*2.3.4. Multiple sclerosis*

Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by demyelinated areas in the brain and spinal cord that heal forming a glial scar (sclerosis). It is believed that MS is caused by T cell-mediated autoimmune reaction against proteins of the myelin sheath inducing oligodendrocytes and neuronal loss. Most of therapies in MS patients target the immune system or the inflammatory process. Since the pathogenic process of MS can be divided into inflammatory and degenerative phases, PMSC-based cell therapy seems appropriate since it may be able to specifically regulate immune responses and also induce neuronal regeneration. The animal model that closely resembles the MS symptoms is the experimental autoimmune encephalomyelitis (EAE) in mice where the animals are injected with myelin antigens that initiate an immune response. Several preclinical trials based on the treatment of EAE animals with PMSC have been published. Intracerebroventricular (ICV) transplantation of PMSC at day 5 (pre-symptomatology) or day 14 (at the beginning of the disease) after immunization, significantly reduced the severity of the disease and prolonged survival without delaying the onset of the disease [72]. Several intraperitoneal injections of PMSC in EAE mice delayed the onset of the symptoms and decreased disease incidence in the treated group respect to control, as well as inhibiting T cell proliferation and downregulating the production of pro-inflammatory factors while increasing the production of anti-inflammatory cytokines [73]. Likewise, ICV or intrathecal (ITH) injection of PMSC in EAE rats, also delayed the onset of motor symptoms, reduced inflammation, prevented axonal loss, and reduced disease severity [74].

#### **2.4. Use of placental mesenchymal stem/stromal cells in bone and cartilage diseases**

Bone regeneration is the physiological process of bone formation, which is involved in continuous remodeling throughout adult life, and can be observed during bone healing after damage. However, there are large lesions created by traumatism, infection, tumor resection or skeletal abnormalities in which physiological bone regeneration is not sufficient. There are also other conditions, such as osteoporosis, in which regeneration is compromised. PMSC have the potential to differentiate into osteogenic lineage, and seem to be an appropriate therapeutic option for bone regeneration. The use of 3D scaffolds that support cell differentiation and improve engraftment has become habitual in PMSC-mediated bone regeneration therapy. Several published studies confirm that PMSC have potent in vivo bone-forming capacity and may be worthwhile candidates for in vivo bone tissue repair. So, when PMSC were subcutaneously injected into severe combined immunodeficiency (SCID) mice with hydroxyapatite/tricalcium phosphate particles as a vehicle, new bone formation was found throughout all implants [75]. Another study showed that PMSC administered in combination with nanobiphasic calcium phosphate ceramics in a rat model of femur bone defects produced complete healing of the defect in 3 months without evidence of fibrosis [76].

*2.3.2. Alzheimer's disease*

236 Stromal Cells - Structure, Function, and Therapeutic Implications

*2.3.3. Amyotrophic lateral sclerosis*

*2.3.4. Multiple sclerosis*

tional deterioration and increasing lifespan [71].

Alzheimer's disease (AD) pathogenesis is characterized by a deposition of β-amyloid peptide and hyperphosphorylation of tau causing loss of the synaptic and neuronal activities and neuroinflammation. It has been demonstrated that PMSC, transplanted into an Alzheimer's disease mouse model, modulated the inflammatory response. Moreover, mice injected with PMSC presented higher levels of β-amyloid degrading enzymes, reduced levels of pro-inflammatory cytokines, and increased levels of anti-inflammatory cytokines (TGF-β and IL-10). The effect

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of nerve cells in the brain and spinal cord, leading to muscle weakness, paralysis, respiratory problems, and eventually, death. Multiple intravenous injections of PMSC in a mouse model of ALS, resulted in a protection of motor neurons from inflammatory effectors delaying func-

Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by demyelinated areas in the brain and spinal cord that heal forming a glial scar (sclerosis). It is believed that MS is caused by T cell-mediated autoimmune reaction against proteins of the myelin sheath inducing oligodendrocytes and neuronal loss. Most of therapies in MS patients target the immune system or the inflammatory process. Since the pathogenic process of MS can be divided into inflammatory and degenerative phases, PMSC-based cell therapy seems appropriate since it may be able to specifically regulate immune responses and also induce neuronal regeneration. The animal model that closely resembles the MS symptoms is the experimental autoimmune encephalomyelitis (EAE) in mice where the animals are injected with myelin antigens that initiate an immune response. Several preclinical trials based on the treatment of EAE animals with PMSC have been published. Intracerebroventricular (ICV) transplantation of PMSC at day 5 (pre-symptomatology) or day 14 (at the beginning of the disease) after immunization, significantly reduced the severity of the disease and prolonged survival without delaying the onset of the disease [72]. Several intraperitoneal injections of PMSC in EAE mice delayed the onset of the symptoms and decreased disease incidence in the treated group respect to control, as well as inhibiting T cell proliferation and downregulating the production of pro-inflammatory factors while increasing the production of anti-inflammatory cytokines [73]. Likewise, ICV or intrathecal (ITH) injection of PMSC in EAE rats, also delayed the onset of motor symptoms, reduced inflammation, prevented axonal loss, and reduced disease severity [74].

**2.4. Use of placental mesenchymal stem/stromal cells in bone and cartilage diseases**

Bone regeneration is the physiological process of bone formation, which is involved in continuous remodeling throughout adult life, and can be observed during bone healing after damage. However, there are large lesions created by traumatism, infection, tumor resection or skeletal

of PMSC injection resulted in an improvement of memory function [70].

Osteoarthritis (OA) is a degenerative process of the cartilage in joints. There is still no treatment available to improve or reverse the degenerative process and current pharmacological treatments are only palliative. Given the potential of PMSC to differentiate into musculoskeletal lineages including bone and cartilage, MSC have been proposed as an optimal regenerative cellular therapy for degenerative musculoskeletal conditions as OA. There are numerous data that support this hypothesis in preclinical models. PMSC embedded in a collagen I gel and transplanted in a rat model of femoral cartilage defect appeared to cover the tissue defects with soft tissue positive for toluidine blue suggesting in vivo differentiation of transplanted cells [77]. Also PMSC grown on silk fibroin and transplanted into the knee in rabbits with knee osteochondral defects resulted in newly created hyaline cartilage without inflammatory response [78]. Similarly, PMSC seeded onto poly lactic-co-glycolic acid (PLGA) and preconditioned in chondrogenic medium were well tolerated and found in the reparative tissue of OA rabbit knees 8 weeks after transplantation [79].
