3D human brain cell models: New frontiers in disease understanding and drug discovery for neurodegenerative diseases

Abstract

Neurodegenerative disorders have an enormous impact on society and healthcare budgets. There has been a high degree of failure in many recent clinical trials for disease-modifying therapeutics. A major factor in this failure is the difficulty of translating findings from animal-based cell models to human patients. The majority of non-animal neurodegenerative disease research has been conducted in 2 dimensional models of rodent neonatal neurons and glia. While these systems have provided valuable insights into neural cell function and dysfunction, they have largely reached the end of their useful life, as human stem cell technologies combined with major advances in microfluidic technologies have opened the door to development of patient-derived 3D brain cell models. These have major advantages in providing a micro-physiological system more closely reflecting the in vivo brain environment, and promote the interaction between different patient-derived brain cell-types. However, major challenges remain before these model systems will replace the 2D rodent models as the workhorse for neurodegenerative disease studies. Despite these challenges, we are likely to experience a rapid transition of research from old models to new patient derived 3D brain cell systems, which will likely improve translational outcomes for disease therapeutics.

In Vitro and in Silico Human Monoamine Oxidase Inhibitory Potential of Anthraquinones, Naphthopyrones, and Naphthalenic Lactones from Cassia obtusifolia Linn Seeds

“…1 The etiopathology and affected brain regions differ among the NDs; however, they all share progressive dysfunction, collapse the neuronal network, neuronal cell death, neuroinflammation, and oxidative damage to the brain. 2…”

“…The number of people with PD is expected to reach 8.7 million by 2040, 4 so it will claim an increasing portion of world healthcare budgets, with an estimated current cost in excess of US$600 billion worldwide. 2 PD is a chronic and progressive disorder of the central nervous system that affects the motor system. It is the second most frequent neurodegenerative disorder and is characterized by resting tremor, rigidity, and bradykinesia due to the loss of dopaminergic (DA) neurons of the midbrain.…”

Using stem cell–derived neurons in drug screening for neurological diseases

“…Furthermore, cells could be grown in three dimensions (3D) to improve physiological relevance, using scaffolds or gels (reviewed recently in Kim et al, 2015;Korhonen et al, 2018;O'Rourke et al, 2017;Pasca, 2018). One published protocol detailed a 3D system of growing human neural progenitor cells within a Matrigel matrix .…”

Re-thinking the Etiological Framework of Neurodegeneration

“…Recent trends in stem cell methods have also opened new possibilities for human brain cell cultures, which can in turn be used to model neurodegeneration. Induced pluripotent stem cells and neural stem cell cultures can now be used to generate human neurons from human and sometimes patient cells (Abud et al, 2017; Korhonen et al, 2018). This has been reviewed extensively elsewhere (Xie and Tang, 2016; Robbins and Price, 2017).…”