Background and Purpose— To date, stem cell graft-mediated neuroprotection is equated with graft survival and secretion of neurotrophic factors in the brain. Here, we examined whether neuroprotection by systemically delivered human umbilical cord blood (HUCB) cells was dependent on their entry into the central nervous system in a rodent model of acute stroke. Methods— Adult male Sprague-Dawley rats were subjected to right middle cerebral artery occlusion for 60 minutes. During the 1-hour occlusion, animals were randomly assigned to 1 of the following treatments: intravenous injection of HUCB (a subtherapeutic dose of 200 000 cells in 10 μL) with blood–brain barrier (BBB) permeabilizer (1.1 mol/L mannitol at 4°C) or vehicle, intravenous vehicle alone, or intravenous mannitol alone. Behavioral tests, using elevated body swing test and passive avoidance test, were conducted at day 3 poststroke, and thereafter, animals were euthanized for: (1) immunohistochemical examination of HUCB, which were lentivirally labeled with green fluorescent protein; (2) cerebral infarction analysis using 2,3,5-triphenyl-tetrazolium chloride; and (3) enzyme-linked immunosorbent assay of trophic factors within the striatal region. Results— We did not detect intravenously administered low dose of HUCB cells in the brains of animals at day 3 after stroke even when cells were coinfused with a BBB permeabilizer (mannitol). However, HUCB–mannitol treatment significantly increased brain levels of neurotrophic factors, which correlated positively with reduced cerebral infarcts and improved behavioral functions. Conclusions— Our data show that central nervous system availability of grafted cells is not a prerequisite for acute neuroprotection provided that therapeutic molecules secreted by these cells could cross the BBB.

Traumatic brain injury (TBI) is a serious public health problem accounting for 1.4 million emergency room visits by US citizens each year. Although TBI has been traditionally considered an acute injury, chronic symptoms reminiscent of neurodegenerative disorders have now been recognized. These progressive neurodegenerative-like symptoms manifest as impaired motor and cognitive skills, as well as stress, anxiety, and mood affective behavioral alterations. TBI, characterized by external bumps or blows to the head exceeding the brain’s protective capacity, causes physical damage to the central nervous system with accompanying neurological dysfunctions. The primary impact results in direct neural cell loss predominantly exhibiting necrotic death, which is then followed by a wave of secondary injury cascades including excitotoxicity, oxidative stress, mitochondrial dysfunction, blood–brain barrier disruption, and inflammation. All these processes exacerbate the damage, worsen the clinical outcomes, and persist as an evolving pathological hallmark of what we now describe as chronic TBI. Neuroinflammation in the acute stage of TBI mobilizes immune cells, astrocytes, cytokines, and chemokines toward the site of injury to mount an antiinflammatory response against brain damage; however, in the chronic stage, excess activation of these inflammatory elements contributes to an “inflamed” brain microenvironment that principally contributes to secondary cell death in TBI. Modulating these inflammatory cells by changing their phenotype from proinflammatory to antiinflammatory would likely promote therapeutic effects on TBI. Because neuroinflammation occurs at acute and chronic stages after the primary insult in TBI, a treatment targeting neuroinflammation may have a wider therapeutic window for TBI. To this end, a better understanding of TBI etiology and clinical manifestations, especially the pathological presentation of chronic TBI with neuroinflammation as a major component, will advance our knowledge on inflammation-based disease mechanisms and treatments.

This study was designed to explore the efficacy of a human clone cell line as an alternative neural graft source and to validate the practice of cryopreservation and xenografting as logistical approaches toward conducting neural transplantation. We investigated the biological effects of transplanting cultured human neurons (NT2N cells) derived from a well-characterized embryonal carcinoma cell line into the brains of rats subjected to transient, focal cerebral ischemia induced by embolic occlusion of the middle cerebral artery. At 1 month and extending throughout the 6-month posttransplantation test period, ischemic animals that were transplanted with NT2N cells and treated with an immunosuppressive drug displayed a significant improvement in a passive avoidance task as well as a normalization of asymmetrical motor behavior compared to ischemic animals that received rat fetal cerebellar cell grafts or vehicle alone. Remarkably, cryopreserved NT2N cell grafts, compared with fresh NT2N cell grafts, remained viable in the immunosuppressed rat brain and effective in producing behavioral recovery in immunosuppressed ischemic animals. The long-term viability of cryopreserved NT2N cell xenograftsin vivoand their sustained effectiveness in promoting behavioral recovery suggest potential utilization of xenografting and cryopreservation as useful protocols for establishing clone cell lines as graft source in neural transplantation therapies for central nervous system disorders.

Wharton’s jelly (WJ) is a gelatinous tissue within the umbilical cord that contains myofibroblast-like stromal cells. A unique cell population of WJ that has been suggested as displaying the stemness phenotype is the mesenchymal stromal cells (MSCs). Because MSCs’ stemness and immune properties appear to be more robustly expressed and functional which are more comparable with fetal than adult-derived MSCs, MSCs harvested from the “young” WJ are considered much more proliferative, immunosuppressive, and even therapeutically active stem cells than those isolated from older, adult tissue sources such as the bone marrow or adipose. The present review discusses the phenotypic characteristics, therapeutic applications, and optimization of experimental protocols for WJ-derived stem cells. MSCs derived from WJ display promising transplantable features, including ease of sourcing, in vitro expandability, differentiation abilities, immune-evasion and immune-regulation capacities. Accumulating evidence demonstrates that WJ-derived stem cells possess many potential advantages as transplantable cells for treatment of various diseases (e.g., cancer, chronic liver disease, cardiovascular diseases, nerve, cartilage and tendon injury). Additional studies are warranted to translate the use of WJ-derived stem cells for clinical applications.

Traumatic brain injury (TBI) has become the signature wound of wars in Afghanistan and Iraq. Injury may result from a mechanical force, a rapid acceleration-deceleration movement, or a blast wave. A cascade of secondary cell death events ensues after the initial injury. In particular, multiple inflammatory responses accompany TBI. A series of inflammatory cytokines and chemokines spreads to normal brain areas juxtaposed to the core impacted tissue. Among the repertoire of immune cells involved, microglia is a key player in propagating inflammation to tissues neighboring the core site of injury. Neuroprotective drug trials in TBI have failed, likely due to their sole focus on abrogating neuronal cell death and ignoring the microglia response despite these inflammatory cells’ detrimental effects on the brain. Another relevant point to consider is the veracity of results of animal experiments due to deficiencies in experimental design, such as incomplete or inadequate method description, data misinterpretation, and reporting may introduce bias and give false-positive results. Thus, scientific publications should follow strict guidelines that include randomization, blinding, sample-size estimation, and accurate handling of all data (Landis et al., 2012). A prolonged state of inflammation after brain injury may linger for years and predispose patients to develop other neurological disorders, such as Alzheimer’s disease. TBI patients display progressive and long-lasting impairments in their physical, cognitive, behavioral, and social performance. Here, we discuss inflammatory mechanisms that accompany TBI in an effort to increase our understanding of the dynamic pathological condition as the disease evolves over time and begin to translate these findings for defining new and existing inflammation-based biomarkers and treatments for TBI.