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Cell Stem Cell. 2016 Jun 2;18(6):817-26. doi: 10.1016/j.stem.2016.03.014. Epub 2016 Apr 28.

Chemical Control of Grafted Human PSC-Derived Neurons in a Mouse Model of Parkinson's Disease.

Author information

1
Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA. Electronic address: yuejunchenphd@gmail.com.
2
Institute of Pediatrics, Children's Hospital, Fudan University, 399 Wanyuan Road, Shanghai 201102, China.
3
Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA.
4
Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Neurology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA. Electronic address: suchun.zhang@wisc.edu.

Abstract

Transplantation of human pluripotent stem cell (hPSC)-derived neurons is a promising avenue for treating disorders including Parkinson's disease (PD). Precise control over engrafted cell activity is highly desired, as cells do not always integrate properly into host circuitry and can cause suboptimal graft function or undesired outcomes. Here, we show tunable rescue of motor function in a mouse model of PD, following transplantation of human midbrain dopaminergic (mDA) neurons differentiated from hPSCs engineered to express DREADDs (designer receptors exclusively activated by designer drug). Administering clozapine-N-oxide (CNO) enabled precise DREADD-dependent stimulation or inhibition of engrafted neurons, revealing D1 receptor-dependent regulation of host neuronal circuitry by engrafted cells. Transplanted cells rescued motor defects, which could be reversed or enhanced by CNO-based control of graft function, and activating engrafted cells drives behavioral changes in transplanted mice. These results highlight the ability to exogenously and noninvasively control and refine therapeutic outcomes following cell transplantation.

PMID:
27133795
PMCID:
PMC4892985
DOI:
10.1016/j.stem.2016.03.014
[Indexed for MEDLINE]
Free PMC Article

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