title: CXCL12-mediated guidance of migrating embryonic stem cell-derived neural progenitors transplanted into the hippocampus.
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.
authors.affiliation: Department of Biology, Wesleyan University, Middletown, Connecticut, United States of America. nathaniel.hartman@yale.edu
authors.forename: Nathaniel W
authors.initials: NW
authors.lastname: Hartman
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Carpentino
authors.forename: Kristi
authors.initials: K
authors.lastname: LaMonica
authors.forename: Danielle E
authors.initials: DE
authors.lastname: Mor
authors.forename: Janice R
authors.initials: JR
authors.lastname: Naegele
authors.forename: Laura
authors.initials: L
authors.lastname: Grabel
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D002470:Cell Survival; D054377:Chemokine CXCL12 / Q000378:metabolism*; D018891:Dentate Gyrus; D053595:Embryonic Stem Cells / Q000166:cytology*; D004833:Epilepsy, Temporal Lobe / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D012640:Seizures / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse