Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1α/CXC chemokine receptor 4 pathway

Jaime Imitola, Khadir Raddassi, Kook In Park, Franz Josef Mueller, Marta Nieto, Yang D. Teng, Dan Frenkel, Jianxue Li, Richard L. Sidman, Christopher A. Walsh, Evan Y. Snyder, Samia J. Khoury

Research output: Contribution to journalArticlepeer-review

Abstract

Migration toward pathology is the first critical step in stem cell engagement during regeneration. Neural stem cells (NSCs) migrate through the parenchyma along nonstereotypical routes in a precise directed manner across great distances to injury sites in the CNS, where they might engage niches harboring local transiently expressed reparative signals. The molecular mechanisms for NSC mobilization have not been identified. Because NSCs seem to home similarly to pathologic sites derived from disparate etiologies, we hypothesized that the inflammatory response itself, a characteristic common to all, guides the behavior of potentially reparative cells. As proof of concept, we show that human NSCs migrate in vivo (including from the contralateral hemisphere) toward an infarcted area (a representative CNS injury), where local astrocytes and endothelium up-regulate the inflammatory chemoattractant stromal cell-derived factor 1α (SDF-1α). NSCs express CXC chemokine receptor 4 (CXCR4), the cognate receptor for SDF-1α. Exposure of SDF-1α to quiescent NSCs enhances proliferation, promotes chain migration and transmigration, and activates intracellular molecular pathways mediating engagement. CXCR4 blockade abrogates their pathology-directed chain migration, a developmentally relevant mode of tangential migration that, if recapitulated, could explain homing along nonstereotypical paths. Our data implicate SDF-1α/CXCR4, representative of the inflammatory milieu characterizing many pathologies, as a pathway that activates NSC molecular programs during injury and suggest that inflammation may be viewed not simply as playing an adverse role but also as providing stimuli that recruit cells with a regenerative homeostasis-promoting capacity. CXCR4 expression within germinal zones suggests that NSC homing after injury and migration during development may invoke similar mechanisms.

Original languageEnglish
Pages (from-to)18117-18122
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number52
DOIs
StatePublished - 28 Dec 2004
Externally publishedYes

Keywords

  • Homing chain migration stroke
  • Human stem cells
  • Hypoxia-ischemia

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