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Mechano-sensation has only recently been linked to key regulators of healing such as BMP-signaling and to immune-response itself. Most recently early inflammation is discussed as key element to all regenerative cascades. For both cascades, windows of successful healing have been identified in model systems. However, it remains completely unknown to what degree these windows are altered during aging, despite the fact that aged patients belong to the main patient group that requires regenerative therapies.
Thus we aim to understand the alteration of these key elements in healing in aged and when an otherwise positive stimulus turns into a detrimental stressor to regeneration.
To learn more, click to one of the following subprojects.
Coordinating animal models, human hematoma harvest, scientific networking and structured education
Georg Duda, Berlin
The TP-Z provides the link to the clinic by providing through the BCRT multiuser unit "Cell and Tissue Harvest" human hematoma for comparison with the mouse model data and two GEROK positions that will be managed through the graduate school BSRT towards Clinical Scientist Career pathways. In addition, a core unit on mouse surgery and µCT analyses will be provided to all projects that deal with mouse experiments (TP 1, 2, 4, 5 and 6).
Longitudinal intravital imaging of dynamics of osteo-immunological interactions during bone healing
Anja E. Hauser, Berlin; Raluca Niesner, Berlin; Georg N. Duda, Berlin
The immune system is frequently understood as a static system residing in bone. Bone healing challenges this view because immune cells are specially activated by injury and migrate to the site of injury. The aim of this project is to characterize the reactions of immune cells in connection with MSC activation in a simple cortex injury model, a bone defect healing model, and a bone healing model using in vivo multiphoton imaging technology. This approach will allow the identification of cellular activities and cell-cell interactions in vivo during the healing processes at different stages of aging.
Influence of age and posttraumatic immune response on fracture healing following multiple injury
Klaus-Dieter Schaser, Berlin; Hans-Dieter Volk, Berlin; Christian Kleber, Berlin
The aim of our study is to better understand the impact of polytrauma (with/without sTBI) on fracture healing depending on age. Firstly, we will retrospectively investigate the impact/causative effect of polytrauma (depending on age and sTBI) on fracture healing in patients. Secondly, we will establish and validate a murine polytrauma model to enable future studies to understand the molecular mechanisms behind the interplay of trauma and immune response in regeneration.
Beneficial and unfavorable immune cells in fracture healing
Katharina Schmidt-Bleek, Berlin
Immune cells are essential for the onset of regeneration. Specifically, adaptive mmunity seems to play a key role in the healing cascades of bone. Previous investigations on large animal models and human hematoma showed that adaptive T cells are key players in the regenerative cascade. Specific immune cell subsets will be investigated for their influence on the bone regenerative capacity in animal models. A mouse model with a humanized immune system will also be used to address the question of the influence of an experienced (previously exposed) immune system (this represents the immune system of an older patient) on bone regeneration. Additionally, the connection between mechanics and immune reaction will be evaluated with a focus on endothelial cells which could be the intermediary between these two constraints.
Mechano-responsiveness in aging and its influence on the regulation of bone healing
Georg N. Duda, Berlin; Sara Checa Esteban, Berlin
Mechanics is essential to bone healing, but how aging affects the mechanical regulation of the tissue formation process during healing remains unknown. Using a combined in vivo/in silico approach, we aim to identify tissue and cell mechano-sensitivity during bone regeneration and how this is altered with aging using a mouse model. To understand the underlying strain levels experienced by the tissue and cells, a previously validated formation and remodeling algorithm (in silico) will be employed that allows for the identification of how local strains affect matrix and tissue formation in vivo and how this compares to in vitro findings of cellular straining.
Crosstalk between BMP signaling and mechano-transduction: signaltransduction towards the cytoskeleton?
Petra Knaus, Berlin; Ansgar Petersen, Berlin
BMP signaling is a key player in bone regeneration and its link to mechanics has recently been described by us. How aging influences BMP signaling in general and specifically the mechano-sensitive aspects of the signaling pathway will be the focus of this project. The role of mechanics on BMP signaling will be characterized in depth and compared at different age groups using human MSCs and human osteoblasts.
The role of cellular senescence in bone regeneration
Uwe Kornak, Berlin; Sven Geißler, Berlin
Mechanical loading is a fundamental determinant of skeletal homeostasis and bone regeneration after fracture. However, the sensitivity to mechanical signals declines with increasing age of the individual. Mesenchymal Stem/Stromal Cells (MSCs) are considered to be essential for bone regeneration and have proven to be highly sensitive to mechanical forces in their microenvironment. A general characteristic of MSC aging is a reduced response to stimuli from their microenvironment, which leads to increased cellular senescence and a progressive decline in regenerative capacity. However, recent evidence implies that the mechanism of cellular senescence can also play a positive role in tissue regeneration, possibly due to paracrine signaling. The interplay between aging, mechanical stimulation and senescence of stem cells and its consequence for bone regeneration is still poorly understood. Using a 3D bioreactor system we will investigate the response of human MSCs from young and elderly donors at the molecular (e.g. proteome & secretome pattern) and cellular level. Concurrently, we will explore the interaction of mechanical stimulation and cellular senescence in vivo using mouse osteotomy models with reduced and enhanced cellular senescence.
Adaptive and regenerative response of bone to mechanical strain in a mouse model of premature aging
Bettina Willie, Berlin; Uwe Kornak, Berlin
Bone adapts to mechanical loading, but there seems to be a reduced adaptive and regenerative response of the skeleton with aging. We intend to investigate the molecular mechanisms of this age-related reduced adaptive and regenerative response in young, middle-aged and elderly C57Bl/6 mice as well as in a model of premature aging (Gorabdeficient mice). The overall goal of the project is to understand the influence of mechanical strain on the adaption and regeneration with aging. We hypothesize that the osteoporotic murine phenotype caused by loss of GORAB can be explained by an altered behaviour of cells of the osteoblast lineage (osteoblasts and osteocytes) under stress, due to a direct effect of mechanical stimulation and/or high secretion rates induced by mechanical stimulation. Studies on bone mass and architecture as well as fate, structure, and expression of osteoblastic cells will be complemented by in vitro investigations to unravel the mechanism of this progeroid disease and skeletal aging. Mouse model healing will be compared to healing in human patients.