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

Cell Stem Cell. 2016 Jun 2;18(6):817-826. doi: 10.1016/j.stem.2016.03.014. Epub 2016 Apr 28.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Line
  • Clozapine / analogs & derivatives
  • Disease Models, Animal
  • Dopaminergic Neurons / metabolism
  • Drug Design
  • Excitatory Postsynaptic Potentials
  • Glutamates / metabolism
  • Human Embryonic Stem Cells / metabolism
  • Humans
  • Mesencephalon / pathology
  • Mice
  • Motor Activity
  • Neostriatum / metabolism
  • Neurons / transplantation*
  • Parkinson Disease / pathology
  • Parkinson Disease / physiopathology
  • Parkinson Disease / therapy*
  • Pluripotent Stem Cells / cytology*
  • Receptors, Dopamine D1 / metabolism
  • Stem Cell Transplantation*
  • gamma-Aminobutyric Acid / metabolism


  • Glutamates
  • Receptors, Dopamine D1
  • gamma-Aminobutyric Acid
  • Clozapine
  • clozapine N-oxide