Human Stem Cell-Based Disease Models of Sensory Mechanotransduction and the Extracellular Matrix

Nickolls, Alec

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Year:: 2020
Contributor:: Nickolls, Alec (creator); Bonnemann, Carsten (Advisor); Wainger, Brian (Reader); Fallon, Justin (Reader); Mallon, Barbara (Reader); Hoffman, Dax (Reader); Roche, Katherine (Reader); Brown University. Department of Neuroscience (sponsor)
Genre:: theses
Subject:: Stem cells--Research; Neurosciences; induced pluripotent stem cells; Extracellular matrix; Senses and sensation; Stem cells; Muscular dystrophy; Mechanoreceptors; Sensory neurons
Extent:: xvi, 199 p.

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Abstract:: Human pluripotent stem cells have the theoretical capacity to produce every cell type of the body in vitro. Such stem cell-derived tissue grants unprecedented access to investigate human physiology and disease, particularly in the neurosciences, where living neural tissue is relatively inaccessible. However, harnessing the potential of human stem cells to generate specific neural cell types remains a major unmet challenge. In this dissertation, I developed several unique approaches that leverage pluripotent stem cell technology for modeling neurological disease. First, I established a set of novel methods to generate functionally pure cultures of peripheral sensory neurons from induced pluripotent stem cells (iPSCs). These include a polymodal neuron subtype that detects both mechanical force and cold temperature – a previously undescribed class of sensory neuron not found in mice but for which I provide molecular evidence in adult human tissue. This technique was applied to model the rare human disorder of PIEZO2 deficiency, where individuals genetically lack the senses of vibration, gentle touch, and proprioception. The results confirmed that PIEZO2 is a crucial stretch-gated ion channel underlying mechanotransduction in human sensory neurons. I then turned to a spectrum of neuromuscular conditions called the dystroglycanopathies, characterized by muscular dystrophy and a range of brain malformations. Here, I established human iPSC-derived 3D tissue models of the disease that corroborate extracellular matrix defects seen in animal models. Finally, using this system, I determined the efficacy of a recently proposed therapeutic substrate for the dystroglycanopathies in a genotypic subset of patients. Collectively, the findings in this dissertation emphasize the translational versatility of stem cell-based models and offer new paths to uncover mechanisms of human biology in vitro.
Notes:: Thesis (Ph. D.)--Brown University, 2020

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Rights: In Copyright
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Citation

Nickolls, Alec, "Human Stem Cell-Based Disease Models of Sensory Mechanotransduction and the Extracellular Matrix" (2020). Neuroscience Theses and Dissertations. Brown Digital Repository. Brown University Library. https://repository.library.brown.edu/studio/item/bdr:1129500/

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Neuroscience Theses and Dissertations

Theses and Dissertations for the Neuroscience department.
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