Wnt3a recapitulates the neuroprotective effects of mesenchymal stem cells and promotes neurocognitive recovery in traumatic brain injury

Mesenchymal stem cells (MSCs) have been shown to have therapeutic potential in treating a number of neurological and neurodegenerative diseases, including traumatic brain injury (TBI), yet their exact mechanisms of action are not well understood. We have shown that, intravenously administered bone marrow MSCs reduce TBI induced blood brain barrier permeability through release of the soluble factor TIMP3. These effects occur in the absence of engraftment and differentiation of the MSCs in the injured brain. In the present study, we sought to determine if intravenously administered MSCs (IV-MSCs) enhance hippocampal neurogenesis and neuronal survival after TBI. Our results show that IV-MSCs attenuate the loss of neural progenitors, promote neurogenesis, and enhance neuronal dendritic outgrowth in TBI mice. To determine if these effects are dependent upon production of a soluble factor, we have identified the protein Wnt3a that is increased in the serum of TBI mice following IV-MSC administration. Wnts have been known to modulate neurogenesis and neuronal survival. Concurrent with this finding, we detected increased activation of the Wnt/β-catenin signaling pathway in dentate gyrus hippocampal neurons. Furthermore, IV recombinant Wnt3a administered acutely after injury, reproduced the neuroprotective and neurogenic effects observed with IV-MSCs and furthermore improved neurocognitive function in TBI mice. Taken together, our results demonstrate a role for Wnt3a in the biological actions of MSCs on hippocampal neurogenesis and neuroprotection, and identify Wnt3a as a potential therapeutic candidate for use in the treatment of TBI. These results are novel, have not been previously reported and support the clinical investigation of IV Wnt3a as cell free therapeutic in the treatment of TBI patients.