Chemokine receptor expression by neural progenitor cells in neurogenic regions of mouse brain

Abstract

We previously demonstrated that chemokine receptors are expressed by neural progenitors grown as cultured neurospheres. To examine the significance of these findings for neural progenitor function in vivo, we investigated whether chemokine receptors were expressed by cells having the characteristics of neural progenitors in neurogenic regions of the postnatal brain. Using in situ hybridization we demonstrated the expression of CCR1, CCR2, CCR5, CXCR3, and CXCR4 chemokine receptors by cells in the dentate gyrus (DG), subventricular zone of the lateral ventricle, and olfactory bulb. The pattern of expression for all of these receptors was similar, including regions where neural progenitors normally reside. In addition, we attempted to colocalize chemokine receptors with markers for neural progenitors. In order to do this we used nestin-EGFP and TLXLacZ transgenic mice, as well as labeling for Ki67, a marker for dividing cells. In all three areas of the brain we demonstrated colocalization of chemokine receptors with these three markers in populations of cells. Expression of chemokine receptors by neural progenitors was further confirmed using CXCR4-EGFP BAC transgenic mice. Expression of CXCR4 in the DG included cells that expressed nestin and GFAP as well as cells that appeared to be immature granule neurons expressing PSA-NCAM, calretinin, and Prox-1. CXCR4-expressing cells in the DG were found in close proximity to immature granule neurons that expressed the chemokine SDF-1/CXCL12. Cells expressing CXCR4 frequently coexpressed CCR2 receptors. These data support the hypothesis that chemokine receptors are important in regulating the migration of progenitor cells in postnatal brain. Indexing terms stem cells; development; chemotaxis; brain repairDuring embryogenesis, neural stem/progenitor cells must migrate long distances from the germinal epithelia where they are born to their final destinations (Hatten, 1999;Alvarez-Buylla et al., 2001). During migration, stem cells may continue to divide and also become restricted in terms of their ultimate phenotypes. Thus, the timing of neuro-and gliogenesis in the developing embryo is precisely controlled (Rallu et al., 2002). The factors that determine the migration, proliferation, and differentiation of embryonic stem cells have been widely investigated and numerous factors have been shown to influence these processes (Lindvall et al., 2004). One group of molecules that has recently been shown to control progenitor cell migration in the nervous system are the chemokines (CHEMO-tactic cytoKINES) (Tran and © NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript Miller, 2003). The chemokines are a family of small secreted proteins that are known to be important regulators of leukocyte trafficking under both normal conditions and during inflammatory responses (Moser et al., 2004). Furthermore, it is now known that chemokine signaling has an important role to play in the developing embryo. Deletion of the genes for the CXCR4 chemokine receptor or f...

Mesenchymal stem cells increase hippocampal neurogenesis and counteract depressive-like behavior

“…Similarly, the observed reduction in the chemokine stromal cell-derived factor 1 and its receptor CXCR4 (Figure 4b) can be explained by the reduction in GFAPexpressing glial cells, as they too express these chemokines. 51,52 In contradistinction to this reduction in GFAP expression, DCX mRNA expression was significantly increased in MSC-treated hippocampi compared with controls (Figure 4b), indicating an increased number of newly formed neurons in the hippocampus. Similarly, the mRNA of FGF-2, a potent modulator of hippocampal neurogenesis, 53,54 increased significantly in MSCtreated hippocampi compared with controls ( Figure 4b).…”

CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis

“…Mice were anesthetized by ketamine and xylazine and perfused transcardially with PBS followed by 4% (wt/vol) paraformaldehyde in PBS (40). The spinal column was dissected and postfixed in 4% paraformaldehyde overnight followed by cryopreservation in 30% (wt/vol) sucrose in PBS.…”

“…Isotype-specific secondary AlexaFluor-488 or AlexaFluor-633 antibodies (Invitrogen) were used. All captured images were exported to Adobe Photoshop CS 5.1 (Adobe) and adjustments were made to the brightness and contrast to reflect true colors (40).…”

CXCR4 signaling in the regulation of stem cell migration and development

“…These include deficits in β-lymphopoiesis and myelopoiesis (Nagasawa, 2007;Nagasawa et al, 1996;Nie et al, 2004;Zou et al, 1998), cardiogenesis (Miao et al, 2007;Nagasawa et al, 1996;Zou et al, 1998), angiogenesis (Tachibana et al, 1998;Zou et al, 1998), neurogenesis (Lu et al, 2002;Stumm et al, 2003;Tran et al, 2007) and germ cell migration and development (Dumstrei et al, 2004). Basically, all of these phenotypes can be explained by the observation that CXCR4 signaling is important in regulating the migration of different types of stem/ progenitor cells.…”

“…One may therefore ask whether there is a role for chemokine signaling in the development of adult neural stem cells under these various circumstances? It is certainly clear that neural stem cells located in the SVZ and DG express chemokine receptors including high levels of CXCR4 receptors (Berger et al, 2007;Tran et al, 2007). If we consider the DG as an example, CXCR4 is expressed by the most immature radial glia like stem cells as well as their progeny including rapidly amplifying cells, neuroblasts and immature granule neurons.…”