Plasticity of Cultured Mesenchymal Stem Cells: Switch from Nestin‐Positive to Excitable Neuron‐Like Phenotype

Abstract

Bone marrow mesenchymal stem cells (MSCs) can differentiate into several types of mesenchymal cells, including osteocytes, chondrocytes, and adipocytes, but, under appropriate experimental conditions, can also differentiate into nonmesenchymal cells-for instance, neural cells. These observations have raised interest in the possible use of MSCs in cell therapy strategies for various neurological disorders. In the study reported here, we addressed the question of in vitro differentiation of MSCs into functional neurons. First, we demonstrate that when they are co-cultured with cerebellar granule neurons, adult MSCs can express neuronal markers. Two factors are needed for the emergence of neuronal differentiation of the MSCs: the first one is nestin expression by MSCs (nestin is a marker for the responsive character of MSCs to extrinsic signals), and the second one is a direct cell-cell interaction between neural cells and MSCs that allows the integration of these extrinsic signals. Three different approaches suggest that neural phenotypes arise from MSCs by a differentiation rather than a cell fusion process, although this last phenomenon can also coexist. The expression of several genes-including sox, pax, notch, delta, frizzled, and erbB-was analyzed by quantitative reverse transcription polymerase chain reaction (RT-PCR) in order to further characterize the nestin-positive phenotype compared to the nestin-negative one. An overexpression of sox2, sox10, pax6, fzd, erbB2, and erbB4 is found in nestin-positive MSCs. Finally, electrophysiological analyses demonstrate that MSC-derived neuron-like cells can fire single-action potentials and respond to several neurotransmitters such as GABA, glycine, and glutamate. We conclude that nestin-positive MSCs can differentiate in vitro into excitable neuron-like cells. Stem Cells 2005;23:392-402

RETRACTED ARTICLE: Mesenchymal stem cells and neural crest stem cells from adult bone marrow: characterization of their surprising similarities and differences

“…Mouse cerebellar granule neurons (CGNs) were prepared from 3-days-old GFP or wild type C57BL/6J mice (The Jackson Laboratory, Bar Harbor, ME, USA, http://www.jax.org), [11]. Green mice express green fluorescent protein (GFP) under control of the β-actin promoter [11]. Wild-type CGNs were only used with NCSC clones as those clones would express LacZ, which was used to discriminate both cell types.…”

“…As only little information could be found on neural crest-derived cells from adult bone marrow, we decided to further characterize those cells by comparing them to the nestin-positive cell population initially described as a neurogenic population. Indeed, we demonstrated several years ago that only nestin-positive cells isolated from adult bone marrow could differentiate into functional neurons [10,11]. Working with cell clones, we performed a direct comparison of neural crest stem cells (NCSC) and mesenchymal stem cells (MSC), both isolated from adult bone marrow.…”

Cell Therapy for Multiple Sclerosis

“…These type of cells burst into the regenerative neuroscience field with the suggestion that promiscuity of stem cells may allow them to transdifferentiate into mature cells of other tissues [244,245]. Specifically, a number of investigators have reported that adult mouse and human BMSCs can differentiate in vitro into other cell types, including muscle, skin, liver, lung, and neural cells [246][247][248][249][250]. It was also suggested that bone marrow-derived stromal cells can generate astrocytes [251], as wedll as produce myelin and remyelinate a demyelinated lesion of the spinal cord of the rat [252,253].…”

Synthetic nanostructures inducing differentiation of human mesenchymal stem cells into neuronal lineage

“…After Woodbury et al demonstrated the differentiation of rat and human bone marrow stromal cells into neurons [14], neuronal differentiation of hMSCs has been studied by other groups. The transdifferentiation can be induced by neuronal induction medium [14][15][16][17] and/ or cell contact with neurons [18]. The mechanism responsible for the transdifferentiation of mesenchymal stem cells to neurons, which are non-mesenchymal derivatives, is not well understood.…”