Abstract
After cerebral ischemia, the ratio between astroglial cells and neurons in the neurovascular unit is disrupted in the perilesional area. We hypothesized that restoring the balance within the neurovascular unit may lead to an improved neurorestoration after focal ischemia. Recently, an innovative technology has been invented to efficiently convert proliferating astroglial cells into neurons in the injured young brain. However, the conversion efficacy of this technology has not been explored in the post-stroke brains of the aged rodents. To this end, we used a retroviral delivery system encoding the transcription factor Ngn2 alone or in combination with the antiapoptotic factor Bcl-2 to target proliferating astrocytes in the neocortex of young and aged mice after cerebral ischemia. Successful direct in vivo reprogramming of reactive glia into neuroblasts and mature neurons was assessed by cellular phenotyping. We found that the conversion efficacy of proliferating astrocytes into neurons after cerebral ischemia in young and aged mice is disappointingly low, most likely because the therapeutic vectors carrying the conversion gene are engulfed by phagocytes shortly after intracortical administration. We conclude that other viral vectors and combinations of transcription factors should be employed to improve the efficacy of glia-to-neuron conversion after stroke in young and aged rodents.
Highlights
Ischemic stroke is an acute disease that often results in severe long-term consequences such as physical disability, depression, cognitive decline or even dementia.Brain infarction has a strong age dependency both in men and women
Of the previously tested transcription factors used to convert astrocyte into neurons, we chose Neurog2, as it converts astrocytes into glutamatergic neurons after stab injury in vivo (Gascón et al, 2016)
Previous reports indicated that following a stab injury to the brain, most of the infected cells the retrovirus carrying the Neurog-2-IRES-RFP sequence were GFAP+ astrocytes
Summary
Ischemic stroke is an acute disease that often results in severe long-term consequences such as physical disability, depression, cognitive decline or even dementia.Brain infarction has a strong age dependency both in men and women. Infarct development is agedependent, suggesting that old age may predict outcome in acute stroke (Ay et al, 2005). The majority of the drugs tested showed safety and therapeutic efficacy in young animal models. Most of the drugs tested in young animals failed to show efficacy when tested in clinical trials. One major reason for this translational failure may be the use of young animals instead of aged subjects in stroke research (Popa-Wagner et al, 2014; Hermann et al, 2019). In the last several years there has been an increased awareness of this shortcoming paralleled by an increased number of studies done in aged rodents as recommended by the Stroke Progress Review Group (Fisher et al, 2009)
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