Induction of Neurotrophin Expression via Human Adult Mesenchymal Stem Cells: Implication for Cell Therapy in Neurodegenerative Diseases

Abstract

In animal models of neurological disorders for cerebral ischemia, Parkinson's disease, and spinal cord lesions, transplantation of mesenchymal stem cells (MSCs) has been reported to improve functional outcome. Three mechanisms have been suggested for the effects of the MSCs: transdifferentiation of the grafted cells with replacement of degenerating neural cells, cell fusion, and neuroprotection of the dying cells. Here we demonstrate that a restricted number of cells with differentiated astroglial features can be obtained from human adult MSCs (hMSCs) both in vitro using different induction protocols and in vivo after transplantation into the developing mouse brain. We then examined the in vitro differentiation capacity of the hMSCs in coculture with slices of neonatal brain cortex. In this condition the hMSCs did not show any neuronal transdifferentiation but expressed neurotrophin low-affinity (NGFR p75 ) and high-affinity (trkC) receptors and released nerve growth factor (NGF) and neurotrophin-3 (NT-3). The same neurotrophin's expression was demonstrated 45 days after the intracerebral transplantation of hMSCs into nude mice with surviving astroglial cells. These data further confirm the limited capability of adult hMSC to differentiate into neurons whereas they differentiated in astroglial cells. Moreover, the secretion of neurotrophic factors combined with activation of the specific receptors of transplanted hMSCs demonstrated an alternative mechanism for neuroprotection of degenerating neurons. hMSCs are further defined in their transplantation potential for treating neurological disorders.Key words: Mesenchymal stem cells; Transplantation; Neurotrophin; Astroglial cells INTRODUCTIONtient, thereby avoiding potential tissue rejection. The identification of a source of readily accessible neural progenitors that can be obtained from the individual reBrain repair has been a particular focus of attention in stem cell (SC) therapy. The benefits of neural SC quiring transplantation therapy without permanent damage could provide a great benefit. transplantation as a means of restoring central nervous system (CNS) diseases or spinal cord injury are quite An important biological finding from several studies is that SCs have a certain degree of flexibility in their recognized (1,14,47,56). The use of human embryonic neural SCs raises ethical issues as well as practical probdifferentiating capacity, resulting in lineage interconversion between precursor cells originating from the same lems due to transdifferentiation in the adult environment and the need for immunosuppression after grafting. One and different germ layer (1,15,16,20). Such plasticity is supported by experiments in which bone marrowadvantage of using adult SCs, therefore, is that they can be derived from and be transplanted into the same paderived SCs can yield not only blood cells but also mus- (6,8,34,44,53,57). There is also evidence that mesenchymal stem cells (MSCs) can give rise to row samples were layered on a Histopaque-1077 gradient (specific ...

Mesenchymal stromal cell therapy: a revolution in Regenerative Medicine?

“…20,21 Besides autoimmune encephalomyelitis, infusion of MSCs have been demonstrated to have a role in the protection of neurons from damage occurring in conditions such as spinal cord injury, stroke and degenerative conditions. [22][23][24][25] Topical implantation of BM-derived MSCs has been shown to be beneficial in promoting the healing process of experimental colitis in rats, confirming the ability of these cells to induce tissue repair. 26 In similar models of experimental colitis, MSCs of different tissue origin alleviated the signs and symptoms of the disease by displaying immunomodulatory functions and ameliorating inflammation-related tissue destruction.…”

Menstrual Blood Cells Display Stem Cell–Like Phenotypic Markers and Exert Neuroprotection Following Transplantation in Experimental Stroke

“…Indeed, examination of trophic factor levels in the media of OGD-exposed cultured menstrual blood-derived stem cells reveals the up-regulation of VEGF, BDNF, NT-3, but not GDNF. Recent reports have implicated this set of trophic factors as mediating therapeutic benefi ts of transplanted stem cells in a variety of CNS disorders, including stroke [42][43][44][45][46][47]. In view of clinical product development, there may be less safety and toxicity concerns for peptide delivery compared to cell therapy.…”

Stem cell sources and therapeutic approaches for central nervous system and neural retinal disorders

“…Human MSCs have been shown to secrete neurotrophin-3 in coculture with neonatal cortical brain slices. 124 The same neurotrophin expression profile was observed at 45 days after transplantation of human MSCs in nude mice. 124 …”

“…Finally, an additional potential therapeutic application of BMSCs is in neuroprotection. These cells have been shown to release a variety of neurotrophic growth factors that can enhance cell survival in injured CNS regions, 124 although again the effectiveness of any neuroprotective applications needs to be further investigated and ultimately assessed in vivo.…”