Bone Marrow-Derived Mesenchymal Stem Cells Promote Neuronal Networks with Functional Synaptic Transmission After Transplantation into Mice with Neurodegeneration

Abstract

Recent studies have shown that bone marrow-derived MSCs (BM-MSCs) improve neurological deficits when transplanted into animal models of neurological disorders. However, the precise mechanism by which this occurs remains unknown. Herein we demonstrate that BM-MSCs are able to promote neuronal networks with functional synaptic transmission after transplantation into Niemann-Pick disease type C (NP-C) mouse cerebellum. To address the mechanism by which this occurs, we used gene microarray, whole-cell patch-clamp recordings, and immunohistochemistry to evaluate expression of neurotransmitter receptors on Purkinje neurons in the NP-C cerebellum. Gene microarray analysis revealed upregulation of genes involved in both excitatory and inhibitory neurotransmission encoding subunits of the ionotropic glutamate receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, AMPA) GluR4 and GABA(A) receptor beta2. We also demonstrated that BM-MSCs, when originated by fusion-like events with existing Purkinje neurons, develop into electrically active Purkinje neurons with functional synaptic formation. This study provides the first in vivo evidence that upregulation of neurotransmitter receptors may contribute to synapse formation via cell fusion-like processes after BM-MSC transplantation into mice with neurodegenerative disease. Disclosure of potential conflicts of interest is found at the end of this article.

Intracerebellar Transplantation of Neural Stem Cells into Mice with Neurodegeneration Improves Neuronal Networks with Functional Synaptic Transmission

“…Pathological characteristics are progressive Purkinje neuron loss, intracellular accumulation of sphingomyelin, cholesterol and neuroglial cell (astrocyte, microglial cell) infiltration in the cerebellum [6,11]. Our studies have shown that transplantation of bone marrowderived mesenchymal stem cells (BM-MSC) results in alleviation of pathology associated with murine NP-C cerebellum through fusion of BM-MSC and Purkinje neuron and promotion of neuronal networks with functional synaptic transmission [1][2][3]. Herein, we assessed the therapeutic effects of conditionally immortalized multipotential neural stem cells (NSCs), Maudsley hippocampal clone 36 (MHP36), in a NP-C model mice.…”

“…The NP-C Gsbs GFP+ mice were created by crossing NP-C mice with Gsbs GFP+ mice, which carry a null allele of Gsbs (GeneBank accession No. 1333876) on BALB/c back ground and concomitantly have the green fluorescent protein (GFP) reporter gene inserted into the Gsbs locus [2,6]. Animals were housed on a 12 hr light/dark cycle and given water and food ad libitum.…”

“…Skin of the head was incised along the midline, and the skull was exposed. Hole at the appropriate site of the skull and then, mouse were placed on the Styrofoam platform and were transplanted cells using stereotaxic frame (Stoelting Co., Wood Dale, IL, U.S.A.) as described [2]. U373, glioma cell line, was used as a non-stem cell control condition.…”

Therapeutic potential of genetically modified mesenchymal stem cells

“…9 Mesenchymal stem cells can also be differentiated into neurons, astrocytes, tenocytes, skeletal myocytes and cells of visceral mesoderm (endothelial cells). [10][11][12][13][14] Bone targeting of culture-expanded murine MSC by ectopic expression of murine a4 integrin Despite the potential of MSC in tissue regeneration, a major limitation remains in the delivery of ex vivo modified MSC to target tissues upon autologous transfer. In our recent study, we have shown that ectopic expression of a4 integrin on mouse MSC resulted in significant increase in bone specific retention of transplanted mouse MSC.…”

The isolation and cultivation of bone marrow stem cells and evaluation of differences for neural-like cells differentiation under the induction with neurotrophic factors

“…A number of investigations have demonstrated that cell-based transplantation therapies have been proven to be promising strategies for relieving symptoms of various neuronal diseases and improving function of damaged neuronal tissues in experimental models (Bae et al 2007;Dezawa et al 2005;Lu et al 2001). As reported by Hu et al, glial restricted precursor cells (GRPs) and Schwann cells (SCs) were co-grafted into normal or injured spinal cord.…”