Human Neural Stem Cell Systems to Explore Pathogen-Related Neurodevelopmental and Neurodegenerative Disorders

Abstract

Building and functioning of the human brain requires the precise orchestration and execution of myriad molecular and cellular processes, across a multitude of cell types and over an extended period of time. Dysregulation of these processes affects structure and function of the brain and can lead to neurodevelopmental, neurological, or psychiatric disorders. Multiple environmental stimuli affect neural stem cells (NSCs) at several levels, thus impairing the normal human neurodevelopmental program. In this review article, we will delineate the main mechanisms of infection adopted by several neurotropic pathogens, and the selective NSC vulnerability. In particular, TORCH agents, i.e., Toxoplasma gondii, others (including Zika virus and Coxsackie virus), Rubella virus, Cytomegalovirus, and Herpes simplex virus, will be considered for their devastating effects on NSC self-renewal with the consequent neural progenitor depletion, the cellular substrate of microcephaly. Moreover, new evidence suggests that some of these agents may also affect the NSC progeny, producing long-term effects in the neuronal lineage. This is evident in the paradigmatic example of the neurodegeneration occurring in Alzheimer’s disease.

A Monolayer System for the Efficient Generation of Motor Neuron Progenitors and Functional Motor Neurons from Human Pluripotent Stem Cells

“…Their loss results in diseases such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (SLA) [ 2 , 3 ]. At present, pluripotent stem cells (PSCs) represent the most promising tool for the generation of large populations of human neural stem cells, committed progenitors and neurons in vitro, and for the establishment of patient-specific neuronal disease models [ 4 , 5 , 6 ]. Various methods have been developed for MNs production from PSCs, both of embryonic and somatic origin, generated by means of reprogramming techniques [ 7 , 8 ].…”

Neural Stem Cells: What Happens When They Go Viral?

“…Nevertheless, it is clear that the age of the host and the maturation of the NSCs are key variables in how viruses impact NSCs. TORCH pathogens [toxoplasmosis, other pathogens (e.g., syphilis, parvovirus), rubella, CMV, HSV], which are associated with congenital infections of the fetus or newborn, can cause catastrophic dysregulation and depletion of NSCs, contributing to a long-term loss of both neural progenitors and new neurons associated with microcephaly (see [ 107 ] for a comprehensive review). In a model of adult WNV infection, cytokine-mediated inhibition of hippocampal neurogenesis is associated with memory impairments, even though the number of NSCs remained stable [ 100 ].…”

The Effects of Environmental Adversities on Human Neocortical Neurogenesis Modeled in Brain Organoids

“…The syncytiotrophoblast cells, which form the fetal part of placental barrier, are permissive to viral infection and replication in the first and second trimester ( Fisher et al, 2000 ). This may lead to viral infection of multiple cell types within the embryo, including NSCs ( Baggiani et al, 2020 ). Infection of murine embryos with murine CMV showed that ventricular and subventricular zones are the most affected ( Tsutsui et al, 2005 ).…”