UCSF

In recent years, the complexity of chemotherapies and their interactions with the peripheral nervous system have come into focus but limitations in experimental models have remained a significant challenge in the field. As evidence, despite most chemotherapy drugs being around for decades, there are currently no therapies approved that target chemotherapy-peripheral nervous system interactions as an anti-neurotoxic agent. Human pluripotent stem cells offer an appealing model system that, unlike rodent models, are compatible with high throughput, high content applications; techniques that reflect modern drug discovery methodologies. Thus, utilizing the key advantages of stem cell-based models in tandem with the strengths of traditional animal models offers a complementary and interdisciplinary strategy to advance chemotherapy-peripheral nervous system research and drug discovery.

This dissertation begins with an overview of the current status of chemotherapy-peripheral nervous system research, describing examples of taxane chemotherapy-induced damage to the sensory nerves and platin chemotherapy-induced damage to the enteric nerves. Avenues where stem cell-based models may further advance the field are also presented. Based on this foundation, I established a stem cell-based model of chemotherapy-induced enteric neuropathy, focusing my efforts on the platin chemotherapy drug class as they are heavily prescribed and highly neurotoxic to the enteric neurons, which innervates and controls the gastrointestinal tract.

To uncover the mechanism of platin-induced gastrointestinal neurotoxicity, I leveraged my scalable stem cell-derived enteric neuron model, performing high throughput screens and transcriptomic analyses to reveal excitotoxicity through muscarinic cholinergic signaling as a key driver of platin-induced enteric neuropathy. Single nuclei transcriptomics identified inhibitory nitrergic neurons as selectively vulnerable to platins, which we validated through histological analysis of the enteric nervous system in platin chemotherapy-treated patients. Lastly, we found that dampening muscarinic signaling through either pharmacologic or genetic methods is sufficient to prevent platin-induced excitotoxicity in vitro and platin-induced constipation and degeneration of nitrergic neurons in mice.

Altogether, this work succeeds in defining the mechanism underlying platin-induced gastrointestinal neurotoxicity. Furthermore, it serves as an example and framework for how stem cell-based models of the peripheral nervous system can be utilized to rapidly deconvolute mechanisms of chemotherapy-induced neurotoxicity and power drug discovery pipelines to tackle numerous peripheral neuropathies that have been intractable to date.