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Ectopic niche formation by grafted neural stem/progenitors in the ischemic cerebral cortex

English title Ectopic niche formation by grafted neural stem/progenitors in the ischemic cerebral cortex
Applicant Kiss Jozsef Zoltan
Number 128015
Funding scheme SCOPES
Research institution Dépt des Neurosciences Fondamentales Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Neurophysiology and Brain Research
Start/End 01.01.2010 - 31.12.2012
Approved amount 100'000.00
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Keywords (5)

neonatal ischemia; stem/progenitor cells; transplantation; cortex; brain repair

Lay Summary (English)

Lead
Lay summary
The postnatal cerebral cortex has a very limited ability to regenerate neurons after brain insults. This is related in part, to the lack of specific stem cell niches that could be activated by injury-derived signals to provide new neurons for repair. To overcome this limitation, the manipulation and transplantation of neural stem/progenitor cells (NPCs) have developed into a key strategy for neuronal replacement. A fundamental challenge is to find ways to construct ectopic neurogenic niches using grafted progenitor cells that would provide new neurons for repair.In a previous study, we developed a novel system to overexpress FGF-2 in transplanted NPCs and showed that this manipulation significantly enhanced the capacity of these cells to generate a pool of progenitors and immature neurons in the ischemic cortex. A closer look revealed that FGF-2-transduced NPCs had the distinct tendency to associate with the vas-culature and establish multiple proliferative clusters in the perivascular environment. Strik-ingly, the vascular clusters of progenitor cells can generate immature neurons in an ischemic environment, raising prospect for the formation of ectopic neurogenetic niches for repair.Here, we propose to investigate the architecture of these specialized anatomical entities in the cerebral cortex. This is a key issue if we want develop new strategies to restore tran-siently the neurogenetic potential of injured brain tissue and to generate a robust source of immature neurons for brain repair. We will determine the cell composition and organization of the perivascular cluster of grafted cells and investigate its relationship with the host vas-cular structures. For this purpose we will use various morphological and functional tech-niques including confocal time-lapse imaging and electron microscopy. We will focus on a recently established neonatal ischemia model of the somatosensory barrel cortex that allows for exploring both stem/progenitor cell-based structural repair and functional recovery. The main strategy will involve the use of lentivirus-based technologies to genetically engineer stem/progenitor cells to express FGF-2 before transplantation thereby improving their ca-pacity to integrate into host circuitries. Repair and functional recovery following brain damage represents a major challenge for cur-rent clinical and basic research. The proposed studies should provide new insight into the interactions of grafted FGF-2 secreting NPCs and the vascular environment. Positive results of this project could open new possibilities to induce ectopic neurogenesis and to generate a robust source of immature neurons for brain repair.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
American Neuroscience Meeting Washington DC 10.02.2011 Washington DC USA


Associated projects

Number Title Start Funding scheme
124101 From cortex to classroom: enhancing brain development for premature infants 01.10.2009 SPUM
116613 Potential of FGF2-transduced neural progenitors for generating vascular niches 01.04.2007 Project funding (Div. I-III)

Abstract

The postnatal cerebral cortex has a very limited ability to regenerate neurons after brain insults. This is related in part, to the lack of specific stem cell niches that could be activated by injury-derived signals to provide new neurons for repair. To over-come this limitation, the manipulation and transplantation of neural stem/progenitor cells (NPCs) have developed into a key strategy for neuronal replacement. A fundamental challenge is to find ways to construct ectopic neurogenic niches using grafted progenitor cells that would provide new neurons for repair.In a previous study, we developed a novel system to overexpress FGF-2 in trans-planted NPCs and showed that this ma-nipulation significantly enhanced the capacity of these cells to generate a pool of progenitors and immature neurons in the ischemic cortex. A closer look revealed that FGF-2-transduced NPCs have the distinct tendency to associate with the vasculature and establish multiple proliferative clusters in the perivascular environment. Strikingly, the vascular clusters of progenitor cells can generate immature neurons in an ischemic environment, raising prospect for the for-mation of ectopic neurogenetic niches for repair.Here, we propose to investigate the architecture of these specialized anatomical entities in the cerebral cortex. This is a key issue if we want develop new strategies to restore transiently the neurogenetic poten-tial of injured brain tissue and to generate a robust source of immature neurons for brain repair. We will determine the cell composition and organization of the peri-vascular cluster of grafted cells and inves-tigate the its relationship with the host vascular structures. For this purpose we will use various morphological and func-tional techniques including confocal time-lapse imaging and electron microscopy. We will focus on a recently established neona-tal ischemia model of the somatosensory barrel cortex that allows for exploring both stem/progenitor cell-based structural re-pair and functional recovery. The main strategy will involve the use of lentivirus-based technologies to genetically engineer stem/progenitor cells to express FGF-2 before transplantation thereby improving their capacity to integrate into host circuitries. Repair and functional recovery following brain damage represents a major challenge for current clinical and basic research. The proposed studies should provide new in-sight into the interactions of grafted FGF-2 secreting NPCs and the vascular environ-ment. Positive results of this project could open new possibilities to induce ectopic neurogenesis and to generate a robust source of immature neurons for brain repair.
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