Early injury-induced responses in the transected adult human sural nerve

Performing a transection injury is a safe and practical method to potentially enhance the therapeutic value of transplantable nerve grafts. Our team has tested the autologous implantation of denervated fascicle pieces from a fully transected sural nerve as an experimental treatment for Parkinson's disease. This study used nerve biospecimens from the clinical trial participants to investigate the cytological changes of axotomized sural nerves using histological, immunochemical, and quantitative image analysis combined with -omics approaches. Our examination of donor-matched intact and injured nerves revealed that the distal nerve segment experiences a major structural and cellular remodeling of all connective tissue layers within a 2-week time window post-axotomy. These changes occurred in concert with increased cellularization, vascularization, proliferation, and NGFR immunoreactivity, an early indicator of disrupted axonal support, in diverse cell types from the perineurial and epineurial sheaths. Whereas Schwann cells (SCs) did not expand in number, they clearly transformed their phenotype in response to the injury by becoming larger as they engulfed myelin debris and consistently -yet heterogeneously- increased NGFR expression and repair-associated genes. Nevertheless, most of the myelin content remained uncleared and ovoids were found in association with SCs rather than macrophages, which infiltrated poorly into the endoneurium at these early time points. Overall, our observations were consistent with a profile of slow Wallerian degeneration and modest SC activation overtaken by vascular development, ECM remodeling, and a strong reactivity of connective tissue cells. This is to our knowledge, the first description of early cytological changes in axotomized human nerves in an experimentally controlled injury paradigm.