**Abstract**

Since multipotential and immunoregulatory properties were identified in mesenchymal stem cells (MSCs) in the twentieth century, they have been proposed as an effective therapy for many degenerative and traumatic diseases such as spinal cord injury (SCI). SCI is a devastating event with a high mortality rate that evokes the loss of motor and sensory functions due to neurochemical imbalance and an exacerbated immune response as a consequence of the initial mechanical damage, which in conjunction creates a hostile microenvironment that inhibits neuronal circuitry restoration. This chapter pretends to lead the reader towards the immunomodulatory, differentiation, and tissue repairing capacities of MSCs that allow them to be a valuable candidate for clinical trials. In the first section, the physiopathology of SCI will be addressed; after that, the chapter will review the general aspects of MSCs such as origin, molecular markers, and the different mechanisms by which MSCs can heal the target tissues. Finally, we will discuss clinical trials involving autologous MSC transplantation and their limitations.

**Keywords:** SCI, MSCs, clinical trials

### **1. Introduction**

Spinal cord injury (SCI) is an important clinical problem with significant socioeconomic impact worldwide.

SCI is a catastrophic event involving damage to the spinal cord (SC) that causes morphological and physiological changes leading to biomechanical and functional disorders in patients [1]. This condition induces acute and chronic inflammatory processes that can result in temporary or permanent repercussions including paraplegia, quadriplegia, or even death [2].

The pathophysiology of SCI is very complicated, and it consists of a primary and a secondary phase. The primary phase occurs immediately after the damage to the SC causing cell death at the epicenter of the injury as well as the beginning of the pro-inflammatory response [3]. The secondary phase starts 2 hours after the damage and can last up to 6 months. During this phase the extent of the injury increases in response to the augmented pro-inflammatory factors which contribute to induce local edema, ischemia, vascular alterations, ionic dysregulations, and oxidative

stress [3, 4]. These prejudicial mechanisms persist during the chronic stages of the injury, and although their intensity is diminished, the neurological function continues to decline [5]. Most of the post-traumatic neuronal degeneration involves an uncontrollable cascade of destructive mechanisms that are still incompletely understood and remain a challenge for scientists [6].

The current therapy for SCI involves surgical decompression and steroid administration; however, both of them only show minimal efficiency, and the need for an effective therapy is continuously rising [7]. Therefore, the transplantation of stem cells as a novel therapeutic approach has received increasing attention due to their promising results in neurological recovery in SCI [8–10]. Among them, mesenchymal stem cells (MSCs) demonstrate to be a valuable promising therapy due to their significant autocrine and paracrine activity which help to induce the proliferation and differentiation of different cell types and to exert immunomodulatory effects in the microenvironment of the host [6, 11]. MSCs, anti-inflammatory molecules, and trophic factors are capable of supporting axonal growth to promote angiogenesis, remyelination, and protection against apoptotic cell death [12]. Furthermore, MSCs possess a varied spectrum of therapeutic properties such as neuroprotection after glutamate excitotoxicity [13, 14], reduction in protein levels associated with stress and reactive oxygen species [15] and pro-inflammatory cytokines [16], M1 macrophage polarization to the M2 pro-repair activated phenotype [17], secretion of neurotrophic factors [16, 18, 19], and their ability to produce numerous exosomes.

In addition, MSCs have minimal immunoreactivity towards the host as well as a limited chance of developing a tumor and are particularly appealing due to their wide range of advantages over other types of stem cells [20]. Finally, we will discuss clinical trials of improvement using autologous and allogeneic MSCs after acute and chronic SCI.
