title: Fractalkine promotes chemotaxis of bone marrow-derived mesenchymal stem cells towards ischemic brain lesions through Jak2 signaling and cytoskeletal reorganization.
abstract: The fractalkine (FKN)-CX3CR1 (FKN receptor) axis reportedly plays an important role in the progression of many neural pathologies. However, its role in the recruitment of bone marrow-derived progenitor cells for neurogenesis remains elusive. The chemokine-based mechanism underlying the migration of bone marrow-derived mesenchymal stem cells (BMSCs) was investigated in a double-chamber transmigration model with recombinant FKN and endogenous FKN extract, and the results confirmed the involvement of FKN in migration. This chemotactic response was CX3CR1-dependent and FKN-sensitive. Western blotting, immunoprecipitation and transmigration assays revealed that the Janus kinase (Jak)2-signal transducer and activator of transcription (Stat)5α-extracellular signal-related kinase (ERK)1/2 pathway was activated by FKN. Confocal laser scanning microscopy was used to demonstrate cytoskeletal reorganization caused by remodeling of the surface receptor integrin α5β1, intracellular phosphorylation of Fak and Pax, and upregulation of intercellular adhesion molecule-1 during BMSC migration. Moreover, significant inhibition of signaling and migration was detected after treatment of cells with Jak2-interfering RNA or the antagonist AG490. In addition, the results of a fluorescence immunohistochemical analysis of an in vivo chemotactic model, developed via transplantation of BMSCs into transient middle cerebral artery-occluded rats, were consistent with the in vitro results. These findings suggest that FKN activates Jak2-Stat5α-ERK1/2 signaling through CX3CR1, thereby triggering integrin-dependent machinery reorganization to allow chemotactic migration of BMSCs towards an ischemic cerebral lesion.
authors.affiliation: Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Zheng
authors.forename: Zhujuan
authors.initials: Z
authors.lastname: Zhou
authors.forename: Huadong
authors.initials: H
authors.lastname: Zhou
authors.forename: Yanjiang
authors.initials: Y
authors.lastname: Wang
authors.forename: Zili
authors.initials: Z
authors.lastname: Gong
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology; D000073883:CX3C Chemokine Receptor 1; D002465:Cell Movement; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D054428:Chemokine CX3CL1 / Q000235:genetics / Q000378:metabolism*; D002633:Chemotaxis; D003599:Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure*; D057809:HEK293 Cells; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D017208:Rats, Wistar; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; C095235:CX3CR1 protein, human; C516305:CX3CR1 protein, rat; D054428:Chemokine CX3CL1; C515540:Cx3cl1 protein, rat; D019707:Receptors, Chemokine; D050799:STAT5 Transcription Factor; C494094:Stat5a protein, rat; C507927:Jak2 protein, rat; D053614:Janus Kinase 2
keywords: Jak2; bone marrow-derived mesenchymal stem cells; chemotaxis; cytoskeleton; fractalkine