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Macrophage-Induced Blood Vessels Guide Schwann Cell-Mediated Regeneration of Peripheral Nerves.

Cattin AL, Burden JJ, Van Emmenis L, Mackenzie FE, Hoving JJ, Garcia Calavia N, Guo Y, McLaughlin M, Rosenberg LH, Quereda V, Jamecna D, Napoli I, Parrinello S, Enver T, Ruhrberg C, Lloyd AC - Cell (2015)

Bottom Line: Here we show that blood vessels direct the migrating cords of Schwann cells.Importantly, disrupting the organization of the newly formed blood vessels in vivo, either by inhibiting the angiogenic signal or by re-orienting them, compromises Schwann cell directionality resulting in defective nerve repair.This study provides important insights into how the choreography of multiple cell-types is required for the regeneration of an adult tissue.

View Article: PubMed Central - PubMed

Affiliation: MRC Laboratory for Molecular Cell Biology, UCL, Gower Street, London WC1E 6BT, UK.

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SCs Migrate along Endothelial Tubules In Vitro(A) Representative time-lapse microscopy images showing a GFP-positive rat SC migrating along a tubule of HUVECs within a 3D fibrin gel (Movie S3). Scale bar, 40 μm. White arrowheads indicate the cell body of the SC.(B) Images from Movie S4 of a tilted 3D view of a GFP-positive SC (green) interacting with an EC tubule (red). Scale bar, 10 μm.(C) Top: a representative EM image of a cross-section of an EC tubule in contact with a GFP-positive SC within a fibrin gel. Scale bar, 10 μm. Middle: a higher magnification view of the SC/EC contact (black arrowhead). Bottom: a higher magnification view of the EC/EC contact (white arrowhead). Scale bar, 1 μm.(D) Snapshots of Movie S5, showing the amoeboid-like mode of migration observed by the SCs in 3D. White arrowheads and arrows show the leading protrusion and the rear of the cell respectively. Scale bar, 50 μm.See also Figure S4.
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fig4: SCs Migrate along Endothelial Tubules In Vitro(A) Representative time-lapse microscopy images showing a GFP-positive rat SC migrating along a tubule of HUVECs within a 3D fibrin gel (Movie S3). Scale bar, 40 μm. White arrowheads indicate the cell body of the SC.(B) Images from Movie S4 of a tilted 3D view of a GFP-positive SC (green) interacting with an EC tubule (red). Scale bar, 10 μm.(C) Top: a representative EM image of a cross-section of an EC tubule in contact with a GFP-positive SC within a fibrin gel. Scale bar, 10 μm. Middle: a higher magnification view of the SC/EC contact (black arrowhead). Bottom: a higher magnification view of the EC/EC contact (white arrowhead). Scale bar, 1 μm.(D) Snapshots of Movie S5, showing the amoeboid-like mode of migration observed by the SCs in 3D. White arrowheads and arrows show the leading protrusion and the rear of the cell respectively. Scale bar, 50 μm.See also Figure S4.

Mentions: To test whether SCs could interact directly with blood vessels in a simplified system, we co-cultured GFP-positive rat SCs with human umbilical vein endothelial cells (HUVECs), which had been coated onto beads and then placed into a fibrin matrix to form capillary-like structures (Nakatsu et al., 2003). Time-lapse microscopy showed that the vast majority of SCs interacted with the endothelial cell tubules and migrated along them (Figures 4A and S4A; Movie S3). Importantly, confocal microscopy images confirmed that the migrating SCs made direct physical contacts with the ECs as observed in vivo (Figure S4B). A small proportion of the SCs remained within the matrix (<15%) (Figure S4A), yet while these cells were able to form protrusions they were unable to migrate efficiently (Movie S3). In contrast, and consistent with other studies (Hakkinen et al., 2011), we found that fibroblasts, when added to the matrix, did not interact specifically with the tubules but instead spread and migrated within the matrix (Figure S4C). We confirmed that SCs directly migrated along blood vessels by generating tubules of HUVECs in a second matrix, Matrigel and found that SCs migrated efficiently along them (Movie S3). This demonstrates that SCs, unlike fibroblasts, are unable to migrate efficiently within a 3D matrix unless they associate with a scaffold of EC tubules.


Macrophage-Induced Blood Vessels Guide Schwann Cell-Mediated Regeneration of Peripheral Nerves.

Cattin AL, Burden JJ, Van Emmenis L, Mackenzie FE, Hoving JJ, Garcia Calavia N, Guo Y, McLaughlin M, Rosenberg LH, Quereda V, Jamecna D, Napoli I, Parrinello S, Enver T, Ruhrberg C, Lloyd AC - Cell (2015)

SCs Migrate along Endothelial Tubules In Vitro(A) Representative time-lapse microscopy images showing a GFP-positive rat SC migrating along a tubule of HUVECs within a 3D fibrin gel (Movie S3). Scale bar, 40 μm. White arrowheads indicate the cell body of the SC.(B) Images from Movie S4 of a tilted 3D view of a GFP-positive SC (green) interacting with an EC tubule (red). Scale bar, 10 μm.(C) Top: a representative EM image of a cross-section of an EC tubule in contact with a GFP-positive SC within a fibrin gel. Scale bar, 10 μm. Middle: a higher magnification view of the SC/EC contact (black arrowhead). Bottom: a higher magnification view of the EC/EC contact (white arrowhead). Scale bar, 1 μm.(D) Snapshots of Movie S5, showing the amoeboid-like mode of migration observed by the SCs in 3D. White arrowheads and arrows show the leading protrusion and the rear of the cell respectively. Scale bar, 50 μm.See also Figure S4.
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fig4: SCs Migrate along Endothelial Tubules In Vitro(A) Representative time-lapse microscopy images showing a GFP-positive rat SC migrating along a tubule of HUVECs within a 3D fibrin gel (Movie S3). Scale bar, 40 μm. White arrowheads indicate the cell body of the SC.(B) Images from Movie S4 of a tilted 3D view of a GFP-positive SC (green) interacting with an EC tubule (red). Scale bar, 10 μm.(C) Top: a representative EM image of a cross-section of an EC tubule in contact with a GFP-positive SC within a fibrin gel. Scale bar, 10 μm. Middle: a higher magnification view of the SC/EC contact (black arrowhead). Bottom: a higher magnification view of the EC/EC contact (white arrowhead). Scale bar, 1 μm.(D) Snapshots of Movie S5, showing the amoeboid-like mode of migration observed by the SCs in 3D. White arrowheads and arrows show the leading protrusion and the rear of the cell respectively. Scale bar, 50 μm.See also Figure S4.
Mentions: To test whether SCs could interact directly with blood vessels in a simplified system, we co-cultured GFP-positive rat SCs with human umbilical vein endothelial cells (HUVECs), which had been coated onto beads and then placed into a fibrin matrix to form capillary-like structures (Nakatsu et al., 2003). Time-lapse microscopy showed that the vast majority of SCs interacted with the endothelial cell tubules and migrated along them (Figures 4A and S4A; Movie S3). Importantly, confocal microscopy images confirmed that the migrating SCs made direct physical contacts with the ECs as observed in vivo (Figure S4B). A small proportion of the SCs remained within the matrix (<15%) (Figure S4A), yet while these cells were able to form protrusions they were unable to migrate efficiently (Movie S3). In contrast, and consistent with other studies (Hakkinen et al., 2011), we found that fibroblasts, when added to the matrix, did not interact specifically with the tubules but instead spread and migrated within the matrix (Figure S4C). We confirmed that SCs directly migrated along blood vessels by generating tubules of HUVECs in a second matrix, Matrigel and found that SCs migrated efficiently along them (Movie S3). This demonstrates that SCs, unlike fibroblasts, are unable to migrate efficiently within a 3D matrix unless they associate with a scaffold of EC tubules.

Bottom Line: Here we show that blood vessels direct the migrating cords of Schwann cells.Importantly, disrupting the organization of the newly formed blood vessels in vivo, either by inhibiting the angiogenic signal or by re-orienting them, compromises Schwann cell directionality resulting in defective nerve repair.This study provides important insights into how the choreography of multiple cell-types is required for the regeneration of an adult tissue.

View Article: PubMed Central - PubMed

Affiliation: MRC Laboratory for Molecular Cell Biology, UCL, Gower Street, London WC1E 6BT, UK.

Show MeSH
Related in: MedlinePlus