Notch Signaling In Senescent Schwann Cells: A Target For Improving Nerve Regeneration
Gwendolyn M. Hoben, MD, PhD1, Xueping Ee, MD1, Lauren Prange, BS1, Daniel Hunter, RA1, Amy M. Moore, MD1, Sheila Stewart, PhD2, Susan E. Mackinnon, MD1, Matthew D. Wood, PhD1.
1Washington University School of Medicine, Saint Louis, MO, USA, 2Washington University, Saint Louis, MO, USA.
PURPOSE: Nerve gaps repaired with long nerve grafts (autografts or allografts) are associated with poor axonal regeneration and the accumulation of senescent Schwann cells (SenSCs). Recent data shows SenSCs upregulate expression of Notch ligands. We hypothesize that Notch signaling in neurons due to SenSCs reduces axonal regeneration.
METHODS: SCs from rat sciatic nerves were treated with aphidicolin (damages DNA) to induce senescence. In vivo, these SenSCs (compared to normal SCs as a control) were implanted in a rat sciatic nerve transection using a 5mm conduit. After 4 weeks, axonal regeneration was assessed using histomorphometry. The dorsal root ganglia (DRG) from the afflicted nerve were explanted and examined for Notch receptor activation. To further assess the role of Notch ligands, rat DRG neurons were co-cultured with SCs and SenSCs and maximal neurite length was measured over time. DAPT, a gamma-secretase inhibitor which inhibits activation of Notch receptors, was added to the media and compared to untreated cultures.
RESULTS: In vivo, axonal regeneration decreased due to SenSCs concomitant with activation of Notch receptors in DRG neurons. In the presence of cultured SenSCs, neurite extension was decreased 28-40% compared to neurons co-cultured with SCs. In the presence of DAPT, neurite extension increased 13-21% compared to untreated neuron co-cultures with SenSCs.
CONCLUSION: These data suggest SenSCs activate Notch signaling in neurons causing decreased axonal extension. Treatment with a Notch inhibitor was able to partially rescue neurite extension. Inhibition of Notch signaling may improve nerve regeneration in SenSC-rich environments, such as long nerve grafts.
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