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Cell Biology

The research group "Cell Biology" investigates the biology of adult stem cells, immune cells, endothelial precursors and fibroblasts as well as their possible role in musculoskeletal tissue regeneration. We are looking at the interaction between cells, mechanics and the extracellular matrix. Furthermore, we are concentrating on alterations of intrinsic cell functions in response to extrinsic stimuli, such as age or an altered immune response. Our long-term goal is to develop new therapeutic approaches to improve musculoskeletal tissue regeneration, especially for impaired healing cases.

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Aging of Mesenchymal Tissues

‘Aging seems to be the only available way to live a long life.’ (Daniel Francois Esprit Auber) Thus, the only remaining question is HOW do we successfully grow old but avoiding to become frail? We are trying to answer this question with our research.

Normal Aging Processes

Fig. 1 MSC-associated changes in aged individuals might cause a decrease in regeneration capacity. MSC numbers are reduced in the bone marrow of old individuals. Also, due to the lower migratory speed of old mesenchymal stem cells (oMSCs), fewer cells might be capable of homing to the site of injury, thereby further depleting their numbers in the hematoma. Reactive oxygen species, present especially in the early phases of healing, might affect oMSCs more dramatically than young mesenchymal stem cells, because of the age related reduction in antioxidant power. A higher susceptibility toward senescence in oMSCs might additionally contribute to a shortage of functional progenitor cells able to augment a fast and uneventful regeneration.

“Normal” aging itself is a complex degenerative process occurring in all individuals at the molecular, cellular and systemic level, while frailty is a state characterized by a more progressive decline in the physiological and adaptive capacity. Frailty results in morbidity, institutionalization and significantly decreases social participation and the life expectancy.

Since 20% of men and women older than 75 years show no sign of frailty, whereas also 20% of people with same age are highly frail, there is evidence for a wide variety in the degree of frailty among different elderly. The underlying reasons why elderly are differentially affected by frailty still remain elusive. Since adult stem cells, such as Mesenchymal Stromal Cells (MSCs), play a curial role in tissue maintenance & regeneration, it is reasonable to presume that some of these aging aspects reflect a decline of their regenerative potential. Indeed, our previous studies showed an age-related decline in bone repair, which could be tracked back to a decline in MSC’s regenerative function. Aging directly alters MSC’s function, but age-related alterations in the local and systemic environment (serum) additionally impair MSC survival & regeneration ability, thereby contributing to the age-related delay in regeneration. Whether the link between age-related serum changes, compromised MSC function, and tissue properties is also valid for the frailty status is our current focus. We aim to uncover how age-related changes at the molecular, cellular and systemic level contribute to the age-related pathophysiology of frailty. We hypothesize that human MSCs from frail elderly could be, at least partially, “rejuvenated” by specific molecular mediators in the serum of young, healthy donors. Specific aims are: a) to validate our findings using an existing human serum cohort, b) to identify the causative serum factor(s) using “omics” approaches, and c) to characterize the impact of an exercise intervention on the identified molecular alterations and MSC function using longitudinal serum samples of frail elderly.

The role of senescence in regeneration

We want to learn from the nature of the senescence phenotype to take therapeutic advantage of those parts which are positive for (bone) regeneration, but overcome the disadvantages compromising new tissue formation.

ASC (Adult Stem Cell) aging is characterized by a reduced response to environmental stimuli, which leads to increased cellular senescence and a progressive decline in regenerative capacity. However, recent evidence implies that cellular senescence can also play a positive role in tissue regeneration, possibly due to paracrine signaling. The interplay between mechanical stimulation and senescence of ASCs during bone regeneration is still poorly understood. Using 3D bioreactors, we currently investigate the intracellular signaling response to mechanical stimuli of young and aged human MSCs (Mesenchymal Stromal Cells) and analyze their secretion pattern. Concurrently, we explore the interaction of mechanical stimulation and cellular senescence and its relevance for fracture healing in vivo using mouse models with reduced and enhanced cellular senescence.

Senescence is an irreversible cell cycle arrest linked to tumor suppression and aging. In contrast, developmental senescence is a programmed and instructive process, which shares common signatures of stress-induced senescence. Since bone healing is thought to be the repetition of bone neogenesis, it may also depend upon the temporally and spatially regulation of cellular senescence. However, the exact role of senescence in regeneration and the impact of age and the mechanical environment still
Dr.-Ing. Sven Geißler

Principal Investigator - Cell Biology

CVK: Campus Virchow-Klinikum