BACKGROUND:Peripheral nerve tissue engrafted into the central nervous system may provide regenerative effects in various CNS injury models or in a clinical trial using autologous sural nerve tissue grafts implanted into the substantia nigra of patients with Parkinson's disease (PD) as an adjuvant to Deep Brain Stimulation (DBS). NEW METHOD:We describe a proof-of-concept neuro-avatar animal model to inform ongoing and future clinical trials and study the survival, biodistribution, and host responses to allografts or xenografts of human peripheral nerve fascicles. Human peripheral nerve tissue (PNT) was prepared as either injury-naïve or injured and then nerve fascicles were implanted into the rat naïve dorsal striatum or striatum pretreated with a fibril-seeding model of synucleinopathies. RESULTS:At post-implantation, immunohistochemistry and MRI-imaging indicated both injury-naïve and injured nerve xenografts appeared to remain viable and stable at their implantation site with no evidence of nerve cell migration. Proton magnetic resonance spectroscopy of the xenografted brain identified increases in N-acetyl aspartate (NAA), a marker of neuronal integrity, in regions surrounding the xenograft. Preliminary RNAscope analysis of the xenografted brain indicates xenografts express mRNA for NGF and mitochondrial marker, ALDH2. Likewise, allografts of sciatic nerve implanted into the fibril-seeded brain were viable grafts 60 days after being placed into the degenerating brain and induced a sprouting response in the fibril-seeded brain. CONCLUSION:We believe the neuro-avatar rodent model described in this study may be an asset for studying the possible regenerative effects of PNT engrafted into the degenerating brain.

One promising strategy in cell therapies for Parkinson's disease (PD) is to harness a patient's own cells to provide neuroprotection in areas of the brain affected by neurodegeneration. No treatment exists to replace cells in the brain. Thus, our goal has been to support sick neurons and slow neurodegeneration by transplanting living repair tissue from the peripheral nervous system into the substantia nigra of those with PD. Our group has pioneered the transplantation of transection-activated sural nerve fascicles into the brain of human subjects with PD. Our experience in sural nerve transplantation has supported the safety and feasibility of this approach. As part of a paradigm to assess the reparative properties of human sural nerve following a transection injury, we collected nerve tissue approximately 2 weeks after sural nerve transection for immunoassays from 15 participants, and collected samples from two additional participants for single nuclei RNA sequencing. We quantified the expression of key neuroprotective and select anti-apoptotic genes along with their corresponding protein levels using immunoassays. The single nuclei data clustered into 10 distinctive groups defined on the basis of previously published cell type-specific genes. Transection-induced reparative peripheral nerve tissue showed RNA expression of neuroprotective factors and anti-apoptotic factors across multiple cell types after nerve injury induction. Key proteins of interest (BDNF, GDNF, beta-NGF, PDGFB, and VEGF) were upregulated in reparative tissue. These results provide insight on this repair tissue's utility as a neuroprotective cell therapy.

Engagement of multiple learning modalities has been shown to promote learning. This study aimed to develop resources for anatomical sciences educators interested in adding additional teaching modalities into their repertoire. Three review sessions were created for the muscle anatomy unit of an undergraduate anatomy and physiology course, each designed to engage a different learning modality. The first session was a kinesthetic experience in which students were cued through a sequence of body positions similar to yoga poses with instruction of muscle anatomy relevant to each position. The second session was a tactile experience in which students were instructed how to shape clay into models of muscles and place them on a corresponding plastic skeleton. The third session was an audience-response question and answer (Q&A) session in which students responded to questions and received feedback about their performance. Each of the three review sessions was successfully implemented in a large undergraduate course with 445 total students. The authors encourage other anatomy educators to adapt these sessions for use in their own teaching.

The development of regenerative therapies for central nervous system diseases can likely benefit from an understanding of the peripheral nervous system repair process, particularly in identifying potential gene pathways involved in human nerve repair. This study employed RNA sequencing (RNA-seq) technology to analyze the whole transcriptome profile of the human peripheral nerve in response to an injury. The distal sural nerve was exposed, completely transected, and a 1 to 2 cm section of nerve fascicles was collected for RNA-seq from six participants with Parkinson’s disease, ranging in age between 53 and 70 yr. Two weeks after the initial injury, another section of the nerve fascicles of the distal and pre-degenerated stump of the nerve was dissected and processed for RNA-seq studies. An initial analysis between the pre-lesion status and the postinjury gene expression revealed 3,641 genes that were significantly differentially expressed. In addition, the results support a clear transdifferentiation process that occurred by the end of the 2-wk postinjury. Gene ontology (GO) and hierarchical clustering were used to identify the major signaling pathways affected by the injury. In contrast to previous nonclinical studies, important changes were observed in molecular pathways related to antiapoptotic signaling, neurotrophic factor processes, cell motility, and immune cell chemotactic signaling. The results of our current study provide new insights regarding the essential interactions of different molecular pathways that drive neuronal repair and axonal regeneration in humans.

•Approaches to rescue and repair the injured central nervous system have failed in clinical trials.•Repair Schwann cells of the peripheral nerves hold unique neural repair potential.•Grafting of peripheral nerve key components shows promising efficacy in preclinical studies.•Employing peripheral nerve grafts demonstrated promising safety in clinical studies.•Utilizing the regenerative capacity of peripheral nerve tissue may provide opportunity for repair in the CNS.

OBJECTIVECurrently, there is no treatment that slows or halts the progression of Parkinson's disease. Delivery of various neurotrophic factors to restore dopaminergic function has become a focus of study in an effort to fill this unmet need for patients with Parkinson's disease. Schwann cells provide a readily available source of such factors. This study presents a 12-month evaluation of safety and feasibility, as well as the clinical response, of implanting autologous peripheral nerve grafts into the substantia nigra of patients with Parkinson's disease at the time of deep brain stimulation (DBS) surgery.METHODSStandard DBS surgery targeting the subthalamic nucleus was performed in 8 study participants. After DBS lead implantation, a section of the sural nerve containing Schwann cells was harvested and unilaterally grafted to the substantia nigra. Adverse events were continually monitored. Baseline clinical data were obtained during standard preoperative evaluations. Clinical outcome data were obtained with postoperative clinical evaluations, neuropsychological testing, and MRI at 1 year after surgery.RESULTSAll 8 participants were implanted with DBS systems and grafts. Adverse event profiles were comparable to those of standard DBS surgery with the exception of 1 superficial infection at the sural nerve harvest site. Three participants also reported numbness in the distribution of the sural nerve distal to the harvest site. Motor scores on Unified Parkinson's Disease Rating Scale (UPDRS) part III while the participant was off therapy at 12 months improved from baseline (mean ± SD 25.1 ± 15.9 points at 12 months vs 32.5 ± 9.7 points at baseline). An analysis of the lateralized UPDRS scores also showed a greater overall reduction in scores on the side contralateral to the graft.CONCLUSIONSPeripheral nerve graft delivery to the substantia nigra at the time of DBS surgery is feasible and safe based on the results of this initial pilot study. Clinical outcome data from this phase I trial suggests that grafting may have some clinical benefit and certainly warrants further study to determine if this is an efficacious and neurorestorative therapy.Clinical trial registration no.: NCT01833364 (clinicaltrials.gov).