Systematic chromosomal aberrations found in murine bone marrow-derived mesenchymal stem cells.

in Stem Cells & Development (2010), 19(8), 1167-1173

Mesenchymal stem cells (MSCs) are studied as a cellular source for the treatment of various diseases. In this work, we isolated and cultivated murine bone marrow-derived MSCs. After a first observation of ... [more ▼]

Mesenchymal stem cells (MSCs) are studied as a cellular source for the treatment of various diseases. In this work, we isolated and cultivated murine bone marrow-derived MSCs. After a first observation of a solid tumour in a mouse injected with these cells, we systematically explored their chromosomal stability. We observed in all the cytogenetically analysed cases gross chromosomal alterations every time the MSCs went through the senescence crisis while the lymphocytes from the same animals showed a normal chromosome count. This observation was confirmed in different mouse strains, with different culture protocols, and even in short-term cultures after an hematopoietic cell negative immunodepletion performed in order to accelerate the isolation procedure. Therefore, we conclude that murine MSCs display high chromosomal instability, can generate tumours, and that care must be taken before using them for the evaluation of MSC therapeutic potential. [less ▲]

Oligodendrocyte development and myelinogenesis are not impaired by high concentrations of phenylalanine or its metabolites.

in Journal of Inherited Metabolic Disease (2010), 33(2), 113-20

Phenylketonuria (PKU) is a metabolic genetic disease characterized by deficient phenylalanine hydroxylase (PAH) enzymatic activity. Brain hypomyelination has been reported in untreated patients, but its ... [more ▼]

Phenylketonuria (PKU) is a metabolic genetic disease characterized by deficient phenylalanine hydroxylase (PAH) enzymatic activity. Brain hypomyelination has been reported in untreated patients, but its mechanism remains unclear. We therefore investigated the influence of phenylalanine (Phe), phenylpyruvate (PP), and phenylacetate (PA) on oligodendrocytes. We first showed in a mouse model of PKU that the number of oligodendrocytes is not different in corpus callosum sections from adult mutants or from control brains. Then, using enriched oligodendroglial cultures, we detected no cytotoxic effect of high concentrations of Phe, PP, or PA. Finally, we analyzed the impact of Phe, PP, and PA on the myelination process in myelinating cocultures using both an in vitro index of myelination, based on activation of the myelin basic protein (MBP) promoter, and the direct quantification of myelin sheaths by both optical measurement and a bioinformatics method. None of these parameters was affected by the increased levels of Phe or its derivatives. Taken together, our data demonstrate that high levels of Phe, such as in PKU, are unlikely to directly induce brain hypomyelination, suggesting involvement of alternative mechanisms in this myelination defect. [less ▲]