Progress in mimicking brain microenvironments to understand and treat neurological disorders

Abstract

Neurological disorders including traumatic brain injury, stroke, primary and metastatic brain tumors, and neurodegenerative diseases affect millions of people worldwide. Disease progression is accompanied by changes in the brain microenvironment, but how these shifts in biochemical, biophysical, and cellular properties contribute to repair outcomes or continued degeneration is largely unknown. Tissue engineering approaches can be used to develop in vitro models to understand how the brain microenvironment contributes to pathophysiological processes linked to neurological disorders and may also offer constructs that promote healing and regeneration in vivo . In this Perspective, we summarize features of the brain microenvironment in normal and pathophysiological states and highlight strategies to mimic this environment to model disease, investigate neural stem cell biology, and promote regenerative healing. We discuss current limitations and resulting opportunities to develop tissue engineering tools that more faithfully recapitulate the aspects of the brain microenvironment for both in vitro and in vivo applications.

Therapeutic potential of human stem cell transplantations for Vanishing White Matter: A quest for the Goldilocks graft

“…This suggests that additional astrocytic factors might be involved and also indicates differences between the human and mouse VWM microenvironment. Age might additionally be an important factor in microenvironmental changes, both during normal development 29,30 and in a progressive neurodegenerative disease such as VWM 31–33 . It would be interesting to see whether the cell populations tested here can be of benefit when transplanted at a later age, a scenario relevant to many VWM patients.…”

Combination of Stem Cells and Rehabilitation Therapies for Ischemic Stroke

“…Furthermore, novel therapies designed to improve the regenerative microenvironment of brain stroke tissue may improve brain repair and efficacy of stem cell therapy. Stroke entails primary and secondary cell death pathways that create a harsh proinflammatory microenvironment and the ability of both exogenous and endogenous stem cells to facilitate neuroregeneration [ 155 ]. Modifying exogenous stem cells via hypoxic cell culture exposure or genetic modification allows for improved stem cell efficacy.…”

“…Neurodegenerative diseases, stroke, primary and metastatic brain tumors, and TBI are neurological disorders affecting humans across the globe. Disease progression is characterized by alterations in the microenvironment of the brain [ 155 ]. More specifically, stroke entails primary and secondary cell death pathways, altogether creating a harsh microenvironment.…”

“…More specifically, stroke entails primary and secondary cell death pathways, altogether creating a harsh microenvironment. This limits the survival and growth of exogenous and endogenous stem cells, subsequently limiting brain repair [ 155 ]. In order to reduce this limiting factor, novel strategies can be designed to enhance the “regenerative” microenvironment and may promote an improvement in brain repair.…”

Multiscale Mechanobiology in Brain Physiology and Diseases

“…While neuroscience has mostly been limited to electrophysiological, biochemical, and genetic studies over the past few decades, emerging evidence confirms that mechanobiology plays a critical role in modulating brain function and dysfunction ( Tyler, 2012 ). Indeed, accumulative works suggest that mechanical properties of the cell microenvironment can control developmental processes ( Koser et al, 2016 ) and are involved in the progression of brain diseases ( Ngo and Harley, 2021 ), while external mechanical forces can lead to brain injury ( Meaney and Smith, 2011 ). Consequently, a better understanding of mechanobiological processes in brain tissues requires sophisticated in vitro models that capture more realistically the complex characteristics of brain tissues through engineered multi-scale platforms.…”