5. Types of cells used in transplantation for spinal cord injuries

The use of cellular transplantation in SCIs has been reported to encourage regeneration of neural circuitry and recover the associated compromised function of nervous system. Transplanted cells are being observed to perform this job via secretion of indulgent neurotrophic factors at the injury site to boost the reformative capability, followed by developing a scaffold for axonal regeneration, myelination and replacement of damaged nerve cells [35], as depicted in Figure 1. Following are the type of cells that have been shown success in preclinical trials and currently being evaluated in clinical phase trials for treatment of SCIs.

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Figure 1. Graphical representation of cellular transplantation and functional recovery from SCI. Therapeutic cells are derived from different types of sources. Following cellular transplantations into injury site, the transplantable cells secret indulgent neurotrophic molecules to boost the regenerative capability, support axonal regeneration and myelination and replace damaged/loss neurological cells, resulting functional recovery from SCI.

#### 5.1. Embryo-derived cell population

BAK-1 (BCL2-antagonist/killer 1) and CASP3 (caspase 3, apoptosis-related cysteine peptidase), is being reported. In later stages, the upregulation of STAT3 (signal transducer and activator of transcription 3 (acute-phase response factor)) and PI3K (phosphoinositide 3-kinase) and downregulation of GSK-3 (glycogen synthase kinase 3) are being observed [25]. In addition, earlier upregulation of genes that are involved in preventing apoptosis such as PDGF (platelet-derived growth factor), TGFB (transforming growth factor-β), VEGF (vascular endo-

There are well-recognized genes, such as GFAP (glial fibrillary acidic protein), NES (nestin) and VIM (vimentin), that are overexpressed in astrocytes and are found responsible for glial scar formation. They are found upregulated early after SCI [26]. In oligodendrocytes, the gene expression decline due to oligodendrocytic death, while an increase in myelination occurs in

MicroRNAs (miRNAs) have been recognized to play crucial roles in regulating growth signals and immune response [28]. Following SCI, microRNAs play important role in inflammatory pathways or in the invading immune cells. Soon after the SCI, damaged area is infiltrated with blood immune cells [29]. MicroRNAs control upregulation of vascular cell adhesion molecule (VCAM1)-mRNA [25] with downregulation of miR-126 [30]. Neutrophil infiltration clarifies upregulation of miR-223 [31], while overexpression of lymphocyte-specific miR-142 [26] associates with the aggregation of immune cells in the injured site during initial days [32]. Moreover, miRNAs are associated with microglia and macrophages activation. Mainly, the downregulation of miR-124 is associated with microglia by directing CCAAT enhancer-binding protein alpha (CEBPα), which is a principal transcription factor vital for myeloid cells development [33]. After SCI, MiR-124 shows a constant downregulation that causes microglial activation [32]. Other associated roles of miRNAs during different mechanisms of SCIs have been recently reviewed

5. Types of cells used in transplantation for spinal cord injuries

and currently being evaluated in clinical phase trials for treatment of SCIs.

The use of cellular transplantation in SCIs has been reported to encourage regeneration of neural circuitry and recover the associated compromised function of nervous system. Transplanted cells are being observed to perform this job via secretion of indulgent neurotrophic factors at the injury site to boost the reformative capability, followed by developing a scaffold for axonal regeneration, myelination and replacement of damaged nerve cells [35], as depicted in Figure 1. Following are the type of cells that have been shown success in preclinical trials

thelial growth factor) and anti-apoptotic proteins is being reported [24].

4.5. Glial cell alterations

128 Essentials of Spinal Cord Injury Medicine

later stages [26].

4.6. MicroRNAs

in [34].

Although ethical issues are associated with the origin of embryonic stem cells (ESC), their potential use might significantly results into numerous scientific and clinical applications, especially if they are differentiated into desired cell types and are utilized to develop functional body organs [36]. The ESCs have been considered as a leading candidate of therapeutic cells for numerous types of disorders triggered by loss of cells/tissue or any abnormal body function [37]. A gap that has been produced in spinal cord after traumatic or non-traumatic injury can be refilled via new cell transplantation. To date, embryonic stem cells are considered as the most appropriate type of cells that can be used for this purpose. These are the immature cells that can differentiate into any of a cell type in human body including the cells of CNS and PNS. ESCs have been reported to form a bridge across the injury site, as well as they are capable of excreting neuroprotective factors that reduce the harmful effects from inflammation [38–40].

## 5.1.1. Human embryonic stem cell-derived oligodendrocyte progenitors (hESCs-ODPs)

Since the major problem associated to SCIs is "demyelination," a potential treatment option to replace the myelin-forming cells will be of significant interest. For this purpose, a transplantation of hESCs-ODPs into SCI rat model has shown to increase remyelination and promoted improvement in recovery of locomotory function [41]. This study paved the ways for the use of hESCs-ODPs for treatment of SCIs and supported the notion that pre-differentiation of hESCs into active oligodendrocytes progenitors will offer therapeutic option at early time points after SCIs. After preclinical success, the uses of hESCs-ODPs are being evaluated into clinical trials on patients with SCIs. The hESCs-ODPs are currently known as ASTOPC1, while previously it was known as GRNOPC1. It was permitted for clinical trials by US FDA in 2009; however, the proper trials begin in 2010 after being evaluated for safety reason in patients as it developed cysts in animal models [42, 43]. While for some unknown reasons Geron-Corporation ceases the trials, another corporation Asterias Biotherapeutics begin the same trials in phase 1 (NCT01217008) on individuals suffering from subacute thoracic SCIs. The trial was concluded in year 2013 with positive results where safety and tolerability was achieved with no serious fallouts [44, 45]. A year after, Asterias Biotherapeutics initiated a new clinical trial of phase I/IIa (NCT02302157) involving the use of hESCs-ODPs for treatments of sensorimotor complete cervical SCIs, which is expected to complete in year 2018 [44]. Since direct transplantation of hESCs poses a risk of forming teratomas and problem of differentiating into exact cells progeny within a body [41], the highly purified ODPs that are freshly derived from hESCs will offer a best treatment option for patients with SCIs.

brain-derived neutrophic factor into the SCI rat model [54]. In addition to preclinical studies on animal models, a case study on human (37-year-old female) patient with SCI has reported an injection of human umbilical cord blood-derived stem cells. In this study, it was shown that cell transplantation ameliorates sensory perception and movement of body parts, based on functional and morphological analysis [55]. Recently, the transplantation of umbilical cord bloodderived mononuclear cells (UCBMC) has been tested in phase I/II clinical trials (NCT01354483; NCT01471613) for treatment of acute, subacute and chronic SCIs in combination with neuroprotective agents such as lithium carbonate and methylprednisolone [44]. Following transplantation, these cells have been observed to decrease sensimotor injury and other associated cerebral deficiency [56]. In one of the clinical trial outcomes involving UCBMC (NCT01354483), the cellular transplantation was observed to be safe while some recipients

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It has been reported that growth signaling pathway-related factors are able to prompt mouse ESCs differentiation into vertebral progenitor cells, followed by subsequent differentiation into motor neurons [58]. These ESC-derived motor neurons have been recognized with a potential to occupy the embryonic medulla spinalis, lengthen axons and develop synaptic connections with respective muscle tissues [58]. Another study has reported that earlier neuroectodermal cells derived from hESCs population, which expressed Pax6 but not Sox1, were able to differentiate into spinal motor neurons in the presence of retinoic acid and sonic hedgehog. Whereas the neuroectodermal cells in later stages that were expressing both Pax6 and Sox1 were unable to differentiate into spinal motor neurons [59]. Following transplantation, these motoneurons have the ability to quickly engraft, maintain proper phenotype and project axonal elongation into peripheral regions in recipient's tissues [60]. These evidences of in vivo subsistence of hESC-derived motoneurons are a major way forward to treat SCIs via cellular therapy using

The lineage of mesenchymal stem cells (MSCs) is characterized with self-renewal capacity and multipotent stem cells-like abilities. They were originally isolated from the bone marrow [61, 62] and have been reported to differentiate into several cell types [63–68]. The MSCs have also been shown to transdifferentiate into variety of neuronal cells in different animal models [69– 72]. The MSCs that qualify transplantational procedure are known as multipotent mesenchymal stromal cells [73], which are having several subtypes that are being therapeutically evaluated for SCIs in different clinical trials. After their transplantation into lesion site, they are thought to be regulated by secretion of trophic factor, which stimulates new vessels formation and anti-inflammatory factors [74]. Moreover, MSCs are being reported to secrete different cytokines and associated growth promoting factors that exhibit both paracrine and autocrine characteristics. These biologically active secreted factors have been shown to suppress the intrinsic immunological repsonse, prevent apoptosis and formation of glial scars, improve

angiogenesis and stimulate cell cycle to enhance regenerative activities [75].

were appeared to regain sensorimotor function [57].

5.1.4. Human ES-derived motor neurons

motoneurons' transplantation.

5.2. Mesenchymal stem cells
