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SDF1 in the dorsal corticospinal tract promotes CXCR4+ cell migration after spinal cord injury.

Tysseling VM, Mithal D, Sahni V, Birch D, Jung H, Belmadani A, Miller RJ, Kessler JA - J Neuroinflammation (2011)

Bottom Line: In the uninjured spinal cord, SDF1 was expressed in the dorsal corticospinal tract (dCST) as well as the meninges, whereas CXCR4 was found only in ependymal cells surrounding the central canal.The non-ependymal CXCR4+ cells were found to be NG2+ and CD11b+ macrophages that presumably infiltrated through the broken blood-brain barrier.A second population of the CXCR4+ macrophages was present near the SDF1-expressing meningeal cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Northwestern University's Feinberg School of Medicine, Department of Neurology, Chicago, IL 60611, USA. vmtysseling@u.northwestern.edu

ABSTRACT

Background: Stromal cell-derived factor-1 (SDF1) and its major signaling receptor, CXCR4, were initially described in the immune system; however, they are also expressed in the nervous system, including the spinal cord. After spinal cord injury, the blood brain barrier is compromised, opening the way for chemokine signaling between these two systems. These experiments clarified prior contradictory findings on normal expression of SDF1 and CXCR4 as well as examined the resulting spinal cord responses resulting from this signaling.

Methods: These experiments examined the expression and function of SDF1 and CXCR4 in the normal and injured adult mouse spinal cord primarily using CXCR4-EGFP and SDF1-EGFP transgenic reporter mice.

Results: In the uninjured spinal cord, SDF1 was expressed in the dorsal corticospinal tract (dCST) as well as the meninges, whereas CXCR4 was found only in ependymal cells surrounding the central canal. After spinal cord injury (SCI), the pattern of SDF1 expression did not change rostral to the lesion but it disappeared from the degenerating dCST caudally. By contrast, CXCR4 expression changed dramatically after SCI. In addition to the CXCR4+ cells in the ependymal layer, numerous CXCR4+ cells appeared in the peripheral white matter and in the dorsal white matter localized between the dorsal corticospinal tract and the gray matter rostral to the lesion site. The non-ependymal CXCR4+ cells were found to be NG2+ and CD11b+ macrophages that presumably infiltrated through the broken blood-brain barrier. One population of macrophages appeared to be migrating towards the dCST that contains SDF1 rostral to the injury but not towards the caudal dCST in which SDF1 is no longer present. A second population of the CXCR4+ macrophages was present near the SDF1-expressing meningeal cells.

Conclusions: These observations suggest that attraction of CXCR4+ macrophages is part of a programmed response to injury and that modulation of the SDF1 signaling system may be important for regulating the inflammatory response after SCI.

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CXCR4-GFP cells in the general periphery and in the dorsal funiculus express markers of hematopoetic lineage and not neural lineage. At 5 weeks (a, d) and at 2 weeks (b-c, e-f), the putative migrating cell populations are positive for both CD11b and NG2 identifying them as presumptive macrophages. No CXCR4-GFP cells colocalized with either GFAP or Nestin. Scale bars: d: 50 μm. [red:CD11b(a-c), NG2(d-f), GFAP(g-i), Nestin(j-l), green:CXCR4-EGFP, blue:Hoechst].
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Figure 6: CXCR4-GFP cells in the general periphery and in the dorsal funiculus express markers of hematopoetic lineage and not neural lineage. At 5 weeks (a, d) and at 2 weeks (b-c, e-f), the putative migrating cell populations are positive for both CD11b and NG2 identifying them as presumptive macrophages. No CXCR4-GFP cells colocalized with either GFAP or Nestin. Scale bars: d: 50 μm. [red:CD11b(a-c), NG2(d-f), GFAP(g-i), Nestin(j-l), green:CXCR4-EGFP, blue:Hoechst].

Mentions: The number of different cell types in the ependymal layer of the spinal cord is unknown, and their functional phenotypes, especially with respect to their potential as stem/progenitor cells, remain unclear [28-33]. We used the CXCR4-EGFP reporter mouse to help identify specific subsets of cells in the ependymal layer. First we looked for CXCR4+ neural progenitors by co-staining for the neural markers, GFAP and Nestin. Nestin and GFAP both labeled cells in the ependyma and processes extending from the ependymal layer, but neither colabeled with CXCR4 (Figure 5). The CXCR4+ processes also did not colocalize with RC2 that is a marker for radial glial progenitors (data not shown). However Nestin+ fibers sometimes abutted CXCR4+ fibers indicating a close association (Figure 5f). We also looked for potential CXCR4+ progenitors that had migrated out toward the periphery, but we did not see any colocalization of GFAP+ or Nestin+ with the CXCR4+ peripheral cells. However, CXCR4 did colocalize with CD11b and NG2 suggesting that these cells are infiltrating macrophages (Figure 6). By contrast, the CXCR4+ ependymal cells were not positive for CD11b or NG2 (data not shown). These observations suggest that there are at least two distinct populations of CXCR4+ cells after SCI, ependymal cells and migrating macrophages.


SDF1 in the dorsal corticospinal tract promotes CXCR4+ cell migration after spinal cord injury.

Tysseling VM, Mithal D, Sahni V, Birch D, Jung H, Belmadani A, Miller RJ, Kessler JA - J Neuroinflammation (2011)

CXCR4-GFP cells in the general periphery and in the dorsal funiculus express markers of hematopoetic lineage and not neural lineage. At 5 weeks (a, d) and at 2 weeks (b-c, e-f), the putative migrating cell populations are positive for both CD11b and NG2 identifying them as presumptive macrophages. No CXCR4-GFP cells colocalized with either GFAP or Nestin. Scale bars: d: 50 μm. [red:CD11b(a-c), NG2(d-f), GFAP(g-i), Nestin(j-l), green:CXCR4-EGFP, blue:Hoechst].
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3050722&req=5

Figure 6: CXCR4-GFP cells in the general periphery and in the dorsal funiculus express markers of hematopoetic lineage and not neural lineage. At 5 weeks (a, d) and at 2 weeks (b-c, e-f), the putative migrating cell populations are positive for both CD11b and NG2 identifying them as presumptive macrophages. No CXCR4-GFP cells colocalized with either GFAP or Nestin. Scale bars: d: 50 μm. [red:CD11b(a-c), NG2(d-f), GFAP(g-i), Nestin(j-l), green:CXCR4-EGFP, blue:Hoechst].
Mentions: The number of different cell types in the ependymal layer of the spinal cord is unknown, and their functional phenotypes, especially with respect to their potential as stem/progenitor cells, remain unclear [28-33]. We used the CXCR4-EGFP reporter mouse to help identify specific subsets of cells in the ependymal layer. First we looked for CXCR4+ neural progenitors by co-staining for the neural markers, GFAP and Nestin. Nestin and GFAP both labeled cells in the ependyma and processes extending from the ependymal layer, but neither colabeled with CXCR4 (Figure 5). The CXCR4+ processes also did not colocalize with RC2 that is a marker for radial glial progenitors (data not shown). However Nestin+ fibers sometimes abutted CXCR4+ fibers indicating a close association (Figure 5f). We also looked for potential CXCR4+ progenitors that had migrated out toward the periphery, but we did not see any colocalization of GFAP+ or Nestin+ with the CXCR4+ peripheral cells. However, CXCR4 did colocalize with CD11b and NG2 suggesting that these cells are infiltrating macrophages (Figure 6). By contrast, the CXCR4+ ependymal cells were not positive for CD11b or NG2 (data not shown). These observations suggest that there are at least two distinct populations of CXCR4+ cells after SCI, ependymal cells and migrating macrophages.

Bottom Line: In the uninjured spinal cord, SDF1 was expressed in the dorsal corticospinal tract (dCST) as well as the meninges, whereas CXCR4 was found only in ependymal cells surrounding the central canal.The non-ependymal CXCR4+ cells were found to be NG2+ and CD11b+ macrophages that presumably infiltrated through the broken blood-brain barrier.A second population of the CXCR4+ macrophages was present near the SDF1-expressing meningeal cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Northwestern University's Feinberg School of Medicine, Department of Neurology, Chicago, IL 60611, USA. vmtysseling@u.northwestern.edu

ABSTRACT

Background: Stromal cell-derived factor-1 (SDF1) and its major signaling receptor, CXCR4, were initially described in the immune system; however, they are also expressed in the nervous system, including the spinal cord. After spinal cord injury, the blood brain barrier is compromised, opening the way for chemokine signaling between these two systems. These experiments clarified prior contradictory findings on normal expression of SDF1 and CXCR4 as well as examined the resulting spinal cord responses resulting from this signaling.

Methods: These experiments examined the expression and function of SDF1 and CXCR4 in the normal and injured adult mouse spinal cord primarily using CXCR4-EGFP and SDF1-EGFP transgenic reporter mice.

Results: In the uninjured spinal cord, SDF1 was expressed in the dorsal corticospinal tract (dCST) as well as the meninges, whereas CXCR4 was found only in ependymal cells surrounding the central canal. After spinal cord injury (SCI), the pattern of SDF1 expression did not change rostral to the lesion but it disappeared from the degenerating dCST caudally. By contrast, CXCR4 expression changed dramatically after SCI. In addition to the CXCR4+ cells in the ependymal layer, numerous CXCR4+ cells appeared in the peripheral white matter and in the dorsal white matter localized between the dorsal corticospinal tract and the gray matter rostral to the lesion site. The non-ependymal CXCR4+ cells were found to be NG2+ and CD11b+ macrophages that presumably infiltrated through the broken blood-brain barrier. One population of macrophages appeared to be migrating towards the dCST that contains SDF1 rostral to the injury but not towards the caudal dCST in which SDF1 is no longer present. A second population of the CXCR4+ macrophages was present near the SDF1-expressing meningeal cells.

Conclusions: These observations suggest that attraction of CXCR4+ macrophages is part of a programmed response to injury and that modulation of the SDF1 signaling system may be important for regulating the inflammatory response after SCI.

Show MeSH
Related in: MedlinePlus