Regeneration of Spinal Cord Connectivity Through Stem Cell Transplantation and Biomaterial Scaffolds

Abstract

Significant progress has been made in the treatment of spinal cord injury (SCI). Advances in post-trauma management and intensive rehabilitation have significantly improved the prognosis of SCI and converted what was once an "ailment not to be treated" into a survivable injury, but the cold hard fact is that we still do not have a validated method to improve the paralysis of SCI. The irreversible functional impairment of the injured spinal cord is caused by the disruption of neuronal transduction across the injury lesion, which is brought about by demyelination, axonal degeneration, and loss of synapses. Furthermore, refractory substrates generated in the injured spinal cord inhibit spontaneous recovery. The discovery of the regenerative capability of central nervous system neurons in the proper environment and the verification of neural stem cells in the spinal cord once incited hope that a cure for SCI was on the horizon. That hope was gradually replaced with mounting frustration when neuroprotective drugs, cell transplantation, and strategies to enhance remyelination, axonal regeneration, and neuronal plasticity demonstrated significant improvement in animal models of SCI but did not translate into a cure in human patients. However, recent advances in SCI research have greatly increased our understanding of the fundamental processes underlying SCI and fostered increasing optimism that these multiple treatment strategies are finally coming together to bring about a new era in which we will be able to propose encouraging therapies that will lead to appreciable improvements in SCI patients. In this review, we outline the pathophysiology of SCI that makes the spinal cord refractory to regeneration and discuss the research that has been done with cell replacement and biomaterial implantation strategies, both by itself and as a combined treatment. We will focus on the capacity of these strategies to facilitate the regeneration of neural connectivity necessary to achieve meaningful functional recovery after SCI.

Keywords: biomaterials; central nervous system; regeneration; stem cell transplantation; traumatic spinal cord injury.

FIGURE 1

Pathophysiology of spinal cord injury (SCI). (A) The diagram shows the pathophysiological events occurring around the lesion site during the acute to subacute phase of SCI. The primary and secondary injury mechanisms lead to inflammation, hemorrhage, apoptosis, and necrosis. Resident neurons, oligodendrocytes, and astrocytes near the lesion are forced into apoptosis or necrosis, resulting in anterograde (Wallerian degeneration) and retrograde (axonal dieback) axonal degeneration. Reactive astrocytes and other glial cells secrete chondroitin sulfate proteoglycans (CSPGs), which acts as a physical and chemical barrier that impedes endogenous tissue repair processes such as axonal sprouting and synaptic reorganization. (B) The diagram shows the pathophysiological events in the chronic phase of SCI. In the epicenter of the lesion, a cavitation has occurred that is surrounded by connective scar tissues and contains cerebrospinal fluid (CSF). The phenotype of reactive astrocytes has changed into scar-forming astrocytes that impede regenerating axons from crossing the lesion. Some inflammatory immune cells remain around the lesion even in the chronic phase of SCI.

FIGURE 2

Components of spinal cord connectivity. The diagram shows the simplified components of spinal connectivity composed of an upper motor neuron, a lower motor neuron, and targeted muscle fibers. Neurons have cell bodies, dendrites that receive signals, and axons that transmit signals. At the base of the axon is the axon hillock where the signal transmission is initiated, and the axon divides at its end into several branches, each of which ends in synaptic terminals. The site of interactive communication between a transmitting cell (a presynaptic upper motor neuron) and a receiving one (a postsynaptic lower motor neuron) is called the synapse. The axons of most neurons are covered with a lipid layer knows as the myelin sheath, which insulates axons and speeds up transmission of action potentials through the axon. The axon terminals at a synapse contain tiny vesicles filled with chemicals called neurotransmitters. The lower motor neurons take the impulse to the effector (muscle fibers) and control the coordination of muscle contraction.

FIGURE 3

Potential mechanisms of spinal cord repair by stem cell transplantation. The diagram shows potential mechanisms of regeneration brought about by stem cell transplantation. The transplanted stem cells differentiate into neural cells of the three lineages: neurons, astrocytes, and oligodendrocytes (shown in green). The transplanted stem cells and differentiated cells secrete neurotrophic factors that reduce inflammation, degrade CSPGs, and promote endogenous tissue repair. Differentiated oligodendrocytes remyelinate denuded axons. The grafted neurons form synapses with propriospinal neurons and lumbar motor neurons, which reorganize the neuronal circuits by forming de novo synaptic connectivity between host and grafted neurons. The regenerated neuronal circuits bridge the lesion by creating a detour route that passes through areas more favorable to regenerating axons. Transplant-derived interneurons indirectly connect the host injured neural tracts through the propriospinal circuits, whereas transplant-derived neurons participate in the regeneration of the injured corticospinal tract (CST) and directly activate muscle contraction.

FIGURE 4

Combinatorial treatment of stem cells and biomaterials containing ChABC elicits remyelination and synaptic reorganization. (A,B) Representative images of axial (A) and sagittal (B) sections stained for STEM121 (a specific marker for human cytoplasmic protein; green), MBP (red), and NF200 (magenta). Many STEM121-positive/MBP-positive graft-derived myelin sheathes were observed around NF200-positive host axons. (C) Immunoelectron microscopy images show synapses formed between host and graft-derived neurons after the combinatorial treatment. Presynaptic and postsynaptic structures indicate transmission from host neurons to graft-derived neuron (left image), and from graft-derived neurons to host neurons (right image). Annotated (H) indicates host neurons, and (G) indicates graft-derived neurons. Arrowheads indicate postsynaptic density. Figure altered with permission from Nori et al. (2018). Human oligodendrogenic neural progenitor cells delivered with chondroitinase ABC facilitate functional repair of chronic spinal cord injury (2018).