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Abstract
There is an urgent need for new and advanced approaches to modeling the pathological mechanisms of complex human neurological disorders. This is underscored by the decline in pharmaceutical research and development efficiency resulting in a relative decrease in new drug launches in the last several decades. Induced pluripotent stem cells represent a new tool to overcome many of the shortcomings of conventional methods, enabling live human neural cell modeling of complex conditions relating to aberrant neurodevelopment, such as schizophrenia, epilepsy and autism as well as age-associated neurodegeneration. This review considers the current status of induced pluripotent stem cell-based modeling of neurological disorders, canvassing proven and putative advantages, current constraints, and future prospects of next-generation culture systems for biomedical research and translation.
Financial & competing interests disclosure
The authors wish to acknowledge financial support from the Australian Research Council (ARC) and the ARC Centre of Excellence for Electromaterials Science (ACES). G Wallace additionally acknowledges the support of the ARC through an ARC Laureate Fellowship. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
iPSCs can potentially be used to recapitulate the different stages of a neurological disorder, model singular or cumulative effects of defective genes, and study environmental stimuli including physical and chemical stimuli.
The ability to differentiate iPSCs to bone fide neurons and supporting cells that accurately imitate the form and function of cells and tissue of the developing and diseased nervous system is a fundamental requirement for modeling.
iPSC-derived neural cells and tissues offer an in vitro alternative for early-phase drug development including neurotoxicity testing.
Advocating standards for the quality and disclosure of materials and methods used to maintain, culture and differentiate iPSCs, including both their strengths and limits, will benefit both research and translation of modeling.
Natural and synthetic biomaterials are being identified with different mechanical, chemical, electrical, and physical features of micro- and nanoscale proportions to better control cell fate and function for improved modeling of neural tissues and disease phenotypes. Models that recapitulate the qualities of native tissues will enable more accurate and informative preclinical studies of drug- or device-based therapies, with fewer clinical trial failures and better targeted therapies.
The use of material properties to dictate clinically relevant cell phenotypes in vitro will be paralleled by material-mediated correction of aberrant cellular function as another potential therapeutic strategy for TI, NDd and NDg.