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Synaptic inputs from stroke-injured brain to grafted human stem cell-derived neurons activated by sensory stimuli

Tornero, Daniel LU ; Tsupykov, Oleg; Granmo, Marcus LU ; Rodriguez-Fontenla, Cristina; Grønning-Hansen, Marita LU ; Thelin, Jonas LU ; Smozhanik, Ekaterina; Laterza, Cecilia LU ; Wattananit, Somsak LU and Ge, Ruimin LU , et al. (2017) In Brain 140(3). p.692-706
Abstract

Transplanted neurons derived from stem cells have been proposed to improve function in animal models of human disease by various mechanisms such as neuronal replacement. However, whether the grafted neurons receive functional synaptic inputs from the recipient's brain and integrate into host neural circuitry is unknown. Here we studied the synaptic inputs from the host brain to grafted cortical neurons derived from human induced pluripotent stem cells after transplantation into stroke-injured rat cerebral cortex. Using the rabies virus-based trans-synaptic tracing method and immunoelectron microscopy, we demonstrate that the grafted neurons receive direct synaptic inputs from neurons in different host brain areas located in a pattern... (More)

Transplanted neurons derived from stem cells have been proposed to improve function in animal models of human disease by various mechanisms such as neuronal replacement. However, whether the grafted neurons receive functional synaptic inputs from the recipient's brain and integrate into host neural circuitry is unknown. Here we studied the synaptic inputs from the host brain to grafted cortical neurons derived from human induced pluripotent stem cells after transplantation into stroke-injured rat cerebral cortex. Using the rabies virus-based trans-synaptic tracing method and immunoelectron microscopy, we demonstrate that the grafted neurons receive direct synaptic inputs from neurons in different host brain areas located in a pattern similar to that of neurons projecting to the corresponding endogenous cortical neurons in the intact brain. Electrophysiological in vivo recordings from the cortical implants show that physiological sensory stimuli, i.e. cutaneous stimulation of nose and paw, can activate or inhibit spontaneous activity in grafted neurons, indicating that at least some of the afferent inputs are functional. In agreement, we find using patch-clamp recordings that a portion of grafted neurons respond to photostimulation of virally transfected, channel-rhodopsin-2-expressing thalamo-cortical axons in acute brain slices. The present study demonstrates, for the first time, that the host brain regulates the activity of grafted neurons, providing strong evidence that transplanted human induced pluripotent stem cell-derived cortical neurons can become incorporated into injured cortical circuitry. Our findings support the idea that these neurons could contribute to functional recovery in stroke and other conditions causing neuronal loss in cerebral cortex.

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publication status
published
subject
keywords
Functional integration, Stem cells, Stroke, Synapses, Transplantation
in
Brain
volume
140
issue
3
pages
15 pages
publisher
Oxford University Press
external identifiers
  • scopus:85014007992
  • wos:000397317100025
ISSN
0006-8950
DOI
10.1093/brain/aww347
language
English
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yes
id
6421c8f1-e8dc-4369-90f6-88de76b54be9
date added to LUP
2017-03-13 09:12:09
date last changed
2018-05-20 04:32:21
@article{6421c8f1-e8dc-4369-90f6-88de76b54be9,
  abstract     = {<p>Transplanted neurons derived from stem cells have been proposed to improve function in animal models of human disease by various mechanisms such as neuronal replacement. However, whether the grafted neurons receive functional synaptic inputs from the recipient's brain and integrate into host neural circuitry is unknown. Here we studied the synaptic inputs from the host brain to grafted cortical neurons derived from human induced pluripotent stem cells after transplantation into stroke-injured rat cerebral cortex. Using the rabies virus-based trans-synaptic tracing method and immunoelectron microscopy, we demonstrate that the grafted neurons receive direct synaptic inputs from neurons in different host brain areas located in a pattern similar to that of neurons projecting to the corresponding endogenous cortical neurons in the intact brain. Electrophysiological in vivo recordings from the cortical implants show that physiological sensory stimuli, i.e. cutaneous stimulation of nose and paw, can activate or inhibit spontaneous activity in grafted neurons, indicating that at least some of the afferent inputs are functional. In agreement, we find using patch-clamp recordings that a portion of grafted neurons respond to photostimulation of virally transfected, channel-rhodopsin-2-expressing thalamo-cortical axons in acute brain slices. The present study demonstrates, for the first time, that the host brain regulates the activity of grafted neurons, providing strong evidence that transplanted human induced pluripotent stem cell-derived cortical neurons can become incorporated into injured cortical circuitry. Our findings support the idea that these neurons could contribute to functional recovery in stroke and other conditions causing neuronal loss in cerebral cortex.</p>},
  author       = {Tornero, Daniel and Tsupykov, Oleg and Granmo, Marcus and Rodriguez-Fontenla, Cristina and Grønning-Hansen, Marita and Thelin, Jonas and Smozhanik, Ekaterina and Laterza, Cecilia and Wattananit, Somsak and Ge, Ruimin and Tatarishvili, Jemal and Grealish, Shane and Brüstle, Oliver and Skibo, Galina and Parmar, Malin and Schouenborg, Jens and Lindvall, Olle and Kokaia, Zaal},
  issn         = {0006-8950},
  keyword      = {Functional integration,Stem cells,Stroke,Synapses,Transplantation},
  language     = {eng},
  month        = {03},
  number       = {3},
  pages        = {692--706},
  publisher    = {Oxford University Press},
  series       = {Brain},
  title        = {Synaptic inputs from stroke-injured brain to grafted human stem cell-derived neurons activated by sensory stimuli},
  url          = {http://dx.doi.org/10.1093/brain/aww347},
  volume       = {140},
  year         = {2017},
}