanics. Our intuition is usually not adapted well to this degree of complexity and the quantitative aspects of the regulation of regenerative processes remain poorly understood. One way out of this dilemma lies in the combination of experimentation and mathematical modeling within an iterative process of model development/refinement, model predictions for novel experimental conditions, quantitative experiments testing these predictions, and subsequent model refinement. This interdisciplinary approach has already provided key insights into smaller scale processes during embryonic development and a so-far limited number of more complex regeneration processes. This review discusses selected theoretical and interdisciplinary studies and is structured along the three phases of regeneration: (1) initiation of a regeneration response, (2) tissue patterning during regenerate growth, (3) arresting the regeneration response. Moreover, we highlight the opportunities provided by extensions of mathematical models from developmental processes toward the study of related regenerative processes. © 2014 Elsevier Inc.

Michel M.,Center for Regenerative Therapies Dresden
Development (Cambridge, England) | Year: 2012

In the Drosophila testis, germline stem cells (GSCs) and somatic cyst stem cells (CySCs) are arranged around a group of postmitotic somatic cells, termed the hub, which produce a variety of growth factors contributing to the niche microenvironment that regulates both stem cell pools. Here we show that CySC but not GSC maintenance requires Hedgehog (Hh) signalling in addition to Jak/Stat pathway activation. CySC clones unable to transduce the Hh signal are lost by differentiation, whereas pathway overactivation leads to an increase in proliferation. However, unlike cells ectopically overexpressing Jak/Stat targets, the additional cells generated by excessive Hh signalling remain confined to the testis tip and retain the ability to differentiate. Interestingly, Hh signalling also controls somatic cell populations in the fly ovary and the mammalian testis. Our observations might therefore point towards a higher degree of organisational homology between the somatic components of gonads across the sexes and phyla than previously appreciated.

Kempermann G.,Center for Regenerative Therapies Dresden | Kempermann G.,German Center for Neurodegenerative Diseases
Cell | Year: 2011

The reports by Bonaguidi et al. (in this issue of Cell) and Encinas et al. (in Cell Stem Cell) come to differing conclusions about whether and how the proliferation of radial glia-like stem cells of the adult hippocampus impacts their long-term potential for neurogenesis. © 2011 Elsevier Inc.

Schallenberg S.,Center for Regenerative Therapies Dresden | Tsai P.-Y.,Center for Regenerative Therapies Dresden | Riewaldt J.,Center for Regenerative Therapies Dresden | Kretschmer K.,Center for Regenerative Therapies Dresden
Journal of Experimental Medicine | Year: 2010

CD4+CD25+ regulatory T cells (T reg cells) expressing the transcription factor Foxp3 can be induced from peripheral T cell receptor (TCR) transgenic CD4+CD25-Foxp3- T cells stimulated with noninflammatory dendritic cells presenting low amounts of agonist cognate antigen. However, limited evidence exists for extra-thymic T reg cell generation from non-TCR transgenic T cells in unmanipulated mice. We compared events early during agonist-driven generation of Foxp3+ TCR transgenic T cells to polyclonal CD4+ T cell populations in unmanipulated mice. We identified an interleukin-2- and phosphatidylinositol-3- kinase-dependent precommitted Foxp3- precursor to Foxp3+ T reg cells in peripheral lymphoid organs. Transforming growth factor β signaling played a minor role in the generation and subsequent differentiation of these T reg precursor cells. © 2010 Schallenberg et al.

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