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Activity in grafted human iPS cell-derived cortical neurons integrated in stroke-injured rat brain regulates motor behavior

Palma-Tortosa, Sara LU ; Tornero, Daniel LU ; Grønning Hansen, Marita LU ; Monni, Emanuela LU ; Hajy, Mazin LU ; Kartsivadze, Sopiko LU ; Aktay, Sibel LU ; Tsupykov, Oleg ; Parmar, Malin LU and Deisseroth, Karl , et al. (2020) In Proceedings of the National Academy of Sciences of the United States of America 117(16). p.9094-9100
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 show 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 inputs from grafted neurons. Immunoelectron microscopy demonstrates myelination of the graft-derived axons in the corpus callosum and that their... (More)

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 show 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 inputs 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 show that the stroke-induced asymmetry in a sensorimotor (cylinder) test is reversed by transplantation. Light-induced inhibition of halorhodopsin-expressing, grafted neurons does 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 endogenous halorhodopsin-expressing cortical neurons, located in the same area, and after inhibition of endogenous halorhodopsin-expressing cortical neurons by exposure 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 maintaining 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.

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publication status
published
subject
keywords
Action Potentials/physiology, Animals, Behavior Observation Techniques, Behavior, Animal/physiology, Cell Differentiation/physiology, Cell Line, Disease Models, Animal, Humans, Induced Pluripotent Stem Cells/physiology, Infarction, Middle Cerebral Artery/etiology, Male, Motor Activity/physiology, Neurons/physiology, Optogenetics, Patch-Clamp Techniques, Rats, Recovery of Function, Somatosensory Cortex/cytology
in
Proceedings of the National Academy of Sciences of the United States of America
volume
117
issue
16
pages
9094 - 9100
publisher
National Acad Sciences
external identifiers
  • pmid:32253308
  • scopus:85083564169
ISSN
1091-6490
DOI
10.1073/pnas.2000690117
language
English
LU publication?
yes
id
60aeb00f-2c61-471e-be5d-669b95391d07
date added to LUP
2020-08-24 08:47:01
date last changed
2021-06-08 01:14:20
@article{60aeb00f-2c61-471e-be5d-669b95391d07,
  abstract     = {<p>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 show 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 inputs 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 show that the stroke-induced asymmetry in a sensorimotor (cylinder) test is reversed by transplantation. Light-induced inhibition of halorhodopsin-expressing, grafted neurons does 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 endogenous halorhodopsin-expressing cortical neurons, located in the same area, and after inhibition of endogenous halorhodopsin-expressing cortical neurons by exposure 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 maintaining 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.</p>},
  author       = {Palma-Tortosa, Sara and Tornero, Daniel and Grønning Hansen, Marita and Monni, Emanuela and Hajy, Mazin and Kartsivadze, Sopiko and Aktay, Sibel and Tsupykov, Oleg and Parmar, Malin and Deisseroth, Karl and Skibo, Galyna and Lindvall, Olle and Kokaia, Zaal},
  issn         = {1091-6490},
  language     = {eng},
  month        = {04},
  number       = {16},
  pages        = {9094--9100},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences of the United States of America},
  title        = {Activity in grafted human iPS cell-derived cortical neurons integrated in stroke-injured rat brain regulates motor behavior},
  url          = {http://dx.doi.org/10.1073/pnas.2000690117},
  doi          = {10.1073/pnas.2000690117},
  volume       = {117},
  year         = {2020},
}