9.2. Amyotrophic lateral sclerosis

MSCs are capable of differentiating into neurons [60]. An acid sphingomyelinase mouse model was used to conduct the first MSCs transplantation for neurodegenerative disorders. After MSCs injection, an amelioration in the overall survivability of the mouse and a decrease in disease abnormalities were detected [61]. Based on this study, a new study was performed in order to ensure the MSC transplantation efficiency in a neurodegenerative disease that leads to motor neurons degeneration and muscle function distortion, Amyotrophic lateral sclerosis (ALS) [61]. MSCs were isolated from the bone marrow and then reinjected into the spinal cord of the same patients, followed by MRI at 3 and 6 months for MSCs tracking. Results did not reveal any abnormal cells proliferation or structural changes in the spinal cord. However, mild adverse effects occurred which were reversed in few weeks duration e.g. intercostal pain irradiation and leg sensory dysesthesia. In another study, genetically modified AD-MSCs were made to express GDNF to be transplanted in a rat model of ALS, an increased number of neuromuscular connections and an improved pathological phenotype were observed [62].

#### 9.3. Parkinson's disease

Parkinson's disease (PD), a neurodegenerative disorder, characterized by significant loss of dopaminergic neurons. After MSCs transplantation in PD mice model, tyrosine hydroxylase level increased [63]. MSCs participate to neuroprotection by secretion of trophic factors like vascular endothelial growth factor (VEGF), EGF, FGF-2, neurotrophin-3 (NT3), HGF and BDNF without differentiating into neurocytes [64]. Genetically modified hMSCs are used to induce the secretions of specific factors or to increase the dopamine (DA) cell differentiation. BM-MSCs transduction with lentivirus carrying LMX1a gene, resulted in cells which were similar to mesodiencephalic neurons with high DA cell differentiation [65]. Experiments were performed on Parkinson diseased rat, the research group from the university hospital of Tubingen in Germany administered BM-MSCs nasally to treat neurodegenerative patients. MSCs were found in different brain regions after 4.5 months of administration. They have been found in the cerebral cortex, olfactory lobe, hippocampus and brain stem, suggesting that MSCs could successfully survive and proliferate in vivo [66]. Moreover, this type of administration was observed to increase the level of tyrosine hydroxylase and decrease the toxin 6 hydroxydopamine in the ipsilateral striatum and substantia nigra lesions. This novel MSCs administration route could change the face of MSCs transplantation in future.

production to a level which is failed to control the blood glucose. It has been proved that MSCs can differentiate into insulin producing cells and have the capacity to regulate the immunomodulatory effects [75]. Zulewski et al. [76] isolated Nestin positive cells from rat pancreatic islets which differentiated into pancreatic endocrine cells. Nestin positive cells were isolated from human pancreas and transplanted to diabetic nonobese diabetic/severe combined immunodeficiency (NOD-SCID) mice, which improved hyperglycemic condition [77]. However, these studies were found controversial and it was suggested that besides pancreatic tissues, other tissues can be used as an alternative for MSCs isolation to treat type 1 diabetes. Human BM-MSCs can be differentiated efficiently into pancreatic endocrine cells in vitro as well as in vivo [78]. There is an option for the use of UCB-MSCs as insulin producing cells. UCB-MSCs were similar to human ESCs, following similar steps producing the differentiated β-cells [79]. Unsal et al. [80] showed that transplantation of MSCs together with islets cells into streptozotocin

Stromal Stem Cells: Nature, Biology and Potential Therapeutic Applications

http://dx.doi.org/10.5772/intechopen.77346

15

Cardiac cells transplantation is a novel strategy for myocardial repair, which is currently applied in animal models. Although MSCs are a good source for cardiomyocytes differentiation, it was found that in vitro differentiation is effective only from young cell sources and in vivo differentiation of cardiomyocytes is very rare [81]. MSCs, which have differentiated into cardiomyocytes under the effect of cocktail of growth factors [82], were used in treatment of left ventricular heart failure and MI [83]. The systematic injection of BM-MSCs into the infarcted myocardium of rodent models partially produced recompensation [84]. Katritsis et al. [85] reported improvement in myocardial contractibility when autologous MSCs were transplanted with endothelial progenitor cells. Despite the fact that MSCs are proven to be effective in MI and related problems, still the ability of the heart to retain cells is low; only 10% cell retention after 4 h of cells injection and 1% after 24 h [86]. Roura et al. [87] recorded that UCB-MSCs proliferated and then differentiated into endothelial lineage, were retained for several weeks when injected in acute MI mice. Transplantation of UCB-MSCs into myocardial infarction animal model along with fibronectin-

From all the previous studies, it becomes clear that the use of hMSCs in clinical field will increase in future. For clinical applications, a large number of MSCs in an 'off the shelf' format is required. For this purpose, cryopreservation and banking are necessary to be established. This will allow unique opportunities to improve the potential uses of these cells in research and clinical applications. Keeping in mind its use in future clinical and therapeutic applications, there is a need to ensure the safety and efficacy of these cells while cryopreserving and banking. Cryopreservation media should be optimal so uniform change in temperature during freezing and thawing, long-term storage in liquid nitrogen and employed freezing device are

treated diabetic rat model improve the survival rate of engrafted islets.

immobilized polycaprolactone nanofibers were found very effective [88].

10. Cryopreservation and banking

the main factors to consider.

9.8. Cardiovascular diseases

#### 9.4. Alzheimer disease

Alzheimer disease (AD), one of the commonest neurodegenerative diseases, characterized by symptoms as intellectual disabilities, dementia and memory loss. Till present, no treatment was established to slow down or stop the progression of AD [67]. Researchers use stem cell therapy in AD animal model aiming to decrease the neuropathological deficits. Mostly by activating the alternate microglia, increasing the expression of Aβ-degradation enzymes and decreasing the expression of pro-inflammatory cytokines, that the human AD-MSCs modulate the inflammatory environment [68]. Furthermore, MSCs modulate the inflammatory environment of AD and inadequacy of regulatory T-cells (Tregs) and they could modulate microglia activation [69]. Shin et al. [70] demonstrated that human UCB-MSCs increase the neuronal survival and stimulate Tregs which control microglia activation in AD mice model. Most recently, it was confirmed that MSCs stimulates the cell autophagy pathway, causing increased neuronal survivability and clearing of the amyloid plaque both in vivo and in vitro [70].

### 9.5. Autoimmune diseases

MSCs have the ability of regulating immune responses, thus it can treat immune disorders. Other hMSCs can be used for autoimmune diseases treatment, after revealing that human BM-MSCs are able to protect hematopoietic precursors from inflammatory damage [71].

#### 9.6. Rheumatoid arthritis

Rheumatoid arthritis (RA), a joint inflammatory disease resulting from loss of immunological self-tolerance. The use of MSCs in animal models' studies, were successful in slowing disease progression and enhancing the disease recovery. Beside its anti-inflammatory function, IL-10 is an important factor in the activation of Tregs that controls self-reactive T-cells and motivates peripheral tolerance in vivo [72]. Similar effects were produced by human BM-MSCs in the collagen-induced arthritis model in DBA/1 mice [73]. These studies suggest that the improvement of the RA pathogenesis in DBA/1 mice model in case of using MSCs, can be caused by activating Treg cells as well as suppressing the production of inflammatory cytokines. However, MSCs were only effective when administered at the onset of disease, in case of adjuvantinduced and spontaneous arthritis model, which suggests that MSCs lost their immunoregulatory properties when exposed to inflammatory microenvironment [74].

#### 9.7. Type 1 diabetes

Type 1 diabetes, an autoimmune disease caused by the destruction of β-cells due the production of auto antibody directed against these cells. As a result, there is decrease in the insulin production to a level which is failed to control the blood glucose. It has been proved that MSCs can differentiate into insulin producing cells and have the capacity to regulate the immunomodulatory effects [75]. Zulewski et al. [76] isolated Nestin positive cells from rat pancreatic islets which differentiated into pancreatic endocrine cells. Nestin positive cells were isolated from human pancreas and transplanted to diabetic nonobese diabetic/severe combined immunodeficiency (NOD-SCID) mice, which improved hyperglycemic condition [77]. However, these studies were found controversial and it was suggested that besides pancreatic tissues, other tissues can be used as an alternative for MSCs isolation to treat type 1 diabetes. Human BM-MSCs can be differentiated efficiently into pancreatic endocrine cells in vitro as well as in vivo [78]. There is an option for the use of UCB-MSCs as insulin producing cells. UCB-MSCs were similar to human ESCs, following similar steps producing the differentiated β-cells [79]. Unsal et al. [80] showed that transplantation of MSCs together with islets cells into streptozotocin treated diabetic rat model improve the survival rate of engrafted islets.
