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Abstract
Stem cell therapies for neurodegenerative disorders require accurate delivery of the transplanted cells to the sites of damage. Numerous studies have established that fluid injections to the hippocampus can induce lesions in the dentate gyrus (DG) that lead to cell death within the upper blade. Using a mouse model of temporal lobe epilepsy, we previously observed that embryonic stem cell-derived neural progenitors (ESNPs) survive and differentiate within the granule cell layer after stereotaxic delivery to the DG, replacing the endogenous cells of the upper blade. To investigate the mechanisms for ESNP migration and repair in the DG, we examined the role of the chemokine CXCL12 in mice subjected to kainic acid-induced seizures. We now show that ESNPs transplanted into the DG show extensive migration through the upper blade, along the septotemporal axis of the hippocampus. Seizures upregulate CXCL12 and infusion of the CXCR4 antagonist AMD3100 by osmotic minipump attenuated ESNP migration. We also demonstrate that seizures promote the differentiation of transplanted ESNPs toward neuronal rather than astrocyte fates. These findings suggest that ESNPs transplanted into the adult rodent hippocampus migrate in response to cytokine-mediated signals.
Highlights
Stem cell-based treatments for neurodegenerative diseases and central nervous system (CNS) injuries are currently in the pipeline
To determine whether the dispersion was linked to neurodegeneration within the granule cell layer of the dentate gyrus (DG), we examined NeuN+ neurons in the GCL at different times after injections were made
The embryonic stem cell-derived neural progenitors (ESNPs) infiltrated the upper blade by 3 days after transplantation and by 4 weeks had filled in the sites in the GCL where endogenous dentate granule neurons (DGNs) underwent degeneration (Figure S2)
Summary
Stem cell-based treatments for neurodegenerative diseases and central nervous system (CNS) injuries are currently in the pipeline. Embryonic stem cell (ESC)-derived neural progenitors (ESNPs) are among the most promising candidate neural cell types under investigation for CNS repair because they retain the potential to proliferate and differentiate into multiple neuronal and glial subtypes following transplantation [1], with the specific outcome dependent upon local environmental cues [2,3]. As these cells differentiate, they form functional neurons capable of incorporating into the host brain [4]. A better understanding of the molecular mechanisms involved in migration and differentiation of ESNPs and their derivatives is essential for successful stem cell-based CNS therapy design
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