TY - JOUR
T1 - Activity in grafted human iPS cell-derived cortical neurons integrated in stroke-injured rat brain regulates motor behavior
AU - Palma-Tortosa, Sara
AU - Tornero, Daniel
AU - Grønning Hansen, Marita
AU - Monni, Emanuela
AU - Hajy, Mazin
AU - Kartsivadze, Sopiko
AU - Aktay, Sibel
AU - Tsupykov, Oleg
AU - Parmar, Malin
AU - Deisseroth, Karl
AU - Skibo, Galyna
AU - Lindvall, Olle
AU - Kokaia, Zaal
PY - 2020/4/21
Y1 - 2020/4/21
N2 - 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.
AB - 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.
KW - Action Potentials/physiology
KW - Animals
KW - Behavior Observation Techniques
KW - Behavior, Animal/physiology
KW - Cell Differentiation/physiology
KW - Cell Line
KW - Disease Models, Animal
KW - Humans
KW - Induced Pluripotent Stem Cells/physiology
KW - Infarction, Middle Cerebral Artery/etiology
KW - Male
KW - Motor Activity/physiology
KW - Neurons/physiology
KW - Optogenetics
KW - Patch-Clamp Techniques
KW - Rats
KW - Recovery of Function
KW - Somatosensory Cortex/cytology
U2 - 10.1073/pnas.2000690117
DO - 10.1073/pnas.2000690117
M3 - Article
C2 - 32253308
VL - 117
SP - 9094
EP - 9100
JO - Proceedings of the National Academy of Sciences
JF - Proceedings of the National Academy of Sciences
SN - 1091-6490
IS - 16
ER -