Stem cells and chronic spinal cord injury: Overview

Introduction

Spinal cord injury (SCI) is a devastating condition that is associated with a poor prognosis and long-lasting disability. Globally, SCI has an incidence of 8 to 246 per million and a prevalence of 236 to 1298 per million ( ). The lifetime cost for healthcare and living expenses that are attributable to SCI ranges from $1 to $4 million ( ). The destruction and demyelination of neurons that occurs in SCI leads acutely to quadriplegia, paraplegia, quadriparesis, and paraparesis, depending on the degree and location of injury. Furthermore, damage to neurons, glia, and vasculature also triggers a downstream sequence of events mediated primarily by inflammatory cells and cytokines. These events can lead to spreading of injury to adjacent segments. SCI can also lead to chronic complications, including bladder and bowel dysfunction, sexual dysfunction, neurogenic pain, and muscle spasticity. The current available treatments for SCI are limited to those that aim to ameliorate these chronic symptoms and complications ( ; ). There are currently no therapies available that produce neurological improvement for SCI patients. Thus, the development of therapies seeking to restore sensory and motor function has been an active area of investigation. One approach, stem cell transplantation, aims to replace the cells and signaling factors that are lost in SCI. In the following chapter, we will discuss stem cells, with a particular emphasis on their potential role as a therapy in SCI.

Pathophysiology of SCI

The pathophysiology underlying SCI is thought to begin with an initial insult followed by a secondary injury cascade that is characterized by three overlapping phases: acute, sub-acute, and chronic phases ( Table 1 ). The acute phase refers to the period immediately following mechanical insult that leads to compression or transection of the spinal cord. This initial event damages neurons and glial cells, disrupts membrane integrity and electrical conductance, and destroys local vasculature. These processes disturb the blood–spinal cord barrier, leading to ionic imbalance and excitotoxicity ( ). The sub-acute phase encompasses the inflammatory cascade and resultant cell death by apoptosis, ischemic necrosis, ferroptosis, and demyelination through Wallerian degeneration ( ). The chronic phase is defined by remodeling and healing which usually produces a glial scar and cystic cavity at the lesion focus ( ; ).

This influx of immune cells (such as macrophages, microglia, and neutrophils) is critical for clearing of debris and healing of the initial trauma, but they can also induce further inflammation by cytokine release and spreading of injury to adjacent segments ( ; ). In addition to perpetuating further inflammation, immune cells also generate reactive oxygen species (ROS) that can cause oxidative damage to lipids, proteins, and DNA ( ). These oxidative reactions can incite further necrosis and apoptosis ( ; ). After the inflammatory process abates, a glial scar is formed from astrocytes. This glial scar serves as a physical and chemical barrier that impedes axonal regeneration and neurite growth ( ).

Ultimately, these processes result in the loss of three components that are critical for sub-serving sensory and motor networks of the spinal cord: neurons, myelin, and neurotrophic factors. Thus, if stem cells could be directed to differentiate into neurons, oligodendrocytes that promote myelination, or neurotrophic factor-producing cells, meaningful functional and clinical recovery may be possible.

Stem cells: A brief overview

Stem cells are characterized by their capability to undergo both differentiation and self-renewal ( ). Classification of stem cells can be based on their potential differentiation into distinct cell types. Totipotent stem cells can become any cell type in the developing embryo, as well as extra-embryonic cells like the placenta. Pluripotent stem cells have a more restricted differentiation potential and are only able to make cells of the developing embryo. In other words, pluripotent cells can become any cell in the adult body. Multi-potent cells are further restricted and are only able to mature into cell types within a particular germ layer (e.g., any cell type derived from embryonic ectoderm).

Embryonic stem cells—An overview of pre-clinical findings

During development, embryonic cells can differentiate into a multitude of different cell types that compose the different organs and organ systems of an adult animal. Thus, embryonic stem cells (ESCs) were among the first reservoirs of pluripotent stem cells to be tapped for use in SCI cell-based therapy research ( Table 2 ).