Intravenous Transplants of Human Adipose-Derived Stem Cell Protect the Brain from Traumatic Brain Injury-Induced Neurodegeneration and Motor and Cognitive Impairments: Cell Graft Biodistribution and Soluble Factors in Young and Aged Rats

• DOI: 10.1523/jneurosci.2425-13.2014
• Publication Date: 2013-12-31T17:35:03Z
• Authors: Naoki Tajiri; Sandra A. Acosta; Md Shahaduzzaman; Hiroto Ishikawa; Kazutaka Shinozuka; Mibel Pabon; Diana Hernandez-O...; Dae Won Kim; Christopher Metcalf; Meaghan Staples; Travis Dailey; Julie Vasconcellos; Giorgio Franyuti; Lisa Gould; Niketa Patel; Denise Cooper; Yuji Kaneko; Cesar V. Borlongan; Paula C. Bickford
• Keywords: Male; 0301 basic medicine; Age Factors; Brain; Rats, Inbred F344; Rats; Motor Skills Disorders; 03 medical and health sciences; Adipose Tissue; Brain Injuries; Nerve Degeneration; Animals; Humans; Tissue Distribution; Cognition Disorders; Infusions, Intravenous; Cells, Cultured; Stem Cell Transplantation

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 presentin vivostudy, 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 × 106hADSCs (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 imagingin vivoandex vivorevealed 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.