Direct in vivo assessment of human stem cell graft-host neural circuits

Blake Byers; Hyun Joo Lee; Jia Liu; Andrew J Weitz; Peter Lin; Pengbo Zhang; Aleksandr Shcheglovitov; Ricardo Dolmetsch; Renee Reijo Pera; Jin Hyung Lee

doi:10.1016/j.neuroimage.2015.03.079

Direct in vivo assessment of human stem cell graft-host neural circuits

Neuroimage. 2015 Jul 1:114:328-37. doi: 10.1016/j.neuroimage.2015.03.079. Epub 2015 Apr 25.

Authors

Affiliations

¹ Department of Bioengineering, Stanford University, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, CA 94305, USA; Google Ventures, Mountain View, CA 94043, USA.
² Department of Neurology and Neurological Sciences, Stanford University, CA 94305, USA.
³ Department of Neurology and Neurological Sciences, Stanford University, CA 94305, USA; Department of Psychiatry and Biobehavioral Sciences, Neuroscience Interdepartmental Program, University of California, Los Angeles, CA 90095, USA.
⁴ Department of Bioengineering, Stanford University, CA 94305, USA.
⁵ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, CA 94305, USA.
⁶ Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84132, USA; Department of Neurobiology, Stanford University, CA 94305, USA.
⁷ Department of Neurobiology, Stanford University, CA 94305, USA.
⁸ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, CA 94305, USA; Department of Obstetrics and Gynecology, Stanford University, CA 94305, USA.
⁹ Department of Bioengineering, Stanford University, CA 94305, USA; Department of Neurology and Neurological Sciences, Stanford University, CA 94305, USA; Department of Psychiatry and Biobehavioral Sciences, Neuroscience Interdepartmental Program, University of California, Los Angeles, CA 90095, USA; Department of Neurosurgery, Stanford University, CA 94305, USA; Department of Electrical Engineering, Stanford University, CA 94305, USA. Electronic address: ljinhy@stanford.edu.

Abstract

Despite the potential of stem cell-derived neural transplants for treating intractable neurological diseases, the global effects of a transplant's electrical activity on host circuitry have never been measured directly, preventing the systematic optimization of such therapies. Here, we overcome this problem by combining optogenetics, stem cell biology, and neuroimaging to directly map stem cell-driven neural circuit formation in vivo. We engineered human induced pluripotent stem cells (iPSCs) to express channelrhodopsin-2 and transplanted resulting neurons to striatum of rats. To non-invasively visualize the function of newly formed circuits, we performed high-field functional magnetic resonance imaging (fMRI) during selective stimulation of transplanted cells. fMRI successfully detected local and remote neural activity, enabling the global graft-host neural circuit function to be assessed. These results demonstrate the potential of a novel neuroimaging-based platform that can be used to identify how a graft's electrical activity influences the brain network in vivo.

Keywords: Functional MRI; Optogenetics; Stem cell; Transplant.

Publication types

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

MeSH terms

Animals
Brain / physiology
Brain Mapping
Corpus Striatum / physiology*
Corpus Striatum / surgery
Embryonic Stem Cells / physiology
Female
Heterografts / physiology*
Humans
Induced Pluripotent Stem Cells / physiology*
Induced Pluripotent Stem Cells / transplantation*
Magnetic Resonance Imaging / methods
Optogenetics
Rats

Abstract

Publication types

MeSH terms

Grants and funding