Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation

Abstract

Bone marrow stromal cells (MSCs) have the capability under specific conditions of differentiating into various cell types such as osteocytes, chondrocytes, and adipocytes. Here we demonstrate a highly efficient and specific induction of cells with neuronal characteristics, without glial differentiation, from both rat and human MSCs using gene transfection with Notch intracellular domain (NICD) and subsequent treatment with bFGF, forskolin, and ciliary neurotrophic factor. MSCs expressed markers related to neural stem cells after transfection with NICD, and subsequent trophic factor administration induced neuronal cells. Some of them showed voltage-gated fast sodium and delayed rectifier potassium currents and action potentials compatible with characteristics of functional neurons. Further treatment of the induced neuronal cells with glial cell line-derived neurotrophic factor (GDNF) increased the proportion of tyrosine hydroxylase-positive and dopamine-producing cells. Transplantation of these GDNF-treated cells showed improvement in apomorphine-induced rotational behavior and adjusting step and paw-reaching tests following intrastriatal implantation in a 6-hydroxy dopamine rat model of Parkinson disease. This study shows that a population of neuronal cells can be specifically generated from MSCs and that induced cells may allow for a neuroreconstructive approach.

Epigenetics and the plasticity of differentiation in normal and cancer stem cells

“…Mesenchymal stem cells in the bone marrow can differentiate to muscle (Ferrari et al, 1998;Dezawa et al, 2005), neural lineage cells (Kopen et al, 1999;Dezawa et al, 2004) and to various other cell types (Jiang et al, 2002). Another distinct population of bone marrow-derived stem cells can differentiate to cells of various lineages including muscle, endothelial, epithelial and neural cells (Yoon et al, 2005).…”

The secretome of MUSE cells contains factors that may play a role in regulation of stemness, apoptosis and immunomodulation

“…This because MSC cultures showed differentiation not only into the same mesodermal-lineage they belong but also into ectodermal-lineage, such as neural and epidermal cells, as well as into endodermal-lineage, such as hepatocytes and b cells. [1][2][3][4][5][6] However, efficiency of differentiation is usually not high, suggesting that this phenomenon is dependent on a small subpopulation. 7 Previously, we identified unique stem cells that we named multilineage-differentiating stress enduring (Muse) cells as one to several percent of the total MSCs of the bone marrow, adipose tissue and dermis.…”

Cell Therapeutics in Parkinson's Disease

“…Other types of stem cells, such as NSCs and progenitors from the embryonic ventral mesencephalon [64][65][66][67], adult NSCs from the subventricular zone [68], bone marrow stromal cells [69], and fibroblast-derived induced pluripotent stem (iPS) cells [61,[70][71][72] have also been used for this purpose. It has also been shown that human stem cell-derived DA neuroblasts, which will be required for patient application, can survive in animal models of PD and after maturation exert functional effects [54,58,66,69,71,72]. However, some properties that will be fundamental for successful clinical translation have not been demonstrated yet for human stem cell-derived DA neurons, including those that they can substantially reinnervate striatum, restore DA release in vivo, and markedly improve deficits resembling the symptoms experienced by patients with PD.…”