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Review
. 2022 Jul 15;12(7):927.
doi: 10.3390/brainsci12070927.

Mechanical Properties of the Extracellular Environment of Human Brain Cells Drive the Effectiveness of Drugs in Fighting Central Nervous System Cancers

Mateusz Cieśluk  1 , Katarzyna Pogoda  2 , Ewelina Piktel  3 , Urszula Wnorowska  1 , Piotr Deptuła  1 , Robert Bucki  1
Affiliations
Review

Mechanical Properties of the Extracellular Environment of Human Brain Cells Drive the Effectiveness of Drugs in Fighting Central Nervous System Cancers

Mateusz Cieśluk et al. Brain Sci. .

Abstract

The evaluation of nanomechanical properties of tissues in health and disease is of increasing interest to scientists. It has been confirmed that these properties, determined in part by the composition of the extracellular matrix, significantly affect tissue physiology and the biological behavior of cells, mainly in terms of their adhesion, mobility, or ability to mutate. Importantly, pathophysiological changes that determine disease development within the tissue usually result in significant changes in tissue mechanics that might potentially affect the drug efficacy, which is important from the perspective of development of new therapeutics, since most of the currently used in vitro experimental models for drug testing do not account for these properties. Here, we provide a summary of the current understanding of how the mechanical properties of brain tissue change in pathological conditions, and how the activity of the therapeutic agents is linked to this mechanical state.

Keywords: brain; extra cellular matrix; glioblastoma; mechanical properties; rheology.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The composition of major compartments of brain ECM. The ECM in the brain is composed of three primary components, namely the basement membrane (basal lamina) that surrounds the cerebral vasculature, the perineuronal net which lies around neuronal cell bodies and dendrites, and the neural interstitial matrix that is diffusely spread between parenchymal cells. The yellow, purple, and blue cells represent neurons, microglia, and astrocytes, respectively. All of the proteins that make up the ECM have a diameter of tens to hundreds of nanometers, providing inspiration for the next generation of nano-architecture-style cerebral electrodes. Figure adapted with permission from Ref. [24]. 2018, Kim U.
Figure 2
Figure 2
The basal lamina network is depicted schematically. Both laminin and collagen IV form a network resembling a sheet. Entactin and the perlecan complex operate as a connection between these two networks. Laminin, in combination with collagen IV, promotes cell attachment, differentiation, migration, and proliferation. Additionally, type IV collagen and laminin, in addition to fibronectin, are involved in the creation of tight junctions. Perlecan acts as a cross-linker between laminin and collagen IV, hydrating the matrix and contributing to the basal lamina’s selective filtering characteristics. In comparison to those structurally significant components, the loss of the tiny cross-linking molecule entactin appears to have a smaller effect on the structure and function of the basal lamina. Figure adapted with permission from Ref. [39]. 2020, Rauti R.
Figure 3
Figure 3
Tumor stiffness differences for two patients with meningiomas. T2-weighted anatomical images (A,D), curl wave images (B,E) and elastograms (C,F). The first patient (A–C) had a substantially softer meningioma than the second one (D–F). In the first example, the shear wavelength is much shorter than in the second one. Figure adapted with permission from Ref. [108]. 2015, Pepin K.
Figure 4
Figure 4
Rheological measurement setup. (A) White matter sample; (B) gray matter sample; (C) sample glued to upper and lower plates; (D) hydrated sample mounted into device. Figure adapted with permission from Ref. [120]. 2017, Budday S.
Figure 5
Figure 5
Variation in nanomechanical properties among different brain tissues. AFM-measured (A) distribution and (B) mean values of Young’s modulus for healthy brain tissue (red), tissue adjacent to GB (blue), and GB tissue (gray). Statistical differences were measured using Kolmogorov–Smirnov test and unpaired Student’s t-test. *** p ≤ 0.001. Figure adapted with permission from Ref. [16]. 2020, Cieśluk M.
Figure 6
Figure 6
The impact of cold atmospheric plasma (CAP) on cell migration. (A) Control (untreated), CAP-only (180 s), TMZ-only (50 μM), and combined CAP–TMZ treated cells. Red indicates the trajectories of 10 representative cells evaluated during a 16 h period on Day 0–1 and Day 5–6. Images were captured every 10 min until a total of 100 images were acquired. The CAP-TMZ condition results in shorter cell migration paths than the control variables (B,C). The graphs illustrate the velocity and displacement of 60 cells per variable. Persistence was calculated as the ratio of net displacements to total displacements. Unless otherwise specified, error bars represent the standard error of the mean, and an asterisk denotes statistical significance relative to untreated control. Scale bar: 14 μm. Statistical significance was determined as: * p < 0.05; ** p ≤ 0.01; *** p ≤ 0.001, **** p ≤ 0.0001. Figure adapted with permission from Ref. [204]. 2020, Gjika E.
Figure 7
Figure 7
Gel stiffness influence on cells spread area. Phase images of isolated astrocytes on soft and stiff polyacrylamide gels (A). Human glioblastoma cells U-373-MG on hyaluronic acid hydrogels of various stiffness (B). Isolated human glioblastoma cells LN18, LN229 and LBC3 on various polyacrylamide gels (C). Scale bars: A, B—50 µm; C—15 µm. Figure adapted with permission from Refs. A—[219]. 2006, Georges P.C.; B—[220]. 2011, Ananthanarayanan B.; C—[17]. 2017, Pogoda K.
Figure 8
Figure 8
Regulation of glioblastoma cell rigidity by substrate composition and stiffness. (A) Cellular stiffness as a function of substrate stiffness for collagen I or laminin-coated PAA hydrogels. (B) Variations in the cell stiffness when PAA is replaced by HA. (C) The stiffness of GB cells as a function of their spreading area. The unpaired Student’s t-test was used to confirm significant differences in cell stiffness between in panels A (between 0.3 and 14 kPa PAA gels) and B (between 0.3 kPa PAA and 0.3 kPa HA); denotation: ***, p < 0.00). Figure adapted with permission from Ref. [17]. 2017, Pogoda K.
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