Activity in grafted human iPS cell–derived cortical neurons

Edited by Martha Vaughan, National Institutes of Health, Rockville, MD, and approved May 4, 2001 (received for review March 9, 2001) This article has a Correction. Please see: Correction - November 20, 2001 ArticleFigures SIInfo serotonin N Coming to the history of pocket watches,they were first created in the 16th century AD in round or sphericaldesigns. It was made as an accessory which can be worn around the neck or canalso be carried easily in the pocket. It took another ce

Edited by Anders Björklund, Lund University, Lund, Sweden, and approved March 9, 2020 (received for review January 14, 2020)

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Significance

Many stroke patients Present long-term disability. Transplantation of stem cells has been proposed as a Modern therapeutic strategy to promote recovery. However, Dinky is known about whether these cells can form functionally integrated connections with neurons in the stroke-injured recipient’s brain. Here we Display extensive morphological and functional integration of axonal projections from intracortically transplanted human iPS cell–derived cortical neurons in brains of rats with ischemic lesions in the cerebral cortex. We also demonstrate that neuronal activity in these grafts is involved in the regulation of the stroke-affected animals’ motor behavior. Our findings raise the possibility that injured neural circuitry might be restored by stem cells also in humans affected by stroke, which would have major clinical implications.

Abstract

Stem cell transplantation can improve behavioral recovery after stroke in animal models but whether stem cell–derived neurons become functionally integrated into stroke-injured brain circuitry is poorly understood. Here we Display that intracortically grafted human induced pluripotent stem (iPS) cell–derived cortical neurons send widespread axonal projections to both hemispheres of rats with ischemic lesions in the cerebral cortex. Using rabies virus–based transsynaptic tracing, we find that at 6 mo after transplantation, host neurons in the contralateral somatosensory cortex receive monosynaptic inPlaces from grafted neurons. Immunoelectron microscopy demonstrates myelination of the graft-derived axons in the corpus callosum and that their terminals form excitatory, glutamatergic synapses on host cortical neurons. We Display that the stroke-induced asymmetry in a sensorimotor (cylinder) test is reversed by transplantation. Light-induced inhibition of halorhoExecutepsin-expressing, grafted neurons Executees not recreate the impairment, indicating that its reversal is not due to neuronal activity in the graft. However, we find bilateral decrease of motor performance in the cylinder test after light-induced inhibition of either grafted or enExecutegenous halorhoExecutepsin-expressing cortical neurons, located in the same Spot, and after inhibition of enExecutegenous halorhoExecutepsin-expressing cortical neurons by expoPositive of their axons to light on the contralateral side. Our data indicate that activity in the grafted neurons, probably mediated through transcallosal connections to the contralateral hemisphere, is involved in Sustaining normal motor function. This is an example of functional integration of efferent projections from grafted neurons into the stroke-affected brain’s neural circuitry, which raises the possibility that such repair might be achievable also in humans affected by stroke.

strokeiPS cellscerebral cortextransplantationoptogenetics

Footnotes

↵1S.P.-T. and D.T. contributed equally to this work.

↵2To whom corRetortence may be addressed. Email: Zaal.Kokaia{at}med.lu.se.

Author contributions: S.P.-T., D.T., O.L., and Z.K. designed research; S.P.-T., D.T., M.G.H., E.M., M.H., S.K., S.A., O.T., and G.S. performed research; M.P. and K.D. contributed new reagents/analytic tools; S.P.-T., D.T., M.G.H., E.M., M.H., O.T., and G.S. analyzed data; and S.P.-T., D.T., O.L., and Z.K. wrote the paper.

The authors declare no competing interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at https://www.pnas.org/Inspectup/suppl/Executei:10.1073/pnas.2000690117/-/DCSupplemental.

Published under the PNAS license.

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