cxcl12-mediated guidance of migrating embryonic stem cell-derived neural progenitors transplanted into the hippocampuscxcl12-mediated指导移植胚胎干细胞神经祖细胞移植到海马体.pdf

CXCL12-Mediated Guidance of Migrating Embryonic Stem Cell-Derived Neural Progenitors Transplanted into the Hippocampus 1 ¤a 1¤b 1¤c 1 Nathaniel W. Hartman * , Joseph E. Carpentino , Kristi LaMonica , Danielle E. Mor , Janice R. Naegele1,2, Laura Grabel 1 1 Department of Biology, Wesleyan University, Middletown, Connecticut, United States of America, 2 Program in Neuroscience and Behavior, Wesleyan University, Middletown, Connecticut, United States of America 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