Bone marrow stromal cells protect and repair damaged neurons through multiple mechanisms

Abstract

A surprising shortage of information surrounds the mechanism by which bone marrow stromal cells (BMSC) restore lost neurologic functions when transplanted into the damaged central nervous system. To clarify the issue, the BMSC were cocultured with the neurons using two paradigms: the cell-mixing coculture technique and three-dimensional coculture technique. The green fluorescent protein (GFP)-expressing BMSC were cocultured with the PKH-26-labelled neurons, using cell mixing coculture technique. GFP-positive, PKH-26-negative cells morphologically simulated the neurons and significantly increased the expression of MAP-2, Tuj-1, nestin, and GFAP. GFP/nestin-positive, PKH-26-negative cells increased from 13.6% +/- 6.7% to 32.1% +/- 15.5% over 7 days of coculture. They further enhanced Tuj-1 expression when cocultured with neurons exposed to 100 microM of glutamate for 10 min. About 20-30% of GFP-positive cells became positive for PKH-26 through coculture with the neurons, but the doubly positive cells did not increase when cocultured with glutamate-exposed neurons. Alternatively, the BMSC significantly ameliorated glutamate-induced neuronal damage when cocultured with the three-dimensional coculture technique. The protective effect was more prominent when coculture was started prior to glutamate exposure than when coculture was started just after glutamate exposure. ELISA analysis revealed that the BMSC physiologically produce NGF, BDNF, SDF-1alpha, HGF, TGFbeta-1, and IGF-1 and significantly enhanced the production of NGF and BDNF when cocultured with glutamate-exposed neurons. These findings strongly suggest that the BMSC may protect and repair the damaged neurons through multiple mechanisms, including transdifferentiation, cell fusion, and production of growth factors.

CXCL12/SDF-1-Dependent Retinal Migration of Endogenous Bone Marrow-Derived Stem Cells Improves Visual Function after Pharmacologically Induced Retinal Degeneration

“…repeated dosing of NOX-A12 and potentially SDF-1 in order to increase the number of BMSC in the retina might further enhance their regenerative effect. 12 It has been published that BMSCs can protect and repair damaged neurons through multiple mechanisms, including transdifferentiation, cell fusion, and production of growth factors (42). In order to identify the mechanism behind the improved visual function, we have investigated a possible differentiation of the BMSC into retinal cell types.…”

Bone Marrow Stromal Cell Transplantation Attenuates Cognitive Dysfunction due to Chronic Cerebral Ischemia in Rats

“…However, recent studies have shown that the BMSC serve therapeutic benefits through multiple mechanisms. First, the BMSC per se are believed to have the potential to alter their gene expression profile and to differentiate into neural cells in response to the surrounding environment [37,38] . Second, the transplanted BMSC have been known to fuse with host cells and to simulate the differentiation into host cells, although the roles and fates of the BMSC fused with the neurons are still completely unknown [38] .…”

123 I-Iomazenil Single Photon Emission Computed Tomography Visualizes Recovery of Neuronal Integrity by Bone Marrow Stromal Cell Therapy in Rat Infarct Brain

“…For SPECT scan parameters, 60 projection views were acquired at 180 s/view over 360°, with single-pinhole collimator of 2.0-mm aperture, at a radius of rotation of 35 mm. The acquired data were reconstructed in the 3-dimensional ordered subset expectation maximization method with 2 iterations per 6 subsets, a voxel size of 0.5×0.5×0.5 mm 3 . Neither attenuation nor scatter correction was performed.…”

“…1,2 Recent animal studies have demonstrated that the BMSCs significantly enhance functional recovery after ischemic stroke, when directly transplanted into the brain at clinically relevant timing. [3][4][5][6][7] Several clinical trials have also indicated that BMSC transplantation is at least feasible for patients with CNS disorders. 8 As pointed out by several investigators, however, there are several concerns to be resolved before clinical application of BMSC transplantation for CNS disorders.…”

“…Previous studies have shown that the engrafted BMSCs may enhance functional recovery after ischemic stroke through multiple mechanisms. 3 Some of them have the potential to replace the injured tissue by differentiating into the neural cells. Another subpopulation possibly releases the neuroprotective or neurotrophic factors and supports the survival of damaged neurons.…”