Studies of Chemotherapy Induced Peripheral Neuropathy (CIPN) in iPSC-derived

National Center For Advancing Translational Sciences

Investigators

Abstract

Using human iPSC-derived sensory neurons (hiSNs) generated by NCATS, Harvard has found that hiSNs are more mature morphologically and functionally when co-cultured with rodent DRG satellite glia than hiSNs alone. There is also less clustering in coculture with a more even distribution. They found that physical contact between rodent DRG satellite glia and hiSNs is essential for advanced maturation and not secreted factors alone. Specifically, Semaphorin-plexin and glial gap junction signaling appear to contribute to hiSN maturation. They also observed an increase in Nav1.8 and Muscarinic receptor expression under coculture conditions. Interestingly, they found that coculture exacerbates chemotherapy-induced axonal degeneration caused by paclitaxel. Therefore, hiSNs cocultured with satellite glia could provide a more physiologically relevant model of chemotherapy induced peripheral neuropathy (CIPN). A manuscript has been posted on bioRxiv and is currently being prepared for submission to Cell Stem Cell. This year, differentiation of CIPN patient-derived cell lines using our original differentiation protocol were shown to result in reduced differentiation efficiency due to inherent genetic differences between patients. To increase the differentiation efficiency, a novel differentiation workflow was developed allowing to modularly changes are critical induction stages that resulted in reduced progenitor cell populations and increased nociceptor production. This protocol is now being applied to CIPN patient-derived cell lines for generation of nociceptors that will be utilized to test Bclw mimics to prevent CIPN.