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Genetic modification increases the survival and the neuroregenerative properties of transplanted neural stem cells

Korshunova, Irina ; Rhein, Sina ; García-González, Diego ; Stölting, Ines ; Pfisterer, Ulrich LU ; Barta, Anna ; Dmytriyeva, Oksana ; Kirkeby, Agnete LU ; Schwaninger, Markus and Khodosevich, Konstantin (2020) In JCI Insight 5(4).
Abstract

Cell therapy raises hopes high for better treatment of brain disorders. However, the majority of transplanted cells often die soon after transplantation, and those that survive initially continue to die in the subacute phase, diminishing the impact of transplantations. In this study, we genetically modified transplanted human neural stem cells (hNSCs), from 2 distant embryonic stem cell lines (H9 and RC17), to express 1 of 4 prosurvival factors — Hif1a, Akt1, Bcl-2, or Bcl-xl — and studied how these modifications improve short- and long-term survival of transplanted hNSCs. All genetic modifications dramatically increased survival of the transplanted hNSCs. Importantly, 3 out of 4 modifications also enhanced the exit of hNSCs from the... (More)

Cell therapy raises hopes high for better treatment of brain disorders. However, the majority of transplanted cells often die soon after transplantation, and those that survive initially continue to die in the subacute phase, diminishing the impact of transplantations. In this study, we genetically modified transplanted human neural stem cells (hNSCs), from 2 distant embryonic stem cell lines (H9 and RC17), to express 1 of 4 prosurvival factors — Hif1a, Akt1, Bcl-2, or Bcl-xl — and studied how these modifications improve short- and long-term survival of transplanted hNSCs. All genetic modifications dramatically increased survival of the transplanted hNSCs. Importantly, 3 out of 4 modifications also enhanced the exit of hNSCs from the cell cycle, thus avoiding aberrant growth of the transplants. Bcl-xl expression provided the strongest protection of transplanted cells, reducing both immediate and delayed cell death, and stimulated hNSC differentiation toward neuronal and oligodendroglial lineages. By designing hNSCs with drug-controlled expression of Bcl-xl, we demonstrated that short-term expression of a prosurvival factor can ensure the long-term survival of transplanted cells. Importantly, transplantation of Bcl-xl–expressing hNSCs into mice suffering from stroke improved behavioral outcome and recovery of motor activity in mice.

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; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
JCI Insight
volume
5
issue
4
article number
e126268
publisher
The American Society for Clinical Investigation
external identifiers
  • scopus:85081667386
  • pmid:31999645
ISSN
2379-3708
DOI
10.1172/jci.insight.126268
language
English
LU publication?
yes
id
14305032-4abc-437b-a9ba-df0d1151f969
date added to LUP
2020-04-03 13:26:59
date last changed
2024-05-01 07:28:59
@article{14305032-4abc-437b-a9ba-df0d1151f969,
  abstract     = {{<p>Cell therapy raises hopes high for better treatment of brain disorders. However, the majority of transplanted cells often die soon after transplantation, and those that survive initially continue to die in the subacute phase, diminishing the impact of transplantations. In this study, we genetically modified transplanted human neural stem cells (hNSCs), from 2 distant embryonic stem cell lines (H9 and RC17), to express 1 of 4 prosurvival factors — Hif1a, Akt1, Bcl-2, or Bcl-xl — and studied how these modifications improve short- and long-term survival of transplanted hNSCs. All genetic modifications dramatically increased survival of the transplanted hNSCs. Importantly, 3 out of 4 modifications also enhanced the exit of hNSCs from the cell cycle, thus avoiding aberrant growth of the transplants. Bcl-xl expression provided the strongest protection of transplanted cells, reducing both immediate and delayed cell death, and stimulated hNSC differentiation toward neuronal and oligodendroglial lineages. By designing hNSCs with drug-controlled expression of Bcl-xl, we demonstrated that short-term expression of a prosurvival factor can ensure the long-term survival of transplanted cells. Importantly, transplantation of Bcl-xl–expressing hNSCs into mice suffering from stroke improved behavioral outcome and recovery of motor activity in mice.</p>}},
  author       = {{Korshunova, Irina and Rhein, Sina and García-González, Diego and Stölting, Ines and Pfisterer, Ulrich and Barta, Anna and Dmytriyeva, Oksana and Kirkeby, Agnete and Schwaninger, Markus and Khodosevich, Konstantin}},
  issn         = {{2379-3708}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{4}},
  publisher    = {{The American Society for Clinical Investigation}},
  series       = {{JCI Insight}},
  title        = {{Genetic modification increases the survival and the neuroregenerative properties of transplanted neural stem cells}},
  url          = {{http://dx.doi.org/10.1172/jci.insight.126268}},
  doi          = {{10.1172/jci.insight.126268}},
  volume       = {{5}},
  year         = {{2020}},
}