**6. Stem cell treatment for peripheral neuropathy**

Management of peripheral neuropathy in affected patients could be tailored to individual requirements, for instance the presence of other co-morbidities could influence the therapy. Damaged peripheral nerves demonstrate some potential to regenerate, however, complete functional recovery is infrequent. Novel approaches are required in the clinical management of peripheral nerve injuries since the current surgical techniques result in deficient sensory recovery [119].

Nowadays, neuropathy research is focusing on newer cellular and molecular approaches, such as stem cell therapy. Preclinical studies indicate that stem cell therapy represents the great promise for the future of molecular and regenerative medicine, including tissue regeneration. In peripheral neuropathy, stem cells could act in several ways: i) improving the intrinsic regenerative capacity of injured nerves; ii) inhibiting pathogenic immune responses both in the periphery and inside the central nervous system; iii) releasing neuroprotective and antiinflammatory molecules thus favouring tissue repair.

In the last years, it has been demonstrated that stem cells are neuroprotective in a variety of nervous system injury models [120]. Briefly, stem cells have been found in all multi-cellular organisms, they are able to divide and differentiate into diverse specialized cell types. In addition, stem cells self-renew themselves to produce more stem cells. Indeed, in principle, their extraordinary properties are the self-renewal (the ability to perform indefinite cell division cycles while maintaining the undifferentiated state) and the multipotency (the capacity to differentiate into specialized cell types). The availability of multiple stem cell types provides both the opportunity and a reasoned approach for treating several, otherwise untreatable, human diseases [121].

As neurodegenerative disease, also peripheral neuropathy could benefit by stem cell therapy. This cell- based treatment opportunity represents a non-surgical approaches to enhance nerve recovery and re-innervation processes [122, 123]. Indeed, stem cell implan‐

tation appears as a possible curative treatment having the stem cells the ability to incorporate into the site of a lesion, differentiate, and to improve locomotor recovery [124]. Stem cell beneficial effects are due to their properties, as self-renewal ability with the capacity to generate more identical stem cells; the capacity to give rise to more differenti‐ ated cells; the capacity to produce neuroprotective and anti-inflammatory molecules (paracrine regulatory functions) [121].

cannabinoids for the treatment of chronic pain states. The synthesis of CB2 receptorselective agonists which lack of the majority of central side effects and produce antinocicep‐

84 Peripheral Neuropathy - A New Insight into the Mechanism, Evaluation and Management of a Complex Disorder

Cannabinoids can counteract pain in both physiological and pathological conditions. CB1Rs and CB2Rs are both overexpressed during inflammation and neuropathic pain. In this context, selective activation of peripheral CB1 or CB2 receptor by cannabinoid agents which do not penetrate the blood brain barriers or the enhancement of the endocannabinoid levels can be a promising therapeutic approach that avoid the side effects associated with central CB1 receptor activation. Finally the isolation of non psychotropic compounds of *Cannabis Sativa*, such as cannabidiol or cannabichromene, which show antinociceptive properties in physiological [117] and pathological [118] pain conditions, could represent an alternative tool in pain

Management of peripheral neuropathy in affected patients could be tailored to individual requirements, for instance the presence of other co-morbidities could influence the therapy. Damaged peripheral nerves demonstrate some potential to regenerate, however, complete functional recovery is infrequent. Novel approaches are required in the clinical management of peripheral nerve injuries since the current surgical techniques result in deficient sensory

Nowadays, neuropathy research is focusing on newer cellular and molecular approaches, such as stem cell therapy. Preclinical studies indicate that stem cell therapy represents the great promise for the future of molecular and regenerative medicine, including tissue regeneration. In peripheral neuropathy, stem cells could act in several ways: i) improving the intrinsic regenerative capacity of injured nerves; ii) inhibiting pathogenic immune responses both in the periphery and inside the central nervous system; iii) releasing neuroprotective and anti-

In the last years, it has been demonstrated that stem cells are neuroprotective in a variety of nervous system injury models [120]. Briefly, stem cells have been found in all multi-cellular organisms, they are able to divide and differentiate into diverse specialized cell types. In addition, stem cells self-renew themselves to produce more stem cells. Indeed, in principle, their extraordinary properties are the self-renewal (the ability to perform indefinite cell division cycles while maintaining the undifferentiated state) and the multipotency (the capacity to differentiate into specialized cell types). The availability of multiple stem cell types provides both the opportunity and a reasoned approach for treating several, otherwise

As neurodegenerative disease, also peripheral neuropathy could benefit by stem cell therapy. This cell- based treatment opportunity represents a non-surgical approaches to enhance nerve recovery and re-innervation processes [122, 123]. Indeed, stem cell implan‐

tive effects represent an interesting pharmacological tool [116].

**6. Stem cell treatment for peripheral neuropathy**

inflammatory molecules thus favouring tissue repair.

untreatable, human diseases [121].

management.

recovery [119].

The ideal stem cell source for peripheral neuropathy repair should be easily accessible, involve non-invasive harvesting, be rapidly expandable in *in vitro* culture, be able to survive and integrate within the host nerve tissue [125]. Mesenchymal stem cells (MSCs) represent a promising therapeutic approach in nerve tissue engineering [126]. These cells are a population of progenitor cells of mesodermal origin found in the bone marrow of adults, giving rise to skeletal muscle cells, blood, adipose tissue, vascular and urogenital systems, and to connective tissues throughout the body [127]. This type of stem cells yields most prominent results in peripheral nerve re-generation. In addition, MSCs have great potential as therapeutic agents since they are easy to isolate and can be expanded from patients without serious ethical and technical problems [128]. MSC treatment into a polycaprolactone nerve guide was able to improve re-innervation and activity in mice undergone to nerve transection [129]. Interestingly, some transplanted stem cells as‐ sumed a Schwann-cell-like phenotype.

In a murine model of sciatic nerve crush injury, intravenous administration of adipose-derived MSC (ASC) significantly accelerated the functional recovery [126]. Mice showed significant improvement in fiber sprouting and the reduction of inflammatory infiltrates. The authors proposed that ASC-mediated positive effects were due to the production of *in situ* molecules, which, directly or indirectly through a cross-talk with local glia cells, could modulate the local environment with the down-regulation of inflammation and the promotion of axonal regen‐ eration. Peripheral neuropathy is a dramatic symptom in Krabbe disease [130]. Hematopoietic stem cell (HSC) transplantation proved effective in slow the progression of this disease. HSCs were able to achieve improvement in peripheral nerve conduction abnormalities in Krabbe patients, suggesting remyelination of the nerves [131]. Diabetic neuropathy is the most common complication of diabetes, frequently leads to foot ulcers and may progress to limb amputations [132].

It has been proposed that autologous transplantation of bone marrow-derived mononuclear cells (BM-MNCs) could be a novel strategy for the treatment of painful diabetic neuropathy [133]. Indeed, transplantation of BM-MNCs is able to alleviate neuropathic pain in the early stage of streptozotocin-induced diabetic rats. The BM-MNC transplantation significantly ameliorated mechanical hyperalgesia and cold allodynia. Diabetic neuropathy is attracting most research strategies. Several clinical trials have been performed on the use of stem cells for the treatment of human peripheral diabetic neuropathy (www.clinicaltrials.gov). Induced pluripotent stem (iPS) cell technology has enormous potentials to advance medical therapy by personalizing regenerative medicine [134]. iPS cells offer great potentials as a future tool also for the treatment of peripheral neuropathy. Cell incorporation into conduit repair of peripheral nerves demonstrates experimental promise as a novel intervention. Tissue-engineered bioabsorbable nerve conduits coated with iPS cell-derived neurospheres were able to repair peripheral nerve gaps in mice [135].

apoptotic factors, i.e. fermented soybean extracts or granulocyte-colony stimulating factor (G-

New Insights on Neuropathic Pain Mechanisms as a Source for Novel Therapeutical Strategies

http://dx.doi.org/10.5772/55276

87

In some cases, stem cell therapy does not provide optimal results. The multipotent capacity of stem cells to differentiate into many cell types has led to successful therapy, but concerns remain about the possible negative or harmful effects of the transplanted cultured cells [148]. Mahdi-Rogers et al. treated six patients with chronic acquired demyelinating neuropathy with autologous peripheral blood stem cell transplantation (PBSCT) [149]. These patients were refractory to other treatments; however, the authors reported serious adverse events and lack of sustained response. There have been reports of inflammatory peripheral neuropathy or polyneuropathy associated with chronic graft-versus-host disease (GVHD) [150], even if pathogenesis has not been fully cleared. Doi et al. report a case of immune-mediated neuro‐ pathy after allogenic hematopoietic stem cell transplantation for Philadelphia-chromosomepositive acute lymphoblastic leukemia [151].On the other hand, a case of peripheral neuropathy induction was reported after autologous blood stem cell transplantation for multiple myeloma [152]. Overall, these data indicate that before being suitable for clinical applications, stem cell biology needs to be investigated further and in greater detail [153].

Neuropathic pain involves a complex network of mechanisms involving peripheral and central nervous system. The peripheral nerve injury produces abnormal peripheral afferent inputs at the spinal dorsal horn which leads to development of central sensitization and plastic changes in supraspinal areas. The precise contribute of the different brain sites in neuropathic pain development and maintenance is still far to be established. In particular the contribute of the descending pain modulatory system including the PAG and the RVM is dual varying from inhibitory to facilitatory. By this subject strategies able to shift the balance between facilitatory versus inhibitory influences of the descending pathway may be useful to counteract neuro‐ pathic pain symptoms. Cannabinoids have been proved to stimulate the PAG-RVM inhibitory

Neurons are not the only cell type involved in plastic changes at the base of pain hypersensi‐ tivity and activated microglia actively contribute to pain facilitation through a tight interaction with neuron activity and the release of pain mediators. Novel strategies based on switching off the microglia activation represents a possible therapeutic intervention to alleviate neuro‐

Human mesenchymal stem cell transplantation has shown to reduce astrocytic and microglial cell activation, mechanical allodynia and cellular and molecular pain mechanisms. The therapeutic potentiality of stem cell to alleviate neuropathic pain appears encouraging, however, its clinical application in peripheral neuropathy requires and deserves further

pain control and inhibit neuropathic pain-related allodynia and hyperalgesia.

CSF) [146, 147].

**7. Conclusions**

pathic pain.

investigations.

Achieving peripheral nerve regeneration, axonal regeneration and re-myelination with stem cells is a challenging research goal. This process is very complex, with Wallerian degeneration being the most elementary reaction and Schwann cells playing an important role. An emerging solution to improve upon this intrinsic regenerative capacity is to supplement injured nerves with stem cells [136]. Stem cells effectiveness in the treatment of peripheral nerve injury may lie in their ability to differentiate into Schwann cells, secrete neurotrophic factors, and assist in myelin formation [137, 136]. This strategy of introduction autologous stem cells directly into the site of a nerve injury represents a promising therapy. Skin-derived precursor cells (SKPs) were successfully transplanted in the sciatic nerve of Lewis rats bridged by a freeze-thawed nerve graft.

The cells were able to improve nerve re-generation, probably their effect was due to the ability to secrete bioactive neurotrophins [138]. Another stem cell type, the multipotent hair follicle stem cells, could provide a potential accessible, autologous source of stem cells for regeneration therapy of damaged nerves [139]. More recently, in an interesting study, Amoh et al. trans‐ planted hair follicle stem cells around the impinged sciatic nerve of the mice. The cells differentiated into glia fibrillary acidic protein-positive Schwann cells, promoting the recovery of pre-existing axons. Authors reported that the regenerated sciatic nerve was functionally recovered [140]. These hair follicle stem cells could differentiate into several cell types, i.e. neurons, glia, keratinocytes, smooth muscle cells and melanocytes. They are nestin-positive cells and once implanted into the gap region of the sciatic or tibial nerve, are able to enhance the rate of nerve regeneration and the restoration of nerve function [141]. Wharton's jelly fishderived mesenchymal stem cells (WJMSCs) could be also a promising cell source for nerve tissue engineering. It has been demonstrated that these cells can be differentiated into Schwann-like cells and could be suitable Schwann-cell substitutes for nerve repair in clinical applications [142]. A recent strategy for peripheral nerve regeneration is based on the use of CD34(+) cells. Indeed, integration of CD34(+) cells in injured nerve significantly promotes nerve regeneration [143]. However, limited migration and short survival of CD34(+) cells could counteract this beneficial effect. One strategy could be the potentiation of CD34(+) cell recruitment triggered by stromal cell-derived factor-1α (SDF-1α) [143]. This strategy based on the over-expression of SDF-1α is providing interesting results in the peripheral neuropathy treatment. It has been proposed that the expression of SDF-1α in the injured nerve exerts a trophic effect by recruiting progenitor cells that promote nerve regeneration. Intravenous administration of human amniotic fluid-derived mesenchymal stem cells facilitated neural regeneration in a sciatic nerve crush injury model, when recruited by expression of SDF-1α in muscle and nerve after nerve crush injury [144]. As mesenchymal stem cells, amniotic fluidderived mesenchymal stem cells have the ability to secrete neurotrophic factors that are able to promote neuron survival. Their transplantation was able to regenerate the sciatic nerve after crush injury by secretion of neurotrophic factors [145]. Interestingly, the stem cell mediated effects could be enhanced by co-administration of several anti-inflammatory and antiapoptotic factors, i.e. fermented soybean extracts or granulocyte-colony stimulating factor (G-CSF) [146, 147].

In some cases, stem cell therapy does not provide optimal results. The multipotent capacity of stem cells to differentiate into many cell types has led to successful therapy, but concerns remain about the possible negative or harmful effects of the transplanted cultured cells [148]. Mahdi-Rogers et al. treated six patients with chronic acquired demyelinating neuropathy with autologous peripheral blood stem cell transplantation (PBSCT) [149]. These patients were refractory to other treatments; however, the authors reported serious adverse events and lack of sustained response. There have been reports of inflammatory peripheral neuropathy or polyneuropathy associated with chronic graft-versus-host disease (GVHD) [150], even if pathogenesis has not been fully cleared. Doi et al. report a case of immune-mediated neuro‐ pathy after allogenic hematopoietic stem cell transplantation for Philadelphia-chromosomepositive acute lymphoblastic leukemia [151].On the other hand, a case of peripheral neuropathy induction was reported after autologous blood stem cell transplantation for multiple myeloma [152]. Overall, these data indicate that before being suitable for clinical applications, stem cell biology needs to be investigated further and in greater detail [153].
