Macrophage-Induced Blood Vessels Guide Schwann Cell-Mediated Regeneration of Peripheral Nerves.
The peripheral nervous system has remarkable regenerative capacities in that it can repair a fully cut nerve. This requires Schwann cells to migrate collectively to guide regrowing axons across a 'bridge' of new tissue, which forms to reconnect a severed nerve. Here we show that blood vessels direct the migrating cords of Schwann cells. This multicellular process is initiated by hypoxia, selectively sensed by macrophages within the bridge, which via VEGF-A secretion induce a polarized vasculature that relieves the hypoxia. Schwann cells then use the blood vessels as "tracks" to cross the bridge taking regrowing axons with them. 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.
MRC Laboratory for Molecular Cell Biology, UCL, Gower Street, London WC1E 6BT, UK.
Anne-Laure
AL
Cattin
MRC Laboratory for Molecular Cell Biology, UCL, Gower Street, London WC1E 6BT, UK.
Jemima J
JJ
Burden
MRC Laboratory for Molecular Cell Biology, UCL, Gower Street, London WC1E 6BT, UK.
Lucie
L
Van Emmenis
Department of Cell Biology, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
Francesca E
FE
Mackenzie
MRC Laboratory for Molecular Cell Biology, UCL, Gower Street, London WC1E 6BT, UK.
Julian J A
JJ
Hoving
MRC Laboratory for Molecular Cell Biology, UCL, Gower Street, London WC1E 6BT, UK.
Noelia
N
Garcia Calavia
UCL Cancer Institute, UCL, 72 Huntley Street, London WC1E 6DD, UK.
Yanping
Y
Guo
MRC Laboratory for Molecular Cell Biology, UCL, Gower Street, London WC1E 6BT, UK.
Maeve
M
McLaughlin
MRC Laboratory for Molecular Cell Biology, UCL, Gower Street, London WC1E 6BT, UK.
Laura H
LH
Rosenberg
MRC Laboratory for Molecular Cell Biology, UCL, Gower Street, London WC1E 6BT, UK.
Victor
V
Quereda
MRC Laboratory for Molecular Cell Biology, UCL, Gower Street, London WC1E 6BT, UK.
Denisa
D
Jamecna
MRC Laboratory for Molecular Cell Biology, UCL, Gower Street, London WC1E 6BT, UK.
Ilaria
I
Napoli
MRC Laboratory for Molecular Cell Biology, UCL, Gower Street, London WC1E 6BT, UK.
Simona
S
Parrinello
UCL Cancer Institute, UCL, 72 Huntley Street, London WC1E 6DD, UK.
Tariq
T
Enver
Department of Cell Biology, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
Christiana
C
Ruhrberg
MRC Laboratory for Molecular Cell Biology, UCL, Gower Street, London WC1E 6BT, UK; UCL Cancer Institute, UCL, 72 Huntley Street, London WC1E 6DD, UK. Electronic address: alison.lloyd@ucl.ac.uk.
Alison C
AC
Lloyd
D000818:Animals; D001369:Axons / Q000378:metabolism; D001808:Blood Vessels / Q000378:metabolism*; D015687:Cell Hypoxia; D042783:Endothelial Cells / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic; D010525:Peripheral Nerves / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration; D012583:Schwann Cells / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse