Regenerative Rehabilitation and Stem Cell Therapy Targeting Chronic Spinal Cord Injury: A Review of Preclinical Studies

Abstract

Stem cell medicine has led to functional recovery in the acute-to-subacute phase of spinal cord injury (SCI), but not yet in the chronic phase, during which various molecular mechanisms drastically remodel the tissue and render it treatment-resistant. Researchers are attempting to identify effective combinatorial treatments that can overcome the refractory state of the chronically injured spinal cord. Regenerative rehabilitation, combinatorial treatment with regenerative medicine that aims to elicit synergistic effects, is being developed. Rehabilitation upon SCI in preclinical studies has recently attracted more attention because it is safe, induces neuronal plasticity involving transplanted stem cells and sensorimotor circuits, and is routinely implemented in human clinics. However, regenerative rehabilitation has not been extensively reviewed, and only a few reviews have focused on the use of physical medicine modalities for rehabilitative purposes, which might be more important in the chronic phase. Here, we summarize regenerative rehabilitation studies according to the effector, site, and mechanism. Specifically, we describe effects on transplanted cells, microstructures at and distant from the lesion, and molecular changes. To establish a treatment regimen that induces robust functional recovery upon chronic SCI, further investigations are required of combinatorial treatments incorporating stem cell therapy, regenerative rehabilitation, and medication.

Keywords: exercise; graft; neurorehabilitation; physical therapy; plasticity; regenerative medicine; training; transplantation.

Figure 1

A schematic summary of the combinational effects of rehabilitation and regenerative treatment. BDNF: brain-derived neurotrophic factor; CW: continuous wave; IGF-1: insulin-like growth factor 1; KCC2: kalium-chloride cotransporter 2; OEC/SC: olfactory ensheathing cell/Schwann cell; ROS/RNS: reactive oxygen species/reactive nitrogen species; rTMS: repetitive transcranial magnetic stimulation; TMT: treadmill training.