Systemically infused mesenchymal stem cells (MSCs) are emerging therapeutics for treating stroke, acute injuries, and inflammatory diseases of the central nervous system (CNS), as well as brain tumors due to their regenerative capacity and ability to secrete trophic, immune modulatory, or other engineered therapeutic factors. It is hypothesized that transplanted MSCs home to and engraft at ischemic and injured sites in the brain in order to exert their therapeutic effects. However, whether MSCs possess the ability to migrate across the blood-brain barrier (BBB) that separates the blood from the brain remains unresolved. This review analyzes recent advances in this area in an attempt to elucidate whether systemically infused MSCs are able to actively transmigrate across the CNS endothelium, particularly under conditions of injury or stroke. Understanding the fate of transplanted MSCs and their CNS trafficking mechanisms will facilitate the development of more effective stem-cell-based therapeutics and drug delivery systems to treat neurological diseases and brain tumors. 1. Introduction Despite enormous advances in our understanding of the molecular and cellular basis of neurological diseases, therapies that lead to sustained improvement or resolution of symptoms have remained elusive. Regenerative therapeutics, that encompass embryonic, neural, and adult stem cell therapies, possess great potential to reverse neuronal damage associated with CNS diseases such as stroke, multiple sclerosis (MS), Parkinson’s disease (PD), and Alzheimer’s disease (AD) [1]. Mesenchymal stem cells (MSCs) are an especially attractive therapeutic agent due to their ease of isolation, established safety, and potential to target multiple pathways involved in neuronal regeneration. MSCs are connective tissue progenitors that can be readily isolated from multiple tissues including bone marrow and adipose tissue [2–4]. While being initially used for treatment of connective tissue disorders due to their potential to differentiate into bone, cartilage, and fat cells, the discovery that MSCs can secrete cytokines and growth factors with antiapoptotic, proangiogenic, neuroprotective, and immune-modulatory properties has sparked broad clinical interest [2–4]. In fact, MSCs are the world’s first manufactured stem cell product (i.e., Osiris’s Prochymal) approved in Canada to treat graft-versus-host disease (GvHD) [5]. MSCs are currently being tested for treating some neurological diseases in multiple ongoing clinical trials, although their exact therapeutic mechanisms in vivo remain
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