Deng Pan (1st author) with research mentors Susan Mackinnon (left) and
Matthew Wood (right) at Deng's PhD thesis defense.
The accumulation of T cells within acellular nerve allografts is length-dependent and critical for nerve regeneration.
Pan D1, Hunter DA1, Schellhardt L1, Jo S1, Santosa KB1, Larson EL1, Fuchs AG2, Snyder-Warwick AK1, Mackinnon SE1, Wood MD3.
1Division of Plastic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA., 2Section of Acute and Critical Care Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA., 3Division of Plastic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
Exp Neurol. 2019 Aug;318:216-231. doi: 10.1016/j.expneurol.2019.05.009. Epub 2019 May 11.
Q&A with ASPN member and senior author, Matthew Wood:
1) What is the main message you want readers to take away from your study?
Regeneration across a nerve gap repaired using a graft or initially acellular material, such as a processed or acellular nerve allograft (ANA), involves a variety of non-neuronal cells, including the immune response. A critical component of that immune response involves T cells, which have an underappreciated role in nerve regeneration.
2) The role of T cells in nerve regeneration is novel. Do you think T cells could be a future therapeutic target after nerve injury?
A role for T cells during nerve regeneration is generally novel, but as we found, highly context-dependent. Previous studies within the setting of initially vascularized and cellular nerve injuries have demonstrated T cells do not have a major impact on nerve regeneration. However, our data demonstrates that T cells have a major role in nerve regeneration when the setting is initially acellular, such as regeneration across acellular nerve allografts or conduits.
T cells certainly could be a future therapeutic target once we understand more about their role in regeneration. Our follow-up work has determined that at least one component of T cells’ actions involves the regulation of cytokines to facilitate robust regeneration. The more we learn about their various roles, the more it will help us determine if T cells represent both an optimal target, and safe therapy. Even if T cells do not represent a therapeutic target, understanding more about the biology of regeneration across nerve gaps will certainly improve the next generation of solutions for surgeons and the care of nerve defects.
3) Why do you think T cells had a greater impact on acellular nerve allografts compared to isografts?
We are also working on this question in follow-up work currently. For acellular nerve allografts, we found that T cells arrive before Schwann cells, and just after macrophages, migrate within acellular nerve allografts. Our working hypothesis is that T cells are a major regulator of cytokines and recruiter of other immune cells critical during this early period of regeneration, as the nerve is being reconstructed by the body from the “ground-up”. Therefore, if a system is initially acellular, then there is a requirement for T cells to regulate the immune response because other cells have not yet arrived. We believe that other cells (i.e. Schwann cells) might provide some redundancy in the regenerative responses provided by T cells, which would explain why isografts (or autografts) were not impacted.
4) Have T cells been implicated in healing or regeneration in other tissues?
T cells have been implicated in other regenerative responses rather recently. A few years ago at around the same time as we started our studies in this publication, a group published a paper describing the importance of T cells in muscle regeneration after major injury. This was both affirming and reassuring for our novel results, as we were observing similar “universal” mechanisms in tissue regeneration.
5) Where is the research headed next?
Besides the aforementioned studies, we are identifying what T cells produce and regulate that activates the signaling that is beneficial for nerve regeneration. As well, Deng Pan, an MD-PhD candidate, performed this work in the combined laboratories of myself and Dr. Susan Mackinnon and recently defended his thesis on this topic. It has been a great pleasure to see the start of this work on this novel topic published.
See more ASPN member publications on the ASPN Member Publication webpage.