The human brain contains approximately 86 billon neurons of different types, distributed and organized in different areas ; their functions vary according to the neuron type and its localization within the brain. However, the neuronal function also depends on its microenvironment, which is composed of the extracellular matrix (ECM), and of other cells with interact with each other.
The brain ECM represents 20% of the cerebral volume. It is mainly composed of proteoglycans, formed by sulfated glycosaminoglycans (GAGs) covalently bound to a core protein. In the central nervous system, heparan sulfate and chondroitin sulfate proteoglycans (in particular lectican family) are the most present. Hyaluronic acid, a non-sulfated GAG, is also abundant. The cerebral ECM contain also glycoproteins, in particular tenascin-C and tenascin-R. Contrary to the other organs, the brain contains a very low level of fibrous proteins, like collagen. Indeed, the ratio between collagen and GAG in the brain is only 1: 10 (Sood et al., 2016). This makes the brain the organ with the lowest rigidity of the human body. The elastic modulus of brain (a measure of its rigidity), is lower than 1 kPa. In comparison, the elastic modulus of plastic, classically used for cell culture support, ranges from 1 to 10 GPa (Akhmanova et al., 2015).
Glial cells also constitute an important part of neuronal microenvironment. Among them, astrocytes represent 20 to 40% of all glia, in varying proportions according to the brain region. Astrocytes perform many functions in health and disease. In particular, they are involved in the neuroinflammation in brain injuries and neurodegenerative diseases.
In drug discovery, there are 90% of failure in clinical trials, mainly due to safety and efficiency issues. This very high failure rate highlights the irrelevance of current preclinical models. In this context, HCS pharma aims at developing a more predictive cerebral in vitro model by including the microenvironment (ECM + surrounding cells) in neuronal culture. BIOMIMESYS® is a hyaluronan-based hydroscaffold, which mimics the ECM and allows to cultivate cells in 3 dimensions. In this way, we develop a 3D in vitro model of dopaminergic neurons in co-culture with astrocytes in BIOMIMESYS® Brain, to screen molecules and find new neuroprotective treatments in Parkinson’s disease.
Akhmanova, M., Osidak, E., Domogatsky, S., Rodin, S., and Domogatskaya, A. (2015). Physical, Spatial, and Molecular Aspects of Extracellular Matrix of In Vivo Niches and Artificial Scaffolds Relevant to Stem Cells Research. Stem Cells Int 2015, 167025.
Sood, D., Chwalek, K., Stuntz, E., Pouli, D., Du, C., Tang-Schomer, M., Georgakoudi, I., Black, L.D., and Kaplan, D.L. (2016). Fetal brain extracellular matrix boosts neuronal network formation in 3D bioengineered model of cortical brain tissue. ACS Biomater Sci Eng 2, 131–140.