Prof. Kristian Franze

An adverse local environment ("niche") impairs the activity of neural stem cells (NSCs) in the adult brain. We investigate the new hypothesis that NSCs play an active role in generating favorable and adverse niche conditions. Specifically, we will investigate how dysfunctional NSCs generate adverse niche conditions focusing i) on the composition and the biomechanical properties of the extracellular matrix and ii) on NSC-derived exosomes and their composition.

Thecentral nervous system (CNS) is our most complex organ system. Despite tremendousprogress in our understanding of the biochemical, electrical, and geneticregulation of CNS functioning and malfunctioning, many fundamental processesand diseases are still not fully understood. For example, axon growth patterns inthe developing brain can currently not be well-predicted based solely on thechemical landscape that neurons encounter, several CNS-related diseases cannotbe precisely diagnosed in living patients, and neuronal regeneration can stillnot be promoted after spinal cord injuries.

Duringmany developmental and pathological processes, neurons and glial cells aremotile. Fundamentally, motion is drivenby forces. Hence, CNS cells mechanicallyinteract with their surrounding tissue. They adhere to neighbouring cells and extracellular matrix using celladhesion molecules, which provide friction, and generate forces usingcytoskeletal proteins.  These forces aretransmitted to the outside world not only to locomote but also to probe themechanical properties of the environment, which has a long overseen huge impacton cell function.

Onlyrecently, groups of several project leaders in this consortium, and a few other groupsworldwide, have discovered an important contribution of mechanical signalsto regulating CNS cell function. For example, they showed that brain tissuemechanics instructs axon growth and pathfinding in vivo, that mechanicalforces play an important role for cortical folding in the developing humanbrain, that the lack of remyelination in the aged brain is due to an increasein brain stiffness in vivo, and that many neurodegenerative diseases areaccompanied by changes in brain and spinal cord mechanics. These first insights strongly suggest thatmechanics contributes to many other aspects of CNS functioning, and it islikely that chemical and mechanical signals intensely interact at the cellularand tissue levels to regulate many diverse cellular processes.

The CRC 1540 EBM synergises the expertise of engineers, physicists,biologists, medical researchers, and clinicians in Erlangen to explore mechanicsas an important yet missing puzzle stone in our understanding of CNSdevelopment, homeostasis, and pathology. Our strongly multidisciplinary teamwith unique expertise in CNS mechanics integrates advanced invivo, in vitro, and in silico techniques across time(development, ageing, injury/disease) and length (cell, tissue, organ) scalesto uncover how mechanical forces and mechanical cell and tissue properties,such as stiffness and viscosity, affect CNS function. We especially focus on(A) cerebral, (B) spinal, and (C) cellular mechanics. Invivo and in vitro studies provide a basic understanding ofmechanics-regulated biological and biomedical processes in different regions ofthe CNS. In addition, they help identify key mechano-chemical factors forinclusion in in silico models and provide data for model calibration andvalidation. In silico models, in turn, allow us to test hypotheses without the need of excessive or even inaccessibleexperiments. In addition, they enable the transfer and comparison of mechanics data and findingsacross species and scales. They also empower us to optimise processparameters for the development of in vitro brain tissue-like matricesand in vivo manipulation of mechanical signals, and, eventually, pavethe way for personalised clinical predictions.

Insummary, we exploit mechanics-based approaches to advance ourunderstanding of CNS function and to provide the foundation for futureimprovement of diagnosis and treatment of neurological disorders.

ZNS-Gewebe in Fröschen ist vor der Metamorphose regenerativ, nicht jedoch danach. In B02 werden wir mechanische, zelluläre und molekulare Eigenschaften des Rückenmarksgewebes von Xenopus laevis vor und nach der Metamorphose bestimmen. Wir werden testen, ob regeneratives Rückenmark nach einer Verletzung steifer, nicht regeneratives Gewebe jedoch weicher wird, und ob dieser mechanische Unterschied mit ausschlaggebend für den Erfolg neuronaler Regeneration ist. Um dies zu untermauern, werden wir die mechanischen und zellulären Eigenschaften nicht regenerativen Gewebes manipulieren, um so die Regeneration von Nervenzellen zu ermöglichen.

05 widmet sich der Untersuchung der Mechanik des sich entwickelnden Xenopus laevis Gehirns in vivo. Wir werden eine AFM-basierte Methode entwickeln, die es uns erlaubt, viskoelastische Eigenschaften des in vivo Hirns mit zellulärer Auflösung zu messen. Anschließend werden wir testen, wie Mutationen in Genen, die zu Missbildungen führen und in A02 identifiziert wurden, die Hirnmechanik und Zellmotilität beeinflussen. Schließlich werden wir die mechanischen Eigenschaften dieser Gehirne so manipulieren, dass sie denen gesunden Gewebes ähneln, und den Effekt dieser Manipulationen auf die Hirnmorphologie und Zellmotilität untersuchen.