Adult Bone Marrow: Which Stem Cells for Cellular Therapy Protocols in Neurodegenerative Disorders?

The generation of neuronal cells from stem cells obtained from adult bone marrow is of significant clinical interest in order to design new cell therapy protocols for several neurological disorders. The recent identification in adult bone marrow of stem cells derived from the neural crests (NCSCs) might explain the neuronal phenotypic plasticity shown by bone marrow cells. However, little information is available about the nature of these cells compared to mesenchymal stem cells (MSCs). In this paper, we will review all information available concerning NCSC from adult tissues and their possible use in regenerative medicine. Moreover, as multiple recent studies showed the beneficial effect of bone marrow stromal cells in neurodegenerative diseases, we will discuss which stem cells isolated from adult bone marrow should be more suitable for cell replacement therapy

Regulation of nestin expression by thrombin and cell density in cultures of bone mesenchymal stem cells and radial glial cells

BACKGROUND: Bone marrow stromal cells and radial glia are two stem cell types with neural phenotypic plasticity. Bone marrow mesenchymal stem cells can differentiate into osteocytes, chondrocytes and adipocytes, but can also differentiate into non-mesenchymal cell, i.e. neural cells in appropriate in vivo and in vitro experimental conditions. Likewise, radial glial cells are the progenitors of many neurons in the developing cortex, but can also generate astrocytes. Both cell types express nestin, an intermediate filament protein which is the hallmark of neural precursors. RESULTS: In this study, we demonstrate that thrombin, a multifunctional serine protease, stimulates the growth of radial glial cells (RG) and mesenchymal stem cells (MSCs) in a dose-dependent manner. In RG, the mitogenic effect of thrombin is correlated with increased expression of nestin but in MSCs, this mitogenic effect is associated with nestin down-regulation. Both cell types express the PAR-1 type receptor for Thrombin and the effect of Thrombin on both cell types can be mimicked by its analogue TRAP-6 activating specifically this receptor subtype or by serum which contains various amount of thrombin. Moreover, we also demonstrate that serum deprivation-induced expression of nestin in MSCs is inhibited by high cell density (> 50,000 cells/cm2). CONCLUSION: This work shows that thrombin stimulates the growth of both RG and MSCs and that nestin expression by MSCs and RG is regulated in opposite manner by thrombin in vitro. Thrombin effect is thus associated in both cell types with a proliferating, undifferentiated state but in RG this involves the induction of nestin expression, a marker of immaturity for neural progenitors. In MSCs however, nestin expression, as it corresponds to a progression from the mesenchymal "undifferentiated", proliferating phenotype toward acquisition of a neural fate, is inhibited by the mitogenic signal

Regulation of a-Synuclein Membrane Binding and Its Implications

peer reviewe

Nestin-positive mesenchymal stem cells favour the astroglial lineage in neural progenitors and stem cells by releasing active BMP4

BACKGROUND: Spontaneous repair is limited after CNS injury or degeneration because neurogenesis and axonal regrowth rarely occur in the adult brain. As a result, cell transplantation has raised much interest as potential treatment for patients with CNS lesions. Several types of cells have been considered as candidates for such cell transplantation and replacement therapies. Foetal brain tissue has already been shown to have significant effects in patients with Parkinson's disease. Clinical use of the foetal brain tissue is, however, limited by ethical and technical problems as it requires high numbers of grafted foetal cells and immunosuppression. Alternatively, several reports suggested that mesenchymal stem cells, isolated from adult bone marrow, are multipotent cells and could be used in autograft approach for replacement therapies. RESULTS: In this study, we addressed the question of the possible influence of mesenchymal stem cells on neural stem cell fate. We have previously reported that adult rat mesenchymal stem cells are able to express nestin in defined culture conditions (in the absence of serum and after 25 cell population doublings) and we report here that nestin-positive (but not nestin-negative) mesenchymal stem cells are able to favour the astroglial lineage in neural progenitors and stem cells cultivated from embryonic striatum. The increase of the number of GFAP-positive cells is associated with a significant decrease of the number of Tuj1- and O4-positive cells. Using quantitative RT-PCR, we demonstrate that mesenchymal stem cells express LIF, CNTF, BMP2 and BMP4 mRNAs, four cytokines known to play a role in astroglial fate decision. In this model, BMP4 is responsible for the astroglial stimulation and oligodendroglial inhibition, as 1) this cytokine is present in a biologically-active form only in nestin-positive mesenchymal stem cells conditioned medium and 2) anti-BMP4 antibodies inhibit the nestin-positive mesenchymal stem cells conditioned medium inducing effect on astrogliogenesis. CONCLUSIONS: When thinking carefully about mesenchymal stem cells as candidates for cellular therapy in neurological diseases, their effects on resident neural cell fate have to be considered

Correction: In Vivo Tumorigenesis Was Observed after Injection of In Vitro Expanded Neural Crest Stem Cells Isolated from Adult Bone Marrow.

[This corrects the article DOI: 10.1371/journal.pone.0046425.]

Advances in Regenerative Medicine

Even if the origins of regenerative medicine can be found in Greek mythology, as attested by the story of Prometheus, the Greek god whose immortal liver was feasted on day after day by Zeus' eagle; many challenges persist in order to successfully regenerate lost cells, tissues or organs and rebuild all connections and functions. In this book, we will cover a few aspects of regenerative medicine highlighting major advances and remaining challenges in cellular therapy and tissue/organ engineering

Nestin expression in cultivated mesenchymal stem cells: Regulation and potential role in their neural differentiation

Bone marrow stromal cells can differentiate into many types of mesenchymal cells, i.e. osteocyte, chondrocyte, fibroblast and adipocyte, but can also differentiate into non-mesenchymal cell, i.e. neural cells in appropriate in vivo experimental conditions (Kopen and al.,PNAS,96, 10711,1999, Brazelton and al, Science, 290,1175, 2000, Mezey and al, Science, 290,1179, 2000). In neurological disorders, such as Alzheimer's and Parkinson's diseases, auto-transplantation of neural cell types derived from mesenchymal stem cells offers the potential of replacing lost cells and recovering lost functions. Nestin is an intermediate filament protein predominantly expressed by neural stem cells and is used to identify neural progenitor. In this study, we demonstrate that cultured rat mesenchymal stem cells (rMSC) can express nestin in appropriate conditions. Two factors contribute to the regulation of nestin expression by rMSC : 1) the presence of serum-derived components in the culture medium which repress nestin expression and 2) the cell’s number of passages. LPA and thrombin mimic this serum effect. Furthermore, when nestin- positive cells are trypsinized and resuspended into culture conditions used for neural stem cells (NSC), sphere formation is observed. Likewise, by co-cultivating nestin-positive rMSC with NSC derived from green mouse, heterogenous spheres were obtained. When those heterogenous spheres are placed on polyornithine-coated surfaces, a differentiation of some rMSC into GFAP-positive cells occurs. These results indicate that nestin expression might be a pre-requisite for the acquisition by rMSC of the capacity to differentiate into some neural cell types