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Grafted human pluripotent stem cell-derived cortical neurons integrate into adult human cortical neural circuitry

Grønning Hansen, Marita LU ; Laterza, Cecilia LU ; Palma-Tortosa, Sara LU ; Kvist, Giedre LU ; Monni, Emanuela LU ; Tsupykov, Oleg ; Tornero, Daniel LU ; Uoshima, Naomi ; Soriano, Jordi and Bengzon, Johan LU , et al. (2020) In Stem cells translational medicine
Abstract

Several neurodegenerative diseases cause loss of cortical neurons, leading to sensory, motor, and cognitive impairments. Studies in different animal models have raised the possibility that transplantation of human cortical neuronal progenitors, generated from pluripotent stem cells, might be developed into a novel therapeutic strategy for disorders affecting cerebral cortex. For example, we have shown that human long-term neuroepithelial-like stem (lt-NES) cell-derived cortical neurons, produced from induced pluripotent stem cells and transplanted into stroke-injured adult rat cortex, improve neurological deficits and establish both afferent and efferent morphological and functional connections with host cortical neurons. So far, all... (More)

Several neurodegenerative diseases cause loss of cortical neurons, leading to sensory, motor, and cognitive impairments. Studies in different animal models have raised the possibility that transplantation of human cortical neuronal progenitors, generated from pluripotent stem cells, might be developed into a novel therapeutic strategy for disorders affecting cerebral cortex. For example, we have shown that human long-term neuroepithelial-like stem (lt-NES) cell-derived cortical neurons, produced from induced pluripotent stem cells and transplanted into stroke-injured adult rat cortex, improve neurological deficits and establish both afferent and efferent morphological and functional connections with host cortical neurons. So far, all studies with human pluripotent stem cell-derived neurons have been carried out using xenotransplantation in animal models. Whether these neurons can integrate also into adult human brain circuitry is unknown. Here, we show that cortically fated lt-NES cells, which are able to form functional synaptic networks in cell culture, differentiate to mature, layer-specific cortical neurons when transplanted ex vivo onto organotypic cultures of adult human cortex. The grafted neurons are functional and establish both afferent and efferent synapses with adult human cortical neurons in the slices as evidenced by immuno-electron microscopy, rabies virus retrograde monosynaptic tracing, and whole-cell patch-clamp recordings. Our findings provide the first evidence that pluripotent stem cell-derived neurons can integrate into adult host neural networks also in a human-to-human grafting situation, thereby supporting their potential future clinical use to promote recovery by neuronal replacement in the patient's diseased brain.

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Contribution to journal
publication status
epub
subject
keywords
cerebral cortex, human, iPS cells, neural circuitry, regeneration, transplantation
in
Stem cells translational medicine
publisher
AlphaMed Press
external identifiers
  • pmid:32602201
  • scopus:85087302707
ISSN
2157-6564
DOI
10.1002/sctm.20-0134
language
English
LU publication?
yes
id
2c29afc2-8a9e-45e8-9a1f-75241093edaa
date added to LUP
2020-07-17 13:06:50
date last changed
2020-08-27 18:01:37
@article{2c29afc2-8a9e-45e8-9a1f-75241093edaa,
  abstract     = {<p>Several neurodegenerative diseases cause loss of cortical neurons, leading to sensory, motor, and cognitive impairments. Studies in different animal models have raised the possibility that transplantation of human cortical neuronal progenitors, generated from pluripotent stem cells, might be developed into a novel therapeutic strategy for disorders affecting cerebral cortex. For example, we have shown that human long-term neuroepithelial-like stem (lt-NES) cell-derived cortical neurons, produced from induced pluripotent stem cells and transplanted into stroke-injured adult rat cortex, improve neurological deficits and establish both afferent and efferent morphological and functional connections with host cortical neurons. So far, all studies with human pluripotent stem cell-derived neurons have been carried out using xenotransplantation in animal models. Whether these neurons can integrate also into adult human brain circuitry is unknown. Here, we show that cortically fated lt-NES cells, which are able to form functional synaptic networks in cell culture, differentiate to mature, layer-specific cortical neurons when transplanted ex vivo onto organotypic cultures of adult human cortex. The grafted neurons are functional and establish both afferent and efferent synapses with adult human cortical neurons in the slices as evidenced by immuno-electron microscopy, rabies virus retrograde monosynaptic tracing, and whole-cell patch-clamp recordings. Our findings provide the first evidence that pluripotent stem cell-derived neurons can integrate into adult host neural networks also in a human-to-human grafting situation, thereby supporting their potential future clinical use to promote recovery by neuronal replacement in the patient's diseased brain.</p>},
  author       = {Grønning Hansen, Marita and Laterza, Cecilia and Palma-Tortosa, Sara and Kvist, Giedre and Monni, Emanuela and Tsupykov, Oleg and Tornero, Daniel and Uoshima, Naomi and Soriano, Jordi and Bengzon, Johan and Martino, Gianvito and Skibo, Galyna and Lindvall, Olle and Kokaia, Zaal},
  issn         = {2157-6564},
  language     = {eng},
  month        = {06},
  publisher    = {AlphaMed Press},
  series       = {Stem cells translational medicine},
  title        = {Grafted human pluripotent stem cell-derived cortical neurons integrate into adult human cortical neural circuitry},
  url          = {http://dx.doi.org/10.1002/sctm.20-0134},
  doi          = {10.1002/sctm.20-0134},
  year         = {2020},
}