Macrophage-Induced Blood Vessels Guide Schwann Cell-Mediated Regeneration of Peripheral Nerves.
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.
Affiliation: MRC Laboratory for Molecular Cell Biology, UCL, Gower Street, London WC1E 6BT, UK.Show MeSH
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Mentions: New blood vessels normally form in response to decreased oxygen levels (hypoxia) within a tissue. Upon hypoxia, the transcription factor HIF-1α is stabilized and initiates a transcriptional response that induces angiogenesis by upregulating pro-angiogenic factors such as VEGF (Krock et al., 2011; Pugh and Ratcliffe, 2003). To test whether the nerve bridge was hypoxic, we injected rats with hypoxyprobe-1 (pimonidazole hydrochloride) that forms immunofluorescent detectable protein adducts in hypoxic conditions (pO2 < 10 mm Hg) (Young and Möller, 2010). Immunostaining of day 2 nerve bridges revealed the presence of large numbers of hypoxic cells prior to its vascularization (Figures 5A and S5A). Hypoxic cells were found only in the bridge and at the tips of both the distal and proximal stumps but not further along the stumps or in the uncut nerve (Figure S5B). The proportion of hypoxic cells decreased substantially by day 3, when the bridge had become vascularized (Figures 5A and S5A), consistent with the new blood vessels resolving the hypoxic environment of this new tissue.
Affiliation: MRC Laboratory for Molecular Cell Biology, UCL, Gower Street, London WC1E 6BT, UK.