Using a Transection Paradigm to Enhance the Repair Mechanisms of an Investigational Human Cell Therapy

Monica J Chau, Jorge E Quintero, Paula V Monje, Stephen Randal Voss, Andrew S Welleford, Greg A Gerhardt, Craig G van Horne, Monica J Chau, Jorge E Quintero, Paula V Monje, Stephen Randal Voss, Andrew S Welleford, Greg A Gerhardt, Craig G van Horne

Abstract

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.

Keywords: cell therapy; neuroprotection; peripheral nerve; single nuclei RNA sequencing; tissue-based therapy.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Study overview. This overview illustrates our sural nerve transection approach and subsequent tissue collection of the naïve and reparative nerve tissues. One to two centimeters of nerve was excised, which we called “naïve” nerve tissue. Approximately 14 days after, 1 to 2 centimeters from the distal nerve stump of the same nerve was excised, which we called “reparative” nerve tissue. Cross-sections of reparative sural nerve were stained with H&E (left) and Luxol fast blue (LBF)/MCOLL staining to show myelin and collagen. Individual nerve fascicles were separated, snap-frozen, and used for single nuclei RNA sequencing and immunoassays or implanted directly into the brain as part of our clinical trial. Shown here is a 3D view of reparative nerve fascicles implanted into the substantia nigra in the cell therapy trial. H&E: hematoxylin and eosin; CNS: central nervous system; 3D: three dimensional.
Figure 2.
Figure 2.
Reparative peripheral nerve tissue contains several cell types including regenerating cells. (A) Aggregate of single nuclei RNA sequencing from two participants. Ten unique cell type clusters were present in the reparative tissue. (B) Data from two participants show similarity in their cellular profiles. (C) The data clustered into 10 cell groups and were defined based on characteristic genes previously published for each particular cell type. (D) Each cell cluster’s percentage of total number of cells is reported.
Figure 3.
Figure 3.
Reparative peripheral nerve tissue shows RNA expression of neuroprotective factors 2 weeks after nerve transection. (A) Single nuclei RNA sequencing UMAP plots show cell-type expression of the neuroprotective factors of interest: NGF, PDGFB, VEGFA, PDGFA, CDNF, GDNF, BDNF, and EPO. The accompanying violin plots show the relative RNA expression level (log2 average) and frequencies for each cell type in the reparative peripheral nerve tissue. NGF, PDGFA, PDGFB, and VEGF were localized to more than one cell type. NGF was localized to the heterogeneous cell cluster and endoneurial mesenchymal cells, NGFR was localized to Schwann cells and the heterogeneous cell cluster, PDGFA was localized to myelinating Schwann cells and pericytes/vascular smooth muscle cells, PDGFB was highly expressed in endothelial cells. Cell type key: SC: Schwann cell; mySC: myelinating Schwann cells; EC: endothelial cells; PC: proliferating cells; HC: heterogeneous cells; EMC: endoneurial mesenchymal cells; MC: mesenchymal cells; M: macrophages; PC/VMSC: pericytes/vascular smooth muscle cells; TC: T-cells. (B) Repair Schwann cells are a source of neuroprotective factor release. NGFR is an abundantly expressed repair Schwann cell marker that was found in the Schwann and heterogeneous cell clusters. (C) Percentage of total cells expressing each key neuroprotective factors. Note that the x-axis maximum is 20%. Data obtained from N = 2 participants. BDNF: brain-derived neurotrophic factor; CDNF: cerebral dopamine neurotrophic factor; GDNF: glial-cell derived neurotrophic factor; NGF: nerve growth factor; NGFR: nerve growth factor receptor; PDGFA: platelet-derived growth factor–A; PDGFB: platelet-derived growth factor–B; VEGFA: vascular endothelial growth factor A; EPO: erythropoietin; UMAP: Uniform Manifold Approximation and Projection for Dimension Reduction.
Figure 4.
Figure 4.
Reparative peripheral nerve tissue shows RNA expression of anti-apoptotic factors across multiple cell types. (A) Anti-apoptosis factors were expressed broadly and robustly in many of the cell types of the reparative nerve for factors of interest: NFE2L2 (NRF2), BCL2, BCL2L1 (Bcl-xl), BCL6, and MCL1 of reparative peripheral nerve tissue. Violin plots show the relative expression across cell types (log2 average). Cell type key: SC: Schwann cell; mySC: myelinating Schwann cells; EC: endothelial cells; PC: proliferating cells; HC: heterogeneous cells; EMC: endoneurial mesenchymal cells; MC: mesenchymal cells; M: macrophages; PC/VMSC: pericytes/vascular smooth muscle cells; TC: T-cells. (B) Percentage of total cells expressing each anti-apoptotic factors. Note that the x-axis maximum is 40%. Data obtained from N = 2 participants.
Figure 5.
Figure 5.
Protein content of neuroprotective factors and anti-apoptotic factors. The mean protein concentration (and SD) in regenerating peripheral nerve tissue samples is summarized. BDNF (n = 15 participant samples), GDNF (n = 7), beta-NGF (n = 12), PDGFB (n = 15), VEGF (n = 15), NGFR (n = 14), CDNF (n = 15), PDGFA (n = 13), EPO (n = 13), NFE2L2 (n = 14), and BCL-6 (n = 15). BDNF: brain-derived neurotrophic factor; CDNF: cerebral dopamine neurotrophic factor; EPO: erythropoietin; GDNF: glial-cell derived neurotrophic factor; NGF: nerve growth factor; NGFR: nerve growth factor receptor; PDGFA: platelet-derived growth factor–A; PDGFB: platelet-derived growth factor–B; VEGF: vascular endothelial growth factor.
Figure 6.
Figure 6.
Proposed action of reparative peripheral nerve tissue transplant. Reparative peripheral nerve tissue deployed into the substantia nigra of participants with PD may act in multi-factorial ways with paracrine effects on the surrounding tissue. Anti-apoptotic factors may contribute to graft survival. Through this combination, a diversity of cell-types from regenerating peripheral nerve tissue could provide neuroprotective, pro-regenerative, and anti-inflammatory factors interacting with the degenerating cells in the CNS. Created with Biorender.com. CNS: central nervous system; PD: Parkinson’s disease.

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