Mechanical behavior of the hippocampus and corpus callosum: An attempt to reconcile ex vivo with in vivo and micro with macro properties
Gergerly Bertalan,
Julia Becker,
Heiko Tzschätzsch,
Anna Morr,
Helge Herthum,
Mehrgan Shahryari,
Ryan D. Greenhalgh,
Jing Guo,
Leif Schröder, et al.
Journal of the Mechanical Behavior of Biomedical Materials
138
105613
(2022)
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Mechanical properties of brain tissue are very complex and vary with the species, region, method, and dynamic range, and between in vivo and ex vivo measurements. To reconcile this variability, we investigated in vivo and ex vivo stiffness properties of two distinct regions in the human and mouse brain - the hippocampus (HP) and the corpus callosum (CC) - using different methods. Under quasi-static conditions, we examined ex vivo murine HP and CC by atomic force microscopy (AFM). Between 16 and 40Hz, we investigated the in vivo brains of healthy volunteers by magnetic resonance elastography (MRE) in a 3-T clinical scanner. At high-frequency stimulation between 1000 and 1400Hz, we investigated the murine HP and CC ex vivo and in vivo with MRE in a 7-T preclinical system. HP and CC showed pronounced stiffness dispersion, as reflected by a factor of 32-36 increase in shear modulus from AFM to low-frequency human MRE and a 25-fold higher shear wave velocity in murine MRE than in human MRE. At low frequencies, HP was softer than CC, in both ex vivo mouse specimens (p < 0.05) and in vivo human brains (p < 0.01) while, at high frequencies, CC was softer than HP under in vivo (p < 0.01) and ex vivo (p < 0.05) conditions. The standard linear solid model comprising three elements reproduced the observed HP and CC stiffness dispersions, while other two- and three-element models failed. Our results indicate a remarkable consistency of brain stiffness across species, ex vivo and in vivo states, and different measurement techniques when marked viscoelastic dispersion properties combining equilibrium and non-equilibrium mechanical elements are considered.
Retinal regions shape human and murine Müller cell proteome profile and functionality
Lew Kaplan,
Corinne Drexler,
Anna M. Pfaller,
Santra Brenna,
Kirsten A. Wunderlich,
Andrea Dimitracopoulos,
Juliane Merl-Pham,
Maria-Theresa Perez,
Ursula Schlötzer-Schrehardt, et al.
The human macula is a highly specialized retinal region with pit-like morphology and rich in cones. How Müller cells, the principal glial cell type in the retina, are adapted to this environment is still poorly understood. We compared proteomic data from cone- and rod-rich retinae from human and mice and identified different expression profiles of cone- and rod-associated Müller cells that converged on pathways representing extracellular matrix and cell adhesion. In particular, epiplakin (EPPK1), which is thought to play a role in intermediate filament organization, was highly expressed in macular Müller cells. Furthermore, EPPK1 knockout in a human Müller cell-derived cell line led to a decrease in traction forces as well as to changes in cell size, shape, and filopodia characteristics. We here identified EPPK1 as a central molecular player in the region-specific architecture of the human retina, which likely enables specific functions under the immense mechanical loads in vivo.
Unrestrained growth of correctly oriented microtubules instructs axonal microtubule orientation
Maximilian A. H. Jakobs,
Assaf Zemel,
Kristian Franze
In many eukaryotic cells, directed molecular transport occurs along microtubules. Within neuronal axons, transport over vast distances particularly relies on uniformly oriented microtubules, whose plus-ends point towards the distal axon tip (anterogradely polymerizing, or plus-end-out). However, axonal microtubules initially have mixed orientations, and how they orient during development is not yet fully understood. Using live imaging of primary Drosophila melanogaster neurons, we found that, in the distal part of the axon, catastrophe rates of plus-end-out microtubules were significantly reduced compared to those of minus-end-out microtubules. Physical modelling revealed that plus-end-out microtubules should therefore exhibit persistent long-term growth, while growth of minus-end-out microtubules should be limited, leading to a bias in overall axonal microtubule orientation. Using chemical and physical perturbations of microtubule growth and genetic perturbations of the anti -catastrophe factor p150, which was enriched in the distal axon tip, we confirmed that the enhanced growth of plus-end-out microtubules is critical for achieving uniform microtubule orientation. Computer simulations of axon development integrating the enhanced plus-end-out microtubule growth identified here with previously suggested mechanisms, that is, dynein-based microtubule sliding and augmin-mediated templating, correctly predicted the long-term evolution of axonal microtubule orientation as found in our experiments. Our study thus leads to a holistic explanation of how axonal microtubules orient uniformly, a prerequisite for efficient long-range transport essential for neuronal functioning.
Cell surface fluctuations regulate early embryonic lineage sorting
Ayaka Yanagida,
Elena Corujo-Simon,
Christopher K. Revell,
Preeti Sahu,
Giuliano G. Stirparo,
Irene M. Aspalter,
Alex K. Winkel,
Ruby Peters,
Henry De Belly, et al.
In development, lineage segregation is coordinated in time and space. An important example is the mammalian inner cell mass, in which the primitive endoderm (PrE, founder of the yolk sac) physically segregates from the epiblast (EPI, founder of the fetus). While the molecular requirements have been well studied, the physical mechanisms determining spatial segregation between EPI and PrE remain elusive. Here, we investigate the mechanical basis of EPI and PrE sorting. We find that rather than the differences in static cell surface mechanical parameters as in classical sorting models, it is the differences in surface fluctuations that robustly ensure physical lineage sorting. These differential surface fluctuations systematically correlate with differential cellular fluidity, which we propose together constitute a non-equilibrium sorting mechanism for EPI and PrE lineages. By combining experiments and modeling, we identify cell surface dynamics as a key factor orchestrating the correct spatial segregation of the founder embryonic lineages.
Effective cell membrane tension is independent of polyacrylamide substrate stiffness
Eva Kreysing,
Jeffrey Mc Hugh,
Sarah K. Foster,
Kurt Andresen,
Ryan D. Greenhalgh,
Eva K. Pillai,
Andrea Dimitracopoulos,
Ulrich F. Keyser,
Kristian Franze
Most animal cells are surrounded by a cell membrane and an underlying actomyosin cortex. Both structures are linked, and they are under tension. In-plane membrane tension and cortical tension both influence many cellular processes, including cell migration, division, and endocytosis. However, while actomyosin tension is regulated by substrate stiffness, how membrane tension responds to mechanical substrate properties is currently poorly understood. Here, we probed the effective membrane tension of neurons and fibroblasts cultured on glass and polyacrylamide substrates of varying stiffness using optical tweezers. In contrast to actomyosin-based traction forces, both peak forces and steady-state tether forces of cells cultured on hydrogels were independent of substrate stiffness and did not change after blocking myosin II activity using blebbistatin, indicating that tether and traction forces are not directly linked. Peak forces in fibroblasts on hydrogels were about twice as high as those in neurons, indicating stronger membrane-cortex adhesion in fibroblasts. Steady-state tether forces were generally higher in cells cultured on hydrogels than on glass, which we explain by a mechanical model. Our results provide new insights into the complex regulation of effective membrane tension and pave the way for a deeper understanding of the biological processes it instructs.
Prevention of the foreign body response to implantable medical devices by inflammasome inhibition
Damiano G. Barone,
Alejandro Carnicer-Lombarte,
Panagiotis Tourlomousis,
Russell S. Hamilton,
Malwina Prater,
Alexandra L. Rutz,
Ivan B. Dimov,
George G. Malliaras,
Stephanie P. Lacour, et al.
Proceedings of the National Academy of Sciences of the United States of America
119
(12)
e2115857119
(2022)
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SignificanceImplantable electronic medical devices (IEMDs) are used for some clinical applications, representing an exciting prospect for the transformative treatment of intractable conditions such Parkinson's disease, deafness, and paralysis. The use of IEMDs is limited at the moment because, over time, a foreign body reaction (FBR) develops at the device-neural interface such that ultimately the IEMD fails and needs to be removed. Here, we show that macrophage nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activity drives the FBR in a nerve injury model yet integration of an NLRP3 inhibitor into the device prevents FBR while allowing full healing of damaged neural tissue to occur.
Axons in the Chick Embryo Follow Soft Pathways Through Developing Somite Segments
Julia Schaeffer,
Isabell P. Weber,
Amelia J. Thompson,
Roger J. Keynes,
Kristian Franze
Frontiers in Cell and Developmental Biology
10
917589
(2022)
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During patterning of the peripheral nervous system, motor axons grow sequentially out of the neural tube in a segmented fashion to ensure functional integration of the motor roots between the surrounding cartilage and bones of the developing vertebrae. This segmented outgrowth is regulated by the intrinsic properties of each segment (somite) adjacent to the neural tube, and in particular by chemical repulsive guidance cues expressed in the posterior half. Yet, knockout models for such repulsive cues still display initial segmentation of outgrowing motor axons, suggesting the existence of additional, yet unknown regulatory mechanisms of axon growth segmentation. As neuronal growth is not only regulated by chemical but also by mechanical signals, we here characterized the mechanical environment of outgrowing motor axons. Using atomic force microscopy-based indentation measurements on chick embryo somite strips, we identified stiffness gradients in each segment, which precedes motor axon growth. Axon growth was restricted to the anterior, softer tissue, which showed lower cell body densities than the repulsive stiffer posterior parts at later stages. As tissue stiffness is known to regulate axon growth during development, our results suggest that motor axons also respond to periodic stiffness gradients imposed by the intrinsic mechanical properties of somites.
Contact
Neuronal Mechanics Division Prof. Kristian Franze Principal Investigator
Max-Planck-Zentrum für Physik und Medizin Kussmaulallee 2 91054 Erlangen, Germany
