Regeneration of Corticospinal Axons into Neural Progenitor Cell Grafts After Spinal Cord Injury

Abstract

Spinal cord injuries leave patients with lifelong paralysis. To date, there are no therapies that promote the critical step required for the recovery of voluntary motor function: corticospinal axon regeneration. Spinal cord-derived neural progenitor cell (NPC) grafts integrate into the injured host spinal cord, enable robust corticospinal axon regeneration, and restore forelimb function following spinal cord injury in rodents. Consequently, engineered stem cell differentiation and transplantation techniques harbor promising potential for the design and implementation of therapies promoting corticospinal axon regeneration. However, in order to optimize the outcome of clinical trials, it is critical to fully understand the cellular and molecular mechanisms underlying this regeneration. Our recent study highlights the unexpected intrinsic potential of corticospinal neurons to regenerate and allows us to investigate new hypotheses exploiting this newly discovered potential.

Keywords: Neural progenitor cells; axon regeneration; corticospinal tract; transcriptomics.

Figure 1.

NPC-grafts support corticospinal tract (CST) axon regeneration. Sagittal spinal cord sections (40 µm) from non-regenerating conditions: (A) lesion without graft, (B) lesion + mesenchymal stem cell graft (MSC-Graft), and (C) lesion + NPC graft. Sections were labeled for corticospinal tract (CST) axons and in (A) the glial scar marker (GFAP). Drawings were Created with BioRender.com Lesion margins are indicated with white striped/dotted lines. Scale bars: 100 µm.

Figure 2.

CST axon regeneration strategies utilizing NPC/NSC grafts. Schematic overview of possible scenarios of NPC-graft triggered CST regeneration: (A) Functional synaptic relay strategy and (B) Catch and release strategy. NPC-graft derived neurons send out axons into host white and gray matter and reconnect with host motor neurons. In (A) grafted neurons can receive synaptic inputs from regenerating CST axons, while in (B), NPCs/NSCs have been genetically altered to not receive synaptic inputs. Drawings were Created with BioRender.com.