Journal
JOURNAL OF NEUROSCIENCE
Volume 34, Issue 1, Pages 313-326Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2425-13.2014
Keywords
aging; brain injury; stem cell
Categories
Funding
- National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke Grant [1R01NS071956-01]
- Department of Defense Grant [W81XWH1110634]
- James and Esther King Foundation for Biomedical Research Program Grant [1KG01-33966]
- SanBio
- Celgene Cellular Therapeutics
- KM Pharmaceutical Consulting LLC
- NeuralStem
- Veterans Affairs Medical Research Service
- NIH/National Institute on Aging [1PO1AG-04418-27, 1R01 AG044919]
- Michael J. Fox Foundation
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS071956] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P01AG004418, R01AG044919] Funding Source: NIH RePORTER
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Traumatic brain injury (TBI) survivors exhibit motor and cognitive symptoms from the primary injury that can become aggravated over time because of secondary cell death. In the present in vivo study, we examined the beneficial effects of human adipose-derived stem cells (hADSCs) in a controlled cortical impact model of mild TBI using young (6 months) and aged (20 months) F344 rats. Animals were transplanted intravenously with 4 X 10(6) hADSCs (Tx), conditioned media (CM), or vehicle (unconditioned media) at 3 h after TBI. Significant amelioration of motor and cognitive functions was revealed in young, but not aged, Tx and CM groups. Fluorescent imaging in vivo and ex vivo revealed 1,1' dioactadecyl-3-3-3',3'-tetramethylindotricarbocyanine iodide-labeled hADSCs in peripheral organs and brain after TBI. Spatiotemporal deposition of hADSCs differed between young and aged rats, most notably reduced migration to the aged spleen. Significant reduction in cortical damage and hippocampal cell loss was observed in both Tx and CM groups in young rats, whereas less neuroprotection was detected in the aged rats and mainly in the Tx group but not the CM group. CM harvested from hADSCs with silencing of either NEAT1 (nuclear enriched abundant transcript 1) or MALAT1 (metastasis associated lung adenocarcinoma transcript 1), long noncoding RNAs (lncRNAs) known to play a role in gene expression, lost the efficacy in our model. Altogether, hADSCs are promising therapeutic cells for TBI, and lncRNAs in the secretome is an important mechanism of cell therapy. Furthermore, hADSCs showed reduced efficacy in aged rats, which may in part result from decreased homing of the cells to the spleen.
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