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" Investigating the Mechanisms of Neural Stem Cell Mechanotransduction: "
Kang, Phillip
Kumar, Sanjay; Schaffer, David V
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Latin Dissertation
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English
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| Record Number
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905843
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TL2vz6t47p
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| Main Entry
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Kang, Phillip
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| Title & Author
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Investigating the Mechanisms of Neural Stem Cell Mechanotransduction:\ Kang, PhillipKumar, Sanjay; Schaffer, David V
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| College
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UC Berkeley
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| Date
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2019
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| student score
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2019
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| Abstract
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Neural stem cells (NSCs) are remarkable mediators of structural plasticity in the adult mammalian brain and play important roles in physiological and pathophysiological neurobiology. Ongoing research has uncovered that mechanical cues can potently regulate NSC behavior. For example, soft substrates promote the neuronal differentiation of NSCs by suppressing cytoskeletal contractility and perturbation of the same pathway influences neurogenesis in vivo. However, the mechanisms that link cytoskeletal signaling to transcriptional regulation and govern stiffness-dependent NSC fate commitment are not fully understood. Additionally, studies have shown that dysfunction of hippocampal NSCs may underlie the cognitive deficits linked to diabetes. This may be due to the dysregulation of cellular energetics, which is tightly regulated in stem cells and influences cytoskeletal dynamics. Therefore, the effect of hyperglycemia on NSC mechanotransductive signaling warrants further study.In this dissertation, we show that angiomotin (AMOT) is critical for mechanotransduction in NSCs. Loss of AMOT inhibited neurogenesis on soft substrates while also severing the functional tie between reduced myosin contractility and increased neurogenesis. We found that AMOT is critically regulated by its phosphorylation and localization and promotes neurogenesis by inhibiting yes-associated protein (YAP) and upregulating -catenin activity. Additionally, we found that hyperglycemia suppresses NSC growth in culture and that NSC mechanosensitive differentiation can be regulated by glucose concentration. Specifically, activation of 5’adenosine monophosphate-activated protein kinase (AMPK) either by lowering the glucose concentration or metformin treatment rescued neurogenesis on stiff substrates while high glucose or compound C (AMPK inhibitor) treatment suppressed neurogenesis. Therefore, hyperglycemia may have a direct influence on how NSCs sense and respond to their physical microenvironment through an AMPK-dependent mechanism.These findings significantly add to our understanding of how NSCs sense, integrate, and respond to biophysical inputs and how those pathways are influenced by glucose dysregulation. Further elucidation of these mechanisms has the power to inform how NSCs are regulated in health and disease while also advancing how these cells are utilized in regenerative medicine approaches in the nervous system.
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Kumar, Sanjay; Schaffer, David V
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UC Berkeley
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