Towards microstructure-informed material models for human brain tissue.

Emerging evidence suggests that the mechanical behavior of the brain plays a critical role in development, disease, and aging. Recent studies have begun to characterize the mechanical behavior of gray and white matter tissue and to identify sets of material models that best reproduce the stress-strain behavior of different brain regions. Yet, these models are mainly phenomenological in nature, their parameters often lack clear physical interpretation, and they fail to correlate the mechanical behavior to the underlying microstructural composition. Here we make a first attempt towards identifying general relations between microstructure and mechanics with the ultimate goal to develop microstructurally motivated constitutive equations for human brain tissue. Using histological staining, we analyze the microstructure of brain specimens from different anatomical regions, the cortex, basal ganglia, corona radiata, and corpus callosum, and identify the regional stiffness and viscosity under multiple loading conditions, simple shear, compression, and tension. Strikingly, our study reveals a negative correlation between cell count and stiffness, a positive correlation between myelin content and stiffness, and a negative correlation between proteoglycan content and stiffness. Additionally, our analysis shows a positive correlation between lipid and proteoglycan content and viscosity. We demonstrate how understanding the microstructural origin of the macroscopic behavior of the brain can help us design microstructure-informed material models for human brain tissue that inherently capture regional heterogeneities. This study represents an important step towards using brain tissue stiffness and viscosity as early diagnostic markers for clinical conditions including chronic traumatic encephalopathy, Alzheimer's and Parkinson's disease, or multiple sclerosis. STATEMENT OF SIGNIFICANCE: The complex and heterogeneous mechanical properties of brain tissue play a critical role for brain function. To understand and predict how brain tissue properties vary in space and time, it will be key to link the mechanical behavior to the underlying microstructural composition. Here we use histological staining to quantify area fractions of microstructural components of mechanically tested specimens and evaluate their individual contributions to the nonlinear macroscopic mechanical response. We further propose a microstructure-informed material model for human brain tissue that inherently captures regional heterogeneities. The current work provides unprecedented insights into the biomechanics of human brain tissue, which are highly relevant to develop refined computational models for brain tissue behavior or to advance neural tissue engineering.

[Hepatic stellate cells: it's role in normal and pathological conditions]. / Las células estrelladas del hígado: su importancia en condiciones normales y patológicas.

Hepatic fibrosis is a dynamic and sophisticatedly regulated wound healing response to chronic hepatocellular injury. This fibrotic process results from the accumulation of extracellular matrix (ECM) including collagen, proteoglycan, and adhesive glycoproteins which are principally produced by hepatic stellate cells (HSC), a mesenchymal cell type located between parenchymal cell plates and sinusoidal endothelial cells in the space of Disse. In physiological conditions, quiescent HSCs play important roles in the regulation of retinoid homeostasis and ECM remodeling by producing ECM components as well as metalloproteases and its inhibitor. However during hepatic fibrogenesis, HSCs are known to be activated or "transdifferentiated" to myofibroblast-like cells which play a pivotal role in ECM remodeling and hepatic blood flow regulation. Activation of HSC is now well established as the key process involved in the development of hepatic fibrosis. Both basic morphology and functions of HSCs in normal conditions and its role in pathological fibrosis will be discussed in this review.

Las células estrelladas del hígado: su importancia en condiciones normales y patológicas / Hepatic stellate cells: it's role in normal and pathological conditions

La fibrosis hepática es un proceso dinámico y regulado que se desencadena en respuesta a la lesión hepatocelular crónica provocada por diversas causas. La fuente principal de ese tejido fibroso son las células mesenquimales estrelladas del hígado (CEH), que se ubican en el espacio perisinusoidal de Disse entre los hepatocitos y las células endoteliales. En condiciones fisiológicas, las CEH quiescentes desempeñan un papel fundamental al regular la homeostasis de los retinoides y la remodelación de la matriz extracelular (MEC) tanto por medio de su capacidad de sintetizar los componentes de ésta, como por su habilidad para producir diferentes metaloproteinasas degradantes de la MEC y sus inhibidores. Sin embargo, durante la fibrogénesis hepática, las CEH se activan diferenciándose en células parecidas a los miofibroblastos con capacidad proliferativa, fibrogénica y contráctil para desempeñar un papel primordial en la configuración de la fibrosis hepática y en el control del flujo sanguíneo del hígado. En esta revisión se comentarán la morfología básica y las funciones de las CEH en condiciones normales y durante su activación en la fibrosis

Hepatic fibrosis is a dynamic and sophisticatedly regulated wound healing response to chronic hepatocellular injury. This fibrotic process results from the accumulation of extracellular matrix (ECM) including collagen, proteoglycan, and adhesive glycoproteins which are principally produced by hepatic stellate cells (HSC), a mesenchymal cell type located between parenchymal cell plates and sinusoidal endothelial cells in the space of Disse. In physiological conditions, quiescent HSCs play important roles in the regulation of retinoid homeostasis and ECM remodeling by producing ECM components as well as metalloproteases and its inhibitor. However during hepatic fibrogenesis, HSCs are known to be activated or «transdifferentiated» to myofibroblast-like cells which play a pivotal role in ECM remodeling and hepatic blood flow regulation. Activation of HSC is now well established as the key process involved in the development of hepatic fibrosis. Both basic morphology and functions of HSCs in normal conditions and its role in pathological fibrosis will be discussed in this review

Assay of a seric human hexapeptide (HWESAS) using a monoclonal antibody and ELISA.

Human serum contains low-molecular-weight growth factors potentiating some in vitro biological effects of IGF-I and IGF-II and recently two peptides were mainly identified: HWESAS and WGHE. In order to determine seric HWESAS concentration, a specific monoclonal antibody against HWESAS was prepared. Its specificity was studied by inhibition tests: this antibody cross-reacts with Y-HWESAS, Cys-HWESAS. It does not react with HWESAS when its COOH is blocked, or with HWE, WGHE and tryptophan or with C3f (SSKITHRIHWESASLLR) which is a fragment of human complement containing HWESAS motif. Its affinity was measured by non competitive enzyme immunoassay (3.89+/-2.44.10(8) M(-1)). Then, this antibody was used in enzyme-linked immunosorbent assay (ELISA) and the preliminary assays were performed to detect HWESAS in serum. In contrast to healthy subjects, patients with chronic renal failure exhibited undetectable concentration of hexapeptide while after successful renal transplantation values increased to reach levels found in healthy subjects and varying according to post-operative evolution. These data are a strong hint that the kidney plays an important role in the production of this hexapeptide and underly the clinical interest of HWESAS detection in renal pathology.