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Traumatic peripheral nerve lesions affect hundreds of thousands of patients every year; their consequences are life-altering and often devastating and cause alterations in movement and sensitivity. Spontaneous peripheral nerve recovery is often inadequate. In this context, nowadays, cell therapy represents one of the most innovative approaches in the field of nerve repair therapies. The purpose of this systematic review is to discuss the features of different types of mesenchymal stem cells (MSCs) relevant for peripheral nerve regeneration after nerve injury. The published literature was reviewed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A combination of the keywords "nerve regeneration", "stem cells", "peripheral nerve injury", "rat", and "human" were used. Additionally, a "MeSH" research was performed in PubMed using the terms "stem cells" and "nerve regeneration". The characteristics of the most widely used MSCs, their paracrine potential, targeted stimulation, and differentiation potentials into Schwann-like and neuronal-like cells are described in this paper. Considering their ability to support and stimulate axonal growth, their remarkable paracrine activity, their presumed differentiation potential, their extremely low immunogenicity, and their high survival rate after transplantation, ADSCs appear to be the most suitable and promising MSCs for the recovery of peripheral nerve lesion. Clinical considerations are finally reported.

Spinal cord injury (SCI) constitutes an inestimable public health issue. The most crucial phase in the pathophysiological process of SCI concerns the well-known secondary injury, which is the uncontrolled and destructive cascade occurring later with aberrant molecular signaling, inflammation, vascular changes, and secondary cellular dysfunctions. The use of mesenchymal stem cells (MSCs) represents one of the most important and promising tested strategies. Their appeal, among the other sources and types of stem cells, increased because of their ease of isolation/preservation and their properties. Nevertheless, encouraging promise from preclinical studies was followed by weak and conflicting results in clinical trials. In this review, the therapeutic role of MSCs is discussed, together with their properties, application, limitations, and future perspectives., Competing Interests: The authors declare no conflicts of interest.

In this study, murine Mesenchymal Stem Cells (MSCs) labeled with the clinically approved MRI agent Gadoteridol through a procedure based on the hypo-osmotic shock were successfully tracked in vivo in a murine model of Spinal Cord Injury (SCI). With respect to iso-osmotic incubations, the hypo-osmotic labeling significantly increased the Gd(3+) cellular uptake, and enhanced both the longitudinal relaxivity (r1) of the intracellular Gadoteridol and the Signal to Noise Ratio (SNR) measured on cell pellets, without altering the biological and functional profile of cells. A substantial T1 Contrast Enhancement after local transplantation of 3.0×10(5) labeled cells in SCI mice enabled to follow their migratory dynamics in vivo for about 10days, and treated animals recovered from the motor impairment caused by the injury, indicating unaltered therapeutic efficacy. Finally, analytical and histological data corroborated the imaging results, highlighting the opportunity to perform a precise and reliable monitoring of the cell-based therapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is a devastating incurable, neurodegenerative disease that targets motor neurons (MNs) in the primary motor cortex, brainstem, and spinal cord, leading to muscle atrophy, paralysis, and death due to respiratory failure within 2-5 years. Currently, there is no cure for ALS. The development of a therapy that can support or restore MN function and attenuate toxicity in the spinal cord provides the most comprehensive approach for treating ALS. Mesenchymal stem cells might be suitable for cell therapy in ALS because of their immunomodulatory and protective properties. In this review, the authors discuss the major challenges to the translation of in vitro and animal studies of MSCs therapy in the clinical setting., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Urinary incontinence, defined as the complaint of any involuntary loss of urine, is a pathological condition, which affects 30% females and 15% males over 60, often following a progressive decrease of rhabdosphincter cells due to increasing age or secondary to damage to the pelvic floor musculature, connective tissue and/or nerves. Recently, stem cell therapy has been proposed as a source for cell replacement and for trophic support to the sphincter. To develop new therapeutic strategies for urinary incontinence, we studied the interaction between mesenchymal stem cells (MSCs) and muscle cells in vitro; thereafter, aiming at a clinical usage, we analyzed the supporting role of MSCs for muscle cells in vitro and in in vivo xenotransplantation. MSCs can express markers of the myogenic cell lineages and give rise, under specific cell culture conditions, to myotube-like structures. Nevertheless, we failed to obtain mixed myotubes both in vitro and in vivo. For in vivo transplantation, we tested a new protocol to collect human MSCs from whole bone marrow, to get larger numbers of cells. MSCs, when transplanted into the pelvic muscles close to the external urethral sphincter, survived for a long time in absence of immunosuppression, and migrated into the muscle among fibers, and towards neuromuscular endplates. Moreover, they showed low levels of cycling cells, and did not infiltrate blood vessels. We never observed formation of cell masses suggestive of tumorigenesis. Those which remained close to the injection site showed an immature phenotype, whereas those in the muscle had more elongated morphologies. Therefore, MSCs are safe and can be easily transplanted without risk of side effects in the pelvic muscles. Further studies are needed to elucidate their integration into muscle fibers, and to promote their muscular transdifferentiation either before or after transplantation.

Friedreich ataxia golden age: Patients with Friedreich ataxia (FRDA) present neurological deficits and impaired muscle coordination. Mitochondrial energy conversion and oxidative phosphorylation have been shown to contribute to disease pathophysiology. Now, Villa et al. tested whether gold cluster superstructures (Au8-pXs), previously shown to have antioxidant properties, could be effective in reducing the hallmarks of FRDA in vitro and in vivo. Au8-pXs improved mitochondrial function, rescued autophagy flux, and increased FXN protein expression in mesenchymal stem cells from patients. In vivo, the treatment had therapeutic effects in a mouse mode, suggesting that Au8-pXs might be effective in reducing FRDA symptoms. Friedreich ataxia (FRDA) is caused by the reduced expression of the mitochondrial protein frataxin (FXN) due to an intronic GAA trinucleotide repeat expansion in the FXN gene. Although FRDA has no cure and few treatment options, there is research dedicated to finding an agent that can curb disease progression and address symptoms as neurobehavioral deficits, muscle endurance, and heart contractile dysfunctions. Because oxidative stress and mitochondrial dysfunctions are implicated in FRDA, we demonstrated the systemic delivery of catalysts activity of gold cluster superstructures (Au8-pXs) to improve cell response to mitochondrial reactive oxygen species and thereby alleviate FRDA-related pathology in mesenchymal stem cells from patients with FRDA. We also found that systemic injection of Au8-pXs ameliorated motor function and cardiac contractility of YG8sR mouse model that recapitulates the FRDA phenotype. These effects were associated to long-term improvement of mitochondrial functions and antioxidant cell responses. We related these events to an increased expression of frataxin, which was sustained by reduced autophagy. Overall, these results encourage further optimization of Au8-pXs in experimental clinical strategies for the treatment of FRDA. [ABSTRACT FROM AUTHOR]

Background aims. Mesenchymal stromal cells (MSCs), after intraparenchymal, intrathecal and endovenous administration, have been previously tested for cell therapy in amyotrophic lateral sclerosis in the SOD1 (superoxide dismutase 1) mouse. However, every administration route has specific pros and cons. Methods. We administrated human MSCs (hMSCs) in the cisterna lumbaris, which is easily accessible and could be used in outpatient surgery, in the SOD1 G93A mouse, at the earliest onset of symptoms. Control animals received saline injections. Motor behavior was checked starting from 2 months of age until the mice were killed. Animals were killed 2 weeks after transplantation; lumbar motoneurons were stereologically counted, astrocytes and microglia were analyzed and quantified after immunohistochemistry and cytokine expression was assayed by means of real-time polymerase chain reaction. Results. We provide evidence that this route of administration can exert strongly positive effects. Motoneuron death and motor decay were delayed, astrogliosis was reduced and microglial activation was modulated. In addition, hMSC transplantation prevented the downregulation of the anti-inflammatory interleukin-10, as well as that of vascular endothelial growth factor observed in saline-treated transgenic mice compared with wild type, and resulted in a dramatic increase in the expression of the anti-inflammatory interleukin-13. Conclusions. Our results suggest that hMSCs, when intracisternally administered, can exert their paracrine potential, influencing the inflammatory response of the host. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cells (MSCs) are multipotent stem cells that have a supportive role in regenerative therapies, especially in the central nervous system, where spontaneous regeneration is limited. MSCs can exert a paracrine activity and modulate the inflammatory response after a central nervous system injury. Spinal cord injury (SCI) leads to permanent neurologic deficits below the injury site, owing to neuronal and axonal damage. Among experimental treatments after SCI, cell transplantation has emerged as a promising approach. Methods: Using a compression injury model in the mouse spinal cord, MSCs were acutely transplanted into the lesion cavity; injured mice without the graft served as controls. After 26 days, the survival of MSCs was investigated, and their effect on the formation of glial cyst and on injury-related inflammation was evaluated. Results: Grafted MSCs remained permanently undifferentiated. The lesion volume was reduced by 31.6% compared with control mice despite the fact that astroglial and microglial activation was not altered by the graft. Sensory and motor tests showed that MSC cell therapy results in improvement on a battery of behavioral tests compared with control mice: MSC-treated mice versus control mice scored 0.00 versus 0.50 in the posture test, 0.00 versus 1.50 in the hindlimb flexion test, 3.00 versus 2.25 in the sensory test, and 7.50 mistakes versus 15.83 mistakes in the foot-fault test. Conclusions: These results underscore the therapeutic potential of MSCs, making them promising treatments for central nervous system pathologies. [ABSTRACT FROM AUTHOR]