Direct in vivo assessment of human stem cell graft-host neural circuits.
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.
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.
Blake
B
Byers
Department of Neurology and Neurological Sciences, Stanford University, CA 94305, USA.
Hyun Joo
HJ
Lee
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.
Jia
J
Liu
Department of Bioengineering, Stanford University, CA 94305, USA.
Andrew J
AJ
Weitz
Department of Neurology and Neurological Sciences, Stanford University, CA 94305, USA.
Peter
P
Lin
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, CA 94305, USA.
Pengbo
P
Zhang
Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84132, USA; Department of Neurobiology, Stanford University, CA 94305, USA.
Aleksandr
A
Shcheglovitov
Department of Neurobiology, Stanford University, CA 94305, USA.
Ricardo
R
Dolmetsch
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, CA 94305, USA; Department of Obstetrics and Gynecology, Stanford University, CA 94305, USA.
Renee Reijo
RR
Pera
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.
Jin Hyung
JH
Lee
D000818:Animals; D001921:Brain / Q000502:physiology; D001931:Brain Mapping; D003342:Corpus Striatum / Q000502:physiology* / Q000601:surgery; D053595:Embryonic Stem Cells / Q000502:physiology; D005260:Female; D064593:Heterografts / Q000502:physiology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology* / Q000637:transplantation*; D008279:Magnetic Resonance Imaging / Q000379:methods; D062308:Optogenetics; D051381:Rats
Functional MRI; Optogenetics; Stem cell; Transplant