Dissecting the functionality of dopaminergic grafts for parkinsons disease with optogenetics
Final Report Abstract
The overall goal of this project was the combination of human stem cell technologies with optogenetics to investigate the functional connectivity of embryonic stem cell-derived neurons. For this purpose human ESC lines were generated who’s neuronal progeny can be activated or silenced by light. In the first project midbrain dopamine neurons were silenced by light after transplantation in a Parkinson’s disease mouse model. The results demonstrated that dopamine graft functionality is dependent on neuronal activity and dopamine release. In addition, we were able to show how stem cell derived dopamine neurons connect to the diseased brain morphologically and functionally. In general such mechanism-based approaches should allow the development of safer and more effective strategies, as stem cell treatments are approaching the clinic. In the second project we generated spinal motor neurons, which can be activated by light. Co-culture of these neurons with primary human skeletal muscle resulted in the generation of a functional human neuromuscular system. This is the first indication that human stem cell-derived neurons can functionally connect to a bona fide human target population. In addition the co-culture system can be used to model neuromuscular disease in a functional human integrative system. The project was highly collaborative and could never have been completed by one person or one lab alone. The environment with many leading scientific institutions (Sloan-Kettering, Cornell, Rockefeller, Columbia) with exceptional laboratories, dozens of state of the art core facilities literally across the street and a collaborative, forward-thinking mindset were critical determinants of success.
Publications
- MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration. Nature communications 2014;5, 3633
Cebrian, C., Zucca, F.A., Mauri, P., Steinbeck, J.A., et al.
(See online at https://doi.org/10.1038/ncomms4633) - Moving stem cells to the clinic: Potential and limitations for brain repair. Neuron. 2015 Apr 8;86(1):187-206
Steinbeck JA and Studer L
(See online at https://doi.org/10.1016/j.neuron.2015.03.002) - Optogenetic control in a functional human embryonic stem cell-derived neuro-muscular co-culture system. International Society for Stem Cell Research, Stockholm June 24-27th 2015
Steinbeck JA, Jaiswal M, Calder L, Kishinevsky S, Toyka KV, Goldstein P, Studer L
- Optogenetics enables functional analysis of human embryonic stem cell-derived grafts in a Parkinson's disease model. Nat Biotechnol. 2015 Feb;33(2):204-9
Steinbeck JA, Choi SJ, Mrejeru A, Ganat Y, Deisseroth K, Sulzer D, Mosharov EV, Studer L
(See online at https://doi.org/10.1038/nbt.3124)
