Results in this study indicate that BMSC-DSCs have great potential to promote regeneration of peripheral nerves. The artificial graft made with BMSC-DSCs represents an alternative method for the difficult reconstruction of a long distance gap in a peripheral nerve.

Neurons can be specifically induced from bone marrow stromal cells (MSCs) with extremely high efficiency using gene transfection of the Notch intracellular domain and subsequent treatment with basic-fibroblast growth factor, forskolin, and ciliary neurotrophic factor. We investigated the behavioral and histologic efficacy of such bone marrow stromal cell-derived neuronal cell (MSDNC) transplantation into a focal cerebral infarction model in rats. A left middle cerebral artery occlusion (MCAO) was performed on adult Wistar rats. MSDNC transplantation into the ipsilateral hemisphere was performed on day 7 after MCAO. The behavioral analyses were conducted on days 14, 21, 28, 35, and 36-40, and a histologic evaluation was performed on day 41. MSDNC-transplanted rats showed significant recovery compared with controls (MCAO without cell transplantation) in beam balance, limb placing, and Morris water maze tests. Histologically, transplanted cells migrated from the injection site into the ischemic boundary area, including the cortex, corpus callosum, striatum, and hippocampus. Transplanted MSDNCs were positive for MAP-2 (84% +/- 8.11%), whereas only a small number of cells were positive for GFAP (1.0% +/- 0.23%). The survival rates of MSDNCs and MSCs 1 month after transplantation were approximately 45% and 10%, respectively. These results suggest that use of MSDNCs may be a promising therapeutic strategy for cerebral infarction.

Both CBF and CVR decrease with the development of NPH, suggesting that hemodynamic ischemia may be responsible for manifestation of the symptoms. Impaired CVR and reduced CBF with the development of symptoms can be proposed as diagnostic criteria for idiopathic NPH.

Skin-derived precursors (SKPs) from mammalian dermis represent neural crest-related stem cells capable of differentiating into both neural and mesodermal progency. SKPs are of clinical interest because they serve as accessible autologous donor cells for neuronal repair for neuronal intractable diseases. However, little is known about the efficient generation of neurons from SKPs, and phenotypes of neurons generated from SKPs have been restricted. In addition, the neuronal repair using their generated neurons as donor cells has not been achieved. The von Hippel-Lindau protein (pVHL) is one of the proteins that play an important role during neuronal differentiation, and recently neuronal differentiation of neural progenitor cells by intracellular delivery of a synthetic VHL peptide derived from elongin BC-binding site has been demonstrated. In the present study, a synthetic VHL peptide derived from elongin BC-binding site was conjugated to the protein transduction domain (PTD) of HIV-TAT protein (TATVHL peptide) to facilitate entry into cells, and we demonstrate the efficient generation of cells with dopaminergic phenotype from SKPs with the intracellular delivery of TATVHL peptide, and characterized the generated cells. The TATVHL peptide-treated SKPs expressed neuronal marker proteins, particularly dopamine neuron markers, and also up-regulated mRNA levels of proneural basic helix-loop-helix factors. After the TATVHL peptide treatment, transplanted SKPs into Parkinson's disease (PD) model rats sufficiently differentiated into dopamine neuron-like cells in PD model rats, and partially but significantly corrected behavior of PD model rats. The generated dopamine neuron-like cells are expected to serve as donor cells for neuronal repair for PD.

Intracellular delivery of synthetic oligopeptides has the potential to promote the occurrence of various cellular events such as cell death, proliferation, growth inhibition, metabolic changes, and morphological changes. However, the regulation of cellular differentiation by intracellular delivery of synthetic oligopeptides has been little studied. Von Hippel-Lindau protein (pVHL) is one of the proteins that functions to induce the differentiation of neural progenitor cells (NPCs). To function in these cells, pVHL forms a complex composed of itself, elongin BC, Clu-2, and Rbx-1. It is suggested that the binding site of elongin BC in pVHL plays a critical role in pVHL function, i.e., ubiquitination, which is related to neuronal differentiation. So, we synthesized an oligopeptide corresponding to the elongin BC binding site, and delivered the oligopeptide into NPCs by using a mixture of trifluoroacetylated lipopolyamine and diloeoyl phosphatidylethanolamine (BioPorter) to form a peptide-lipid complex. After intracellular delivery of the oligopeptide, induction of differentiation of NPCs was shown in terms of neurite outgrowth and by immunocytochemical and electrophysiological means. The intracellular delivery of the synthetic oligopeptide derived from pVHL may provide a safe and valuable approach for the neuronal differentiation of NPCs.

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