Single-cell transcriptomic atlas reveals temporal dynamics driving chronic peripheral nerve degeneration.

Area of Science:

• Neuroscience
• Regenerative Medicine
• Molecular Biology

Background:

• Peripheral nerve injuries often lead to permanent functional loss due to chronic denervation.
• Current nerve repair strategies are limited by an incomplete understanding of the distal nerve microenvironment's cellular dynamics.

Purpose of the Study:

• To create a detailed transcriptomic atlas of the distal sciatic nerve stump following injury in rats.
• To investigate the dynamic cellular changes and communication within the nerve microenvironment over time.

Main Methods:

• Longitudinal single-nucleus RNA sequencing of rat sciatic nerve stumps at five time points (0, 14, 28, 60, 90 days post-injury).
• Analysis of cell state transitions, proliferation, apoptosis, and cell-cell communication.

Main Results:

• Schwann cells transition to a repair phenotype by 14 days post-injury, supporting regeneration until 28 days.
• Beyond 28 days, chronic denervation causes Schwann cell dysfunction and a pro-inflammatory immune response, hindering regeneration.
• Cell-cell communication analysis revealed Schwann cells as key regulators of the nerve microenvironment.

Conclusions:

• The study identifies 28 days post-injury as a critical threshold for effective peripheral nerve regeneration.
• Beyond this window, progressive cellular changes significantly reduce the nerve's capacity to repair.
• Findings provide insights into chronic denervation pathophysiology and suggest targets for extending the regenerative period.