Study unveils novel reparative function of immune cells in peripheral nerve regeneration

Newswise — Macrophages facilitate peripheral nerve regeneration by organizing regeneration tracks through Plexin-B2

Corresponding Author: Hongyan Zou, MD, PhD, Professor of Neuroscience, Neurosurgery, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York.

Bottom Line:  The study unveils a novel reparative function of immune cells (macrophages) in organizing regeneration tracks for peripheral nerve regeneration—damage to nerves outside the brain and spinal cord. In addition, the study reveals that regenerating axons do not simply follow regeneration tracks in a passive manner, but instead actively participate by interacting with glial cells at the regeneration front.

Results: Nerve regeneration after transection injury requires an intricate interplay of many cell types. This study highlights a reparative function of macrophages, which are immune cells known for inflammation and debris clearing, in organizing regeneration tracks. The team showed the importance of cell contact guidance provided by the cell surface protein Plexin-B2 to steer macrophages clear of colliding axons (nerve fibers of regenerating neurons). One insight arising from the study is that regenerating axons do not just passively follow regeneration tracks laid ahead, but also actively participate in the physical contacts with immune cells (in particular, the highly dynamic growth cones at the tip of regenerating axons), leading to parallel alignment post-collision. This, in turn governs, longitudinal matrix alignment, thereby providing the proper substrate for directed cell migration of Schwann cells, another supporting cell type in the nerve, to fortify the regeneration tracks.

Why the Research Is Interesting: Tissue regeneration requires orchestration of many different cell types to form new tissues with highly organized cytoarchitecture. This study highlights the importance of physical contacts and collision guidance in addition to biochemical cues for successful nerve repair after peripheral nerve injury.

Who:  Animal model of peripheral nerve regeneration

What:  The authors generated mutant mice with specific gene deletion of the guidance receptor Plexin-B2 in immune cells and studied how this impacts axon regeneration, cellular organization, and moto-sensory functional recovery after nerve injury.

How:  Histological examination of regeneration tracks and axon pathfinding, moto-sensory assays of nerve functional recovery, and advanced time lapse live-cell imaging of cell collision behavior in co-culture systems.

 Study Conclusions: The regeneration of peripheral nerves post-injury is guided by the interplay of many cell types, but the underlying signaling pathways remain unclear. Here, we demonstrate that macrophages are mobilized ahead of Schwann cells during nerve repair to participate in building regeneration tracks. This requires the function of guidance receptor Plexin-B2, which is robustly up-regulated in infiltrating macrophages in injured nerves. Plexin-B2 enables macrophages to steer clear of colliding axons, in particular the growth cones at the tip of regenerating axons, leading to parallel alignment post-collision. This leads to matrix and Schwann cells organization to further facilitate the formation of regeneration tracks. Together, our studies unveil a novel reparative function of macrophages and the importance of Plexin-B2-mediated collision-dependent contact avoidance between macrophages and regenerating axons in building the regeneration tracks for peripheral nerve regeneration.

Paper Title: Macrophages facilitate peripheral nerve regeneration by organizing regeneration tracks through Plexin-B2

Said Mount Sinai's Dr. Hongyan Zou of the research: “The regenerative capacity of the peripheral nerve system (PNS) is unparallel in the mammalian nerve system: after peripheral nerve injury, nerves are able to regenerate at a speed of ~1mm a day. Understanding how peripheral nerves achieve robust regeneration while central nerve system (CNS) fails to regenerate is a central question for regenerative biology. The current study, together with another recent study from our laboratory, showed how immune cells take part in cellular organization during tissue repair after both PNS and CNS injury. However, there are major differences between CNS and PNS repair. Could it be that the regenerating axons, which exhibit robust growth capacity after PNS injury but more limited growth capacity after CNS injury, in fact play a role in governing glial cell organization during neural repair? Using mouse genetic studies and time lapse live-cell imaging in co-culture system, we found that macrophages are adept at avoiding colliding axons, in particular the growth cones at the tip of regrowing axons, which is critical for guiding cellular alignment and axon pathfinding during peripheral nerve regeneration.”