Abstract
Administration of mesenchymal stromal cells (MSC) improves functional outcome in the SOD1G93A mouse model of the degenerative motor neuron disorder amyotrophic lateral sclerosis (ALS) as well as in models of other neurological disorders. We have now investigated the effect of the interaction between MSC and motor neurons (derived from both non-transgenic and mutant SOD1G93A transgenic mice), NSC-34 cells and glial cells (astrocytes, microglia) (derived again from both non-transgenic and mutant SOD1G93A ALS transgenic mice) in vitro. In primary motor neurons, NSC-34 cells and astrocytes, MSC conditioned medium (MSC CM) attenuated staurosporine (STS) - induced apoptosis in a concentration-dependent manner. Studying MSC CM-induced expression of neurotrophic factors in astrocytes and NSC-34 cells, we found that glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) gene expression in astrocytes were significantly enhanced by MSC CM, with differential responses of non-transgenic and mutant astrocytes. Expression of Vascular Endothelial Growth Factor (VEGF) in NSC-34 cells was significantly upregulated upon MSC CM-treatment. MSC CM significantly reduced the expression of the cytokines TNFα and IL-6 and iNOS both in transgenic and non-transgenic astrocytes. Gene expression of the neuroprotective chemokine Fractalkine (CX3CL1) was also upregulated in mutant SOD1G93A transgenic astrocytes by MSC CM treatment. Correspondingly, MSC CM increased the respective receptor, CX3CR1, in mutant SOD1G93A transgenic microglia. Our data demonstrate that MSC modulate motor neuronal and glial response to apoptosis and inflammation. MSC therefore represent an interesting candidate for further preclinical and clinical evaluation in ALS.
Highlights
Cellular therapy is currently being investigated as a novel therapeutic option for the treatment of neurodegenerative disorders, including Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis (ALS)
The present study demonstrates that mesenchymal stromal cells (MSC) have protective effects on primary motor neurons, NSC-34 cells and astrocytes against STS-induced apoptosis
In comparison MSC conditioned medium (MSC conditioned medium (CM)) was even more efficient than co-culture of motor neurons together with MSC in a ratio of 1:4, indicating that the effects are mediated in a paracrine manner via release of protective factors by MSC, that exert their effects across cell type barriers, which is typical for growth factors and cytokines
Summary
Cellular therapy is currently being investigated as a novel therapeutic option for the treatment of neurodegenerative disorders, including Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis (ALS). While in some diseases such as Parkinson’s disease, cell replacement seems to be an option worth further exploration, in others such as ALS, cell therapy research rather focuses on the generation of a protective environment for degenerating neurons. This approach is supported by recent evidence that motor neuron death in ALS is non-cell autonomous and that non-neuronal cells can exert protective effects in vitro and in vivo [1,2]. Evidence from preclinical studies suggested that mesenchymal stromal cells (MSC), a subset of adult progenitor cells, can differentiate into neuronal-like cells [5] Their neuroprotective effects, seem to be mainly based on anti-inflammatory and immunomodulatory activities [6]. Bone-marrow-derived MSC have already been used in ALS patients in a clinical phase I trial and few adverse effects have been observed which is in favour of further clinical evaluation of this approach [14,15,16]
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