Distribution pattern following systemic mesenchymal stem cell injection depends on the age of the recipient and neuronal health

BACKGROUND: Mesenchymal stem cells (MSCs) show therapeutic efficacy in many different age-related degenerative diseases, including Alzheimer's disease. Very little is currently known about whether or not aging impacts the transplantation efficiency of MSCs. METHODS: In this study, we investigated the distribution of intravenously transplanted syngeneic MSCs derived from young and aged mice into young, aged, and transgenic APP/PS1 Alzheimer's disease mice. MSCs from male donors were transplanted into female mice and their distribution pattern was monitored by PCR using Y-chromosome specific probes. Biodistribution of transplanted MSCs in the brains of APP/PS1 mice was additionally confirmed by immunofluorescence and confocal microscopy. RESULTS: Four weeks after transplantation into young mice, young MSCs were found in the lung, axillary lymph nodes, blood, kidney, bone marrow, spleen, liver, heart, and brain cortex. In contrast, young MSCs that were transplanted into aged mice were only found in the brain cortex. In both young and aged mouse recipients, transplantation of aged MSCs showed biodistribution only in the blood and spleen. Although young transplanted MSCs only showed neuronal distribution in the brain cortex in young mice, they exhibited a wide neuronal distribution pattern in the brains of APP/PS1 mice and were found in the cortex, cerebellum, hippocampus, olfactory bulb, and brainstem. The immunofluorescent signal of both transplanted MSCs and resident microglia was robust in the brains of APP/PS1 mice. Monocyte chemoattractant-1 levels were lowest in the brain cortex of young mice and were significantly increased in APP/PS1 mice. Within the hippocampus, monocyte chemoattractant-1 levels were significantly higher in aged mice compared with younger and APP/PS1 mice. CONCLUSIONS: We demonstrate in vivo that MSC biodistribution post transplantation is detrimentally affected by aging and neuronal health. Aging of both the recipient and the donor MSCs used attenuates transplantation efficiency. Clinically, our data would suggest that aged MSCs should not be used for transplantation and that transplantation of MSCs into aged patients will be less efficacious

Intranasal administration of mesenchymal stem cells ameliorates the abnormal dopamine transmission system and inflammatory reaction in the R6/2 mouse model of Huntington disease

Intrastriatal administration of mesenchymal stem cells (MSCs) has shown beneficial effects in rodent models of Huntington disease (HD). However, the invasive nature of surgical procedure and its potential to trigger the host immune response may limit its clinical use. Hence, we sought to evaluate the non-invasive intranasal administration (INA) of MSC delivery as an effective alternative route in HD. GFP-expressing MSCs derived from bone marrow were intranasally administered to 4-week-old R6/2 HD transgenic mice. MSCs were detected in the olfactory bulb, midbrain and striatum five days post-delivery. Compared to phosphate-buffered saline (PBS)-treated littermates, MSC-treated R6/2 mice showed an increased survival rate and attenuated circadian activity disruption assessed by locomotor activity. MSCs increased the protein expression of DARPP-32 and tyrosine hydroxylase (TH) and downregulated gene expression of inflammatory modulators in the brain 7.5 weeks after INA. While vehicle treated R6/2 mice displayed decreased Iba1 expression and altered microglial morphology in comparison to the wild type littermates, MSCs restored both, Iba1 level and the thickness of microglial processes in the striatum of R6/2 mice. Our results demonstrate significantly ameliorated phenotypes of R6/2 mice after MSCs administration via INA, suggesting this method as an effective delivering route of cells to the brain for HD therapy

Microglia based Alzheimer therapy [Abstract]

Microglia based Alzheimer therapy [Abstract

Additional file 1: Figure S1. of Distribution pattern following systemic mesenchymal stem cell injection depends on the age of the recipient and neuronal health

showing mesodermal lineage differentiation of bone-marrow-derived MSCs. Bone-marrow-derived MSCs were differentiated in vitro under adipogenic (a), osteogenic (b), or chondrogenic (c) conditions. Verification of the differentiation was done by qualitative analysis: adipogenesis shown by staining lipid vesicles with Oil red-O (a), osteogenesis shown by staining alkaline phosphatase with Fast Red (b), and chondrogenesis shown by staining sulphated proteoglycans typical for extracellular matrix composition with Alcian Blue under acidic conditions

Additional file 3: Figure S3. of Distribution pattern following systemic mesenchymal stem cell injection depends on the age of the recipient and neuronal health

showing cell marker panels of CD11b, CD106, and CD44 in bone-marrow-derived MSCs. A cell marker panel was performed via FACS on Bl6, bone-marrow-derived MSCs at passage 3. P2-Q4 represents the negative quadrant in the bottom left (purple). P2-Q1 represents the positive quadrant in the upper left (green). Bar graph (bottom right) and textual table (bottom left) included to summarize the overall results of the FACS experiments. (TIF 831 kb

Additional file 2: Figure S2. of Distribution pattern following systemic mesenchymal stem cell injection depends on the age of the recipient and neuronal health

showing cell marker panels of Sca1, CD73, CD105, CD29, and CD45 in bone-marrow derived MSCs. A cell marker panel was performed via FACS on Bl6, bone-marrow-derived MSCs at passage 3. P2-Q4 represents the negative quadrant in the bottom left (purple). P2-Q1 represents the positive quadrant in the upper left (green). (TIF 1142 kb

Additional file 4: Figure S4. of Distribution pattern following systemic mesenchymal stem cell injection depends on the age of the recipient and neuronal health

showing a low-magnification image of transplanted MSCs in the brain of APP/PS1 mice. Representative low-magnification image showing the migration of transplanted GFP-positive MSCs (green) into the brains of APP/PS1 mice. GFP-expressing MSCs were found in association with activated microglia (Iba-1, red). Sections were stained with DAPI to highlight nuclei as a positional marker. Scale bar: 50 μM. (TIF 4445 kb

Intranasal administration of mesenchymal stem cells ameliorates the abnormal dopamine transmission system and inflammatory reaction in the R6/2 mouse model of huntington disease [Abstract]

Intranasal administration of mesenchymal stem cells ameliorates the abnormal dopamine transmission system and inflammatory reaction in the R6/2 mouse model of huntington disease [Abstract