Mesenchymal stem cells rescue Purkinje cells and improve motor functions in a mouse model of cerebellar ataxia

9 p., 6 figures and references.Mesenchymal stem cells have been proven to be potentially effective in the treatment of a large variety of diseases, including neurodegenerative disorders. Of these, cerebellar ataxia is a group of disorders characterized by the degeneration of the cerebellum, particularly the Purkinje cells, responsible for motor coordination and control of the motor functions. To analyze the possibility of using bone marrow-derived mesenchymal stem cells in treating ataxia, we transplanted these cells in the cerebellum of newborn Lurcher mutant mice, a very aggressive mouse model characterized by the selective early post-natal death of Purkinje cells in the cerebellum. Two months after the surgical procedure, the treated mice presented significant improvements in the motor behavior tests performed. Histological analysis of the cerebellum indicated that the donor cells had migrated throughout the cerebellum, as well as a significant increase in the number of Purkinje cells. Many grafted stem cells were located adjacent to the Purkinje cell layer, and expressed BDNF, NT-3 or GDNF, neurotrophic factors implicated in Purkinje cell survival. Also, a small percentage of the grafted stem cells had fused with Purkinje cells. Thus, we have shown that mesenchymal stem cells are capable of integrating into the central nervous system, migrate towards the areas where neurodegenerative processes are occurring, and rescue the degenerating cells through cell trophic effects. This is an adequate and feasible model that could be translated into a therapeutic approach for clinical assays in neurodegenerative diseases.This work has been financed by Generalitat Valenciana (INA-SM-00108 and APOSTD/2007/016, 6), Consolider-Ingenio 2010 (CSD2007-00023), ELA Foundation (U01/07), TERCEL (ISCIII, RD06/0010/0023), Spanish National Research Council (CSIC, 5321617002-B10001A201), PROMETEO (/2009/028), and the Ministry of Education and Science (BFU2005-0985).Peer reviewe

Intramuscular transplantation of bone marrow cells prolongs the lifespan of SOD1G93A mice and modulates expression of prognosis biomarkers of the disease

Abstract Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive muscle weakness, paralysis and death. There is no effective treatment for ALS and stem cell therapy has arisen as a potential therapeutic approach. Methods SOD1 mutant mice were used to study the potential neurotrophic effect of bone marrow cells grafted into quadriceps femoris muscle. Results Bone marrow intramuscular transplants resulted in increased longevity with improved motor function and decreased motoneuron degeneration in the spinal cord. Moreover, the increment of the glial-derived neurotrophic factor and neurotrophin 4 observed in the grafted muscles suggests that this partial neuroprotective effect is mediated by neurotrophic factor release at the neuromuscular junction level. Finally, certain neurodegeneration and muscle disease-specific markers, which are altered in the SOD1G93A mutant mouse and may serve as molecular biomarkers for the early detection of ALS in patients, have been studied with encouraging results. Conclusions This work demonstrates that stem cell transplantation in the muscle prolonged the lifespan, increased motoneuron survival and slowed disease progression, which was also assessed by genetic expression analysis

Bone marrow transplantation in hindlimb muscles of motoneuron degenerative mice reduces neuronal death and improves motor function

Bone marrow has proved to be an adequate source of stem cells for the treatment of numerous disorders, including neurodegenerative diseases. Bone marrow can be easily and relatively painlessly extracted from a patient or allogenic donor and then transplanted into the degenerative area. Here, the grafted cells will activate a number of mechanisms in order to protect, repair, and/or regenerate the damaged tissue. These properties make the bone marrow a feasible source for cell therapy. In this work, we transplanted bone marrow cells into a mouse model of motoneuron degeneration, with the particularity of placing the cells in the hindlimb muscles rather than in the spinal cord where neuronal degeneration occurs. To this end, we analyze the possibility for the transplanted cells to increase the survival rate of the spinal cord motoneurons by axonal-guided retrograde neurotrophism. As a result, the mice significantly improved their motor functions. This coincided with an increased number of motoneurons innervating the treated muscle compared with the neurons innervating the non-treated contralateral symmetric muscle. In addition, we detected an increase in glial-derived neurotrophic factor in the spinal cord, a neurotrophic factor known to be involved in the rescue of degenerating motoneurons, exerting a neuroprotective effect. Thus, we have proved that bone marrow injected into the muscles is capable of rescuing these motoneurons from death, which may be a possible therapeutic approach for spinal cord motoneuron degenerative diseases, such as amyotrophic lateral sclerosis.This work was supported by Ministerio Ciencia E Innovacion (MICINN BFU2010-27326), DIGESIC-MEC BFU2008-00588, Ingenio 2010 MEC-CONSOLIDER CSD2007-00023, from the GVA Prometeo grant 2009/028, and ISCIII Cibersam and Tercel (RD06/0010/0023), as well as ELA Foundation, Fundacion Diogenes-Elche City Government, Rotary Club Elche-Illice, and Fundacio Gent per Gent grant 24 NEURO.Peer reviewe

Intramuscular transplantation of bone marrow cells prolongs the lifespan of SOD1 G93A mice and modulates expression of prognosis biomarkers of the disease

Altres ajuts: This study was supported by Red de Terapia Celular, TERCEL (RD12/0019/0024).Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive muscle weakness, paralysis and death. There is no effective treatment for ALS and stem cell therapy has arisen as a potential therapeutic approach. SOD1 mutant mice were used to study the potential neurotrophic effect of bone marrow cells grafted into quadriceps femoris muscle. Bone marrow intramuscular transplants resulted in increased longevity with improved motor function and decreased motoneuron degeneration in the spinal cord. Moreover, the increment of the glial-derived neurotrophic factor and neurotrophin 4 observed in the grafted muscles suggests that this partial neuroprotective effect is mediated by neurotrophic factor release at the neuromuscular junction level. Finally, certain neurodegeneration and muscle disease-specific markers, which are altered in the SOD1 G93A mutant mouse and may serve as molecular biomarkers for the early detection of ALS in patients, have been studied with encouraging results. This work demonstrates that stem cell transplantation in the muscle prolonged the lifespan, increased motoneuron survival and slowed disease progression, which was also assessed by genetic expression analysis

Comparative Effects between Bone Marrow and Mesenchymal Stem Cell Transplantation in GDNF Expression and Motor Function Recovery in a Motorneuron Degenerative Mouse Model

Motorneuron degenerative diseases, such as amyotrophic lateral sclerosis (ALS), are characterized by the progressive and rapid loss of motor neurons in the brain and spinal cord, leading to paralysis and death. GDNF (glial cell line derived neurotrophic factor) has been previously shown to be capable of protecting motor-neurons in ALS animal models although its delivery to the spinal cord after systemic administration is blocked by the blood brain barrier. Thus, it is necessary to develop new neurotrophic approaches to protect these motor neurons from death. Bone marrow-derived stem cells have been shown to be capable of improving a large variety of neurodegenerative disorders through neurotrophic mediated mechanisms. Here we analyzed the effect of transplanting whole bone marrow or cultured mesenchymal stem cells into the spinal cord of a motor neuron degenerative mouse model. Motor functions were analyzed using various behavior tests for several weeks after transplantation. We observed that bone marrow, and to a lesser degree mesenchymal stem cell, treated mice improved significantly in the motor tests performed, coinciding with a higher GDNF immunoreactivity in the grafted spinal cord. In several cases, the treated spinal cords were extracted, the engrafted bone marrow cells isolated and cultured, and finally re-transplanted into the spleen of immunodeficient mice. Re-grafted cells were detected in the host spleen, bloodstream and bone marrow, demonstrating a phenotypic stability. Thus, bone marrow cells do not suffer significant phenotypic modifications and is an efficient procedure to ameliorate motor-neuron degeneration, making it a possible therapeutic approach. © 2011 Springer Science+Business Media, LLC.This work has been financed by EUCOMMTOOLS, Science and Innovation Ministry (MICINN BFU-2008-00588, CONSOLIDER CSD2007-00023), Valencian government (PROMETEO /2009/028), Cell Therapy Network-Carlos III Health Institute (RD06/0010/0023 and RD07/0010/2012), Alicia Koplowitz Foundation, 5P- Syndrome Foundation, and Diógenes Foundation/Elche (CATEDRA ELA).Peer Reviewe