FOR 2165:  Regeneration in Aged Individuals: Using Bone Healing as a Model System to Characterise Regeneration under Compromised Conditions

• Subject Area: Medicine
• Term: from 2014 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 249509554

Regenerative medicine aims at completely restoring tissue structure and function by supporting endogenous regeneration. While regenerative therapies gain more and more attention as innovative therapeutic opportunities, it is essential to identify the road blocks or deficits impairing healing processes in general and specifically in patients that have unmet clinical needs. Regenerative medicine may present solutions for some of those unmet clinical needs; with most therapeutic challenges existing in aged or otherwise compromised patients. Aging appears to substantially alter healing. This alteration in healing cascades is not yet understood. A basic understanding on how endogenous healing is influenced by aging is essential for the successful implementation of regenerative medicine approaches to relevant patient groups. Bone is one of the few tissues in the body that has the general capability of scar-less, endogenous regeneration, resulting in complete functional and structural reconstitution. If an otherwise uneventful healing is altered by aging, the underlying mechanism may be substantial also to tissues that have already in young individuals only limited regenerative capacity. Thus, bone is an ideal model system to evaluate the effect of stress factors or constraints of healing on a cellular and tissue level.Key elements of the regenerative healing process were proposed when this Research Unit was established and have been proven to be correct during the first funding period. (A) The finely tuned mechano-biological regulation of cell and tissue organization during structural re-constitution is altered in aged (by a shift in mechano-sensitivity). (B) An orchestrated regulation of the inflammatoryreaction, indicating long-term dynamics within the immune and the mesenchymal compartments is shifted in aged. During this second funding period, we aim to further the understanding of the mechanisms underlying the age related modulations of endogenous regeneration and how these coincide with alterations due to the metabolic syndrome. We will keep our focus on the three keyelements proposed in the first funding period: a) mechano-sensation in structural reconstitution, b) inflammation, and c) cell lineage commitment upon aging. The overall goal of our Research Unit is to investigate the influence of aging on the bone healingprocesses from the sub-cellular to the organ level, by focusing on well-characterized mechanosensation and immune pathways in age and pathology induced clinical challenges. This allows us to analyse signalling pathways involved in compromised conditions to gain a more detailed understanding of the altered processes that need consideration in the development of new treatment approaches.

• DFG Programme: Research Units

Projects

• Analysis of osteo-immune crosstalk during bone healing by longitudinal intravital imaging (Applicants Hauser, Anja Erika ;  Niesner, Raluca Aura )
• Coordination Funds (Applicant Duda, Georg )
• Mechanical strain and BMP-stimulation instruct the extracellular matrix to control stem cell fate decisions: an age-dependent matrix code? (Applicants Knaus, Petra ;  Petersen, Ansgar )
• Mechano-dependency of early bone healing, angiogenesis, and their interplay across ages (Applicants Duda, Georg ;  Gerhardt, Holger )
• Nutrition, aging and marrow adipose tissue in bone maintenance and regeneration (Applicants Schmidt-Bleek, Katharina ;  Schulz, Tim J. )
• Outer vascular mechanics as an age-dependent regulatory cue in sprouting angiogenesis and vessel patterning (Applicants Checa Esteban, Ph.D., Sara ;  Petersen, Ansgar )
• The role of cellular senescence in bone regeneration (Applicants Fischer-Zirnsak, Björn ;  Geißler, Sven )
• Understand and reshape the impact of “aged” adaptive immunity and type 2 diabetes/obesity on fracture healing (Applicants Schmidt-Bleek, Katharina ;  Volk, Hans-Dieter )

• Spokesperson: Professor Dr.-Ing. Georg Duda