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 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.
Highlights
Cell therapy represents a promising approach to treating brain diseases
We demonstrated that genetically modified human neural stem cells (hNSCs) were better protected from the hostile environment of the infarct zone than naive cells, allowing genetically modified cells to have a stronger effect on recovery from injury in neurological disorders
Poor survival of transplanted cells in brain transplantations decreases the efficacy of cell therapy and requires large numbers of transplanted cells to be generated
Summary
Neural stem cells (NSCs) or precursor cells are usually transplanted at the site of injury to restore function in damaged brain tissue. Such transplantations have provided some positive effects in several animal models of brain diseases, they are accompanied by a high death rate of transplanted cells The bulk of transplanted cells often die during the first phase, and the majority of initially surviving cells die progressively during the following weeks or months [3,4,5,6]. In other cases, when undifferentiated or partially differentiated stem cells of embryonic or pluripotent stem cell origin are transplanted, it is difficult to evaluate cell survival because of the high proliferation rate of transplanted cells. It is important to increase survival of transplanted cells without affecting their proliferation
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