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The Role of Ectopic Adipocyte Progenitors in Age-related Stem Cell Dysfunction, Systemic Inflammation, and Metabolic Disease

Final Report Summary - AGEINGSTEMCELLFATE (The Role of Ectopic Adipocyte Progenitors in Age-related Stem Cell Dysfunction, Systemic Inflammation, and Metabolic Disease)

This project investigates the effect of aging on regeneration. Specifically, it was hypothesized that age-related accumulation and dysfunction of fat cells (adipocytes) in different tissue types negatively affects the processes of tissue repair. The first aim of this project was to analyze the cell types that can give rise to different types of fat cells and to determine their developmental origin. Secondly, the interaction of adipogenic cells with other cell types was to be assessed. Thirdly, the role of secreted signals produced by adipogenic cells, their age-related changes and their effects on regeneration was addressed. As such, the project stipulated that cell-autonomous changes, e.g. intrinsic, as well as an altered microenvironment may impact the ability for tissue regeneration through interactions with the different types of fat cells and their progenitors. Two aspects of adipocyte biology were analyzed: Accumulation of atypical adipocytes in the tissues of the musculoskeletal system and the loss of brown adipocytes during aging. The former may contribute to the age-related degeneration of tissues like skeletal muscle and bone, whereas the latter is involved in metabolic control and may exacerbate the progression of obesity and diabetes during aging.
The main conclusion from this work can be summarized in the recognition that aging affects cell-intrinsic processes within different types of stem cells. However, the microenvironment also provides beneficial as well as pathogenic signals that determine stem cell fate and function. Accordingly, several secreted signals were identified that may in the future be targeted to develop strategies to combat age-related degenerative diseases. The most prominent example is a molecule known as DPP4 (Dipeptidyl-peptidase-4), which is secreted from bone-resident adipogenic cells and impairs bone fracture healing. Inhibition of DPP4 with a well-known drug class used to treat diabetes, the Gliptins, may also be employed in this novel application to treat bone disorders that are associated with excess accumulation of fat cells.
Among the common molecular mechanisms impaired in all tissues during aging, the extracellular matrix was identified. The matrix provides a scaffold for tissue-resident stem cells and its dysfunction may thereby indirectly affect regeneration. This observation has been confirmed, for instance in aging brown adipose tissue as well as skeletal muscles. In summary, the results from this project provide several new insights in the area of adipocyte biology and its interaction with tissue-specific regeneration processes that could be further developed to attenuate detrimental processes associated to aging.