**2. Spinal cord injury: standard of care**

Spinal cord injuries can be subdivided into multiple groups depending on the mechanism of injury, anatomic location of the lesion, type and severity of the injury. The basis of treatment is surgical decompression of the spinal cord to prevent secondary damage associated with hypoxia and ischemia [4]. Besides surgery, there have been numerous neuroprotective drugs that have been assessed in clinical trials, including methylprednisolone, thyrotropin-releasing hormone, nimodipine, and naloxone [5–7]. However most of these drugs were ineffective, and some were associated with wound healing complications and infections that represents a limitation in the management of this population of patients.

The current standard of care for these patients consists of aggressive medical management. This includes prevention of secondary injury with strict maintenance of mean arterial pressure (MAP) [8, 9]. SCI patients are prone to cardiovascular instability, neurogenic shock, respiratory insufficiency, particularly when cervical levels are involved, which then leads to further secondary injury [10]. Multiple studies have shown improved outcome when these patients are managed in the intensive care unit (ICU), with strict monitoring of blood pressure parameters [11, 12]. Studies have shown that augmentation of MAPs to greater than 85 for 7 days is associated with improved outcomes as assessed by American Spinal Cord injury Association (ASIA) impairment scale.

Stems cells have become a hot topic of great interest in various fields such as cancer biology, regenerative medicine, and SCI. There are multiple types of stem cells, with varying capabilities, including embryonic stem cells, (ESC), tissuespecific stem cells, mesenchymal stem cells (MSCs), and induced pluripotent stem cells. (iPSC). MSCs were first discovered in the bone marrow, but since then have been grown from other sources such as adipose tissue, amniotic fluid and umbilical cord blood, making them more easily accessible. MSCs are typically defined as plastic adhering cell populations that can be directed to differentiate *in vitro* into cells of osteogenic, chondrogenic, adipogenic, myogenic, and various other lineages. They are known to have a beneficial effect in SCI, via release of trophic factors for neuroprotection, neovascularization, and immunomodulation [13–15]. These cells naturally secrete various trophic factors, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factors (VEGF). BDNF is of particular interest since it has been shown to induce sprouting of corticospinal tracts in animal models of SCI [16]. MSCs derived from adipose tissue present unique advantages over other mesenchymal stem cell types as bone marrow, umbilical cord, dental pulp and others. In this chapter we'll focus in how MSCs can help in promoting spinal cord recovery after traumatic injury.

#### **3. Mesenchymal stem cell use in the central nervous system**

MSCs have been suggested for the treatment of various diseases. MSCs have also been proposed as a potential treatment for diabetes, inflammatory bowel disease, Parkinson disease, Alzheimer's disease, osteoporosis, bone regeneration, wound healing, skin aging, different inflammatory skin conditions, and others [17–27].

*Use of Mesenchymal Stem Cells in Pre-Clinical Models of Spinal Cord Injury DOI: http://dx.doi.org/10.5772/intechopen.94086*

Among neurologic diseases, the use of MSCs in hypoxic-ischemic encephalopathy, multiple sclerosis, and glioma has been considered. The majority of studies investigating MSCs' impact on the treatment of stroke reported a decrease in the size of stroke volume and improvement in behavioral outcomes [28]. In animal studies, functional improvement, along with decreased seizures and increased long term potentiation, was seen in the hypoxic-ischemic encephalopathy model. In animal models of multiple sclerosis, demyelination and infiltrates were reduced after the treatment with MSCs. In murine studies, targeting of glioma cells with MSCs while loading them with viruses, were effective in impeding the growth of the tumor [29].

Different stem cell types have been used to treat SCI (**Figure 1**). Among them, MSCs are preferred due to several reasons:


## **3.1 Bone marrow mesenchymal stem cells (BM-MSCs)**

The collection of bone marrow tissue for extraction of MSCs is done by aspiration, which is not only invasive and painful for the patient, but also distressing but also carries a risk of infection [32]. Nevertheless, these risks are partially negated by the intriguing properties of BM-MSCs for neuronal regeneration. One of this

#### **Figure 1.**

*Mesenchymal stem cells can be isolated from different sources (a), and can be expanded in vitro; when cultured they have a high proliferative rate (b). When applied to the SCI, they show homing properties, they are attracted by chemotactic signals and migrate towards the injured sire (c). Created with BioRender.com*

properties is their plasticity potential as it allows them to differentiate into a broad spectrum other than mesodermal lineage cells as described by Wislet-Gendebien et al. [33] in which bone marrow stem cells were cultured with cerebellar granule neurons, inducing the expression the genes sox2, sox10, pax6, fzd, erbB2, and erbB4 in nestin-positive MSCs. Furthermore, with the help of electrophysiological analyses, they could establish that BM-MSCs neuron-like cells were able to fire singleaction potentials and respond to the stimulation of distinct neurotransmitters such as GABA, glycine, and glutamate, concluding that nestin-positive bone marrowderived MSCs can differentiate *in vitro* into excitable neuron-like cells.

Numerous authors have described another characteristic of this type of stem cell's source and are the capacity of MSCs to migrate to the injured tissue – a mechanism described as 'homing' - especially in BM-MSCs [34]. This characteristic makes BM-MSCs source very attractive due to the range of alternatives for applying treatment with MSCs to patients other than invasive procedures. *Andersen et al.* [35] put in practice the migration ability by injecting with BMSCs subcutaneously to an immune-deficient mouse with a bone fracture. Besides observing the homing capacity of MSCs, and is mediated by a wide range of growth factors such as PDGF and IGF-1.

BMSCs in a chimeric mice contusion SCI model was more effective in reducing the neuropathic pain and motor and thermal sensitivity if BMSCs were injected 3 days after the injury compared to injections at day 1, 7, or 14 days. This effect was mediated through the suppression of p38 MAPK and ERK1/2 activation in microglia and macrophages, CREB and PKC-c in dorsal horn neurons in the site of the injury and around it, and decreased macrophage infiltration to the epicenter. The latter reduces inflammation and restores Blood Spinal Cord Barrier [36]. Quertainmont et al. observed improved locomotor skills using open field test in the rats treated with BMSCs [37].
