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

Yuejun Chen; Man Xiong; Yi Dong; Alexander Haberman; Jingyuan Cao; Huisheng Liu; Wenhao Zhou; Su Chun Zhang

doi:10.1016/j.stem.2016.03.014

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

Yuejun Chen, Man Xiong, Yi Dong, Alexander Haberman, Jingyuan Cao, Huisheng Liu, Wenhao Zhou, Su Chun Zhang

Research output: Contribution to journal › Article › peer-review

137 Scopus citations

Abstract

Summary 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.

Original language	English
Pages (from-to)	817-826
Number of pages	10
Journal	Cell Stem Cell
Volume	18
Issue number	6
DOIs	https://doi.org/10.1016/j.stem.2016.03.014
State	Published - 2 Jun 2016
Externally published	Yes

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title = "Chemical Control of Grafted Human PSC-Derived Neurons in a Mouse Model of Parkinson's Disease",

abstract = "Summary 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.",

author = "Yuejun Chen and Man Xiong and Yi Dong and Alexander Haberman and Jingyuan Cao and Huisheng Liu and Wenhao Zhou and Zhang, \{Su Chun\}",

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AU - Chen, Yuejun

AU - Xiong, Man

AU - Dong, Yi

AU - Haberman, Alexander

AU - Cao, Jingyuan

AU - Liu, Huisheng

AU - Zhou, Wenhao

AU - Zhang, Su Chun

PY - 2016/6/2

Y1 - 2016/6/2

N2 - Summary 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.

AB - Summary 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.

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JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 6

ER -

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

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