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Stroke, traumatic brain injuries, and other similar conditions often lead to significant loss of functional brain tissue and associated disruption of neuronal signaling. A common strategy for replacing lost neurons is the injection of dissociated neural stem cells or differentiated neurons. However, this method is unlikely to be suitable for replacing large brain cavities, and the resulting distribution of neurons may lack the necessary architecture to support appropriate brain function. Engineered neural tissues may be a viable alternative. Cell death is a prominent concern in neuronal grafting studies, a problem that could be magnified with the transplantation of engineered neural tissues. Here, we examined the effect of one contributor to cell death, acute cerebral inflammation, on neuronal survival after the transplantation of bioengineered constructs based on silk scaffolds. We found evidence of a high degree of inflammation and poor neuronal survival after introducing engineered constructs into the motor cortex of rats. Integrating a corticosteroid (methylprednisolone) into the constructs resulted in significantly improved neuron survival during the acute phase of inflammation. The improved construct survival was associated with decreased markers of inflammation and an anti-inflammatory state of the immune system due to the steroid treatment.
Spinal cord injury (SCI) is a disabling neurological disorder that causes neural circuit dysfunction. Although various therapies have been applied to improve the neurological outcomes of SCI, little clinical progress has been achieved. Stem cell-based therapy aimed at restoring the lost cells and supporting micromilieu at the site of the injury has become a conceptually attractive option for tissue repair following SCI. Adult human neural stem/progenitor cells (hNS/PCs) were obtained from the epileptic human brain specimens. Induction of SCI was followed by the application of lentiviral vector-mediated green fluorescent protein-labeled hNS/PCs seeded in PuraMatrix peptide hydrogel (PM). The co-application of hNS/PCs and PM at the SCI injury site significantly enhanced cell survival and differentiation, reduced the lesion volume, and improved neurological functions compared to the control groups. Besides, the transplanted hNS/PCs seeded in PM revealed significantly higher migration abilities into the lesion site and the healthy host tissue as well as a greater differentiation into astrocytes and neurons in the vicinity of the lesion as well as in the host tissue. Our data suggest that the transplantation of hNS/PCs seeded in PM could be a promising approach to restore the damaged tissues and improve neurological functions after SCI.
Results from the present study demonstrated that transplantation of autologous bone marrow-derived mesenchymal stem cells into the lesion site in rat brain significantly ameliorated brain tissue pathological changes and brain edema, attenuated glial cell proliferation, and increased brain-derived neurotrophic factor expression. In addition, the number of cells double-labeled for 5-bromodeoxyuridine/glial fibrillary acidic protein and cells expressing nestin increased. Finally, blood vessels were newly generated, and the rats exhibited improved motor and cognitive functions. These results suggested that transplantation of autologous bone marrow-derived mesenchymal stem cells promoted brain remodeling and improved neurological functions following traumatic brain injury.
Spinal cord regeneration using stem cell transplantation is a promising strategy for regenerative therapy. Stem cells transplanted onto scaffolds that can mimic natural extracellular matrix (ECM) have the potential to significantly improve outcomes. In this study, we strived to develop a cell carrier by culturing neural stem cells (NSCs) onto electrospun 2D and 3D constructs made up of specific crosslinked functionalized self-assembling peptides (SAPs) featuring enhanced biomimetic and biomechanical properties. Morphology, architecture, and secondary structures of electrospun scaffolds in the solid-state and electrospinning solution were studied step by step. Morphological studies showed the benefit of mixed peptides and surfactants as additives to form thinner, uniform, and defect-free fibers. It has been observed that β-sheet conformation as evidence of self-assembling has been predominant throughout the process except for the electrospinning solution. In vitro NSCs seeded on electrospun SAP scaffolds in 2D and 3D conditions displayed desirable proliferation, viability, and differentiation in comparison to the gold standard. In vivo biocompatibility assay confirmed the permissibility of implanted fibrous channels by foreign body reaction. The results of this study demonstrated that fibrous 2D/3D electrospun SAP scaffolds, when shaped as micro-channels, can be suitable to support NSC transplantation for regeneration following spinal cord injury.
Neural repair in injury and disease presents a pressing unmet need in regenerative medicine. Due to the intrinsically reduced ability of the brain to replace lost and damaged neurons, reversing long-term cognitive and functional impairments poses a unique problem. Over the years, advancements in cellular and molecular understanding of neurogenesis mechanisms coupled with sophistication of biotechnology tools have transformed neural repair into a cross-disciplinary field that integrates discoveries from developmental neurobiology, transplantation and tissue engineering to design disease- and patient-specific remedies aimed at boosting either native rehabilitation or delivering exogenous hypoimmunogenic interventions. Advances in deciphering the blueprint of neural ontogenesis and annotation of the human genome has led to the development of targeted therapeutic opportunities that have the potential of treating the most vulnerable patient populations and whose findings from benchside suggest looming clinical translation. This review discusses how findings from studies of adult neurogenesis have informed development of interventions that target endogenous neural regenerative machineries and how advances in biotechnology, including the use of new gene-editing tools, have made possible the development of promising, complex neural transplant-based strategies. Adopting a multi-pronged strategy that is tailored to underlying neural pathology and that encompasses facilitation of endogenous regeneration, correction of patient's genomic mutations and delivery of transformed neural precursors and mature disease-relevant neuronal populations to replace injured or lost neural tissue remains no longer a fantasy.
Traumatic brain injury (TBI) triggers multiple biochemical and cellular processes that exacerbate brain tissue damage through a secondary injury. Therapies that prevent or limit the evolution of secondary injury could significantly reduce the neurological deficits associated with TBI. Mesenchymal stem cell (MSC) transplantation after TBI can ameliorate neurological deficits by modulating inflammation and enhancing the expression of neurotrophic factors. However, transplanted MSCs can be actively rejected by host immune responses, such as those mediated by cytotoxic CD8+ T cells, thereby limiting their therapeutic efficacy. Here, we designed an agarose hydrogel that releases Fas ligand (FasL), a protein that can induce apoptosis of cytotoxic CD8+ T cells. We studied the immunosuppressive effect of this hydrogel near the allogeneic MSC transplantation site and its impact on the survival of transplanted MSCs in the injured brain. Agarose-FasL hydrogels locally reduced the host cytotoxic CD8+ T cell population and enhanced the survival of allogeneic MSCs transplanted near the injury site. Furthermore, the expression of crucial neurotrophic factors was elevated in the injury penumbra, suggesting an enhanced therapeutic effect of MSCs. These results suggest that the development of immunosuppressive hydrogels for stem cell delivery can enhance the benefits of stem cell therapy for TBI.
Traditional therapeutic strategies for spinal cord injury (SCI) are insufficient to repair locomotor function because of the failure of axonal reconnection and neuronal regeneration in the injured central nervous system (CNS). Neural stem cell (NSC) transplantation has been considered a potential strategy and is generally feasible for repairing the neural circuit after SCI; however, the most formidable problem is that the neuronal differentiation rate of NSCs is quite limited. Therefore, it is essential to induce the neuronal differentiation of NSCs and improve the differentiation rate of NSCs in spinal cord repair. Our results demonstrate that both Wnt5a and miRNA200b-3p could promote NSC differentiation into neurons and that Wnt5a upregulated miRNA200b-3p expression through MAPK/JNK signaling to promote NSC differentiation into neurons. Wnt5a could reduce RhoA expression by upregulating miRNA200b-3p expression to inhibit activation of the RhoA/Rock signaling pathway, which has been reported to suppress neuronal differentiation. Overexpression of RhoA abolished the neurogenic capacity of Wnt5a and miRNA200b-3p. In vivo, miRNA200b-3p was critical for Wnt5a-induced NSC differentiation into neurons to promote motor functional and histological recovery after SCI by suppressing RhoA/Rock signaling. These findings provide more insight into SCI and help with the identification of novel treatment strategies.
Tissue-engineered human allogeneic skin grafts retrieved from a deceased donor play an important role in the therapy of extensive and deeply burned patients. However, there is a vital deficit of allogeneic skin donors, and the reserves of human allogeneic skin grafts are not sufficient. The goal of this work was to analyze the level of knowledge and attitudes of Polish society in the field of transplantation, with particular emphasis on allogeneic skin transplantation. The study used a self-made questionnaire comprised of 23 questions. 1000 respondents took part in this research. The respondents were a diverse group in terms of age, sex, education, and place of residence. The obtained results show a general positive attitude of the respondents towards the idea of transplantology. However, people with lower education presented a more negative attitude towards the donation of tissues and organs. Additionally younger people were not able to clearly declare readiness for organ procurement. What is more data analysis revealed certain gaps in more detailed knowledge and surprising attitudes. In that respect, the lack of awareness about the criteria for determining brain death could be mentioned. There was also a lack of acceptance for skin procurement in specific population groups. It can therefore be concluded that a key role in the success of the idea of transplantation in Poland is the broad and systematic education of the society.
Human skin contains keratinocytes in the epidermis. Such cells share their ectodermal origin with the central nervous system (CNS). Recent studies have demonstrated that terminally differentiated somatic cells can adopt a pluripotent state, or can directly convert its phenotype to neurons, after ectopic expression of transcription factors. In this article we tested the hypothesis that human keratinocytes can adopt neural fates after culturing them in suspension with a neural medium. Initially, keratinocytes expressed Keratins and Vimentin. After neural induction, transcriptional upregulation of NESTIN, SOX2, VIMENTIN, SOX1, and MUSASHI1 was observed, concomitant with significant increases in NESTIN detected by immunostaining. However, in vitro differentiation did not yield the expression of neuronal or astrocytic markers. We tested the differentiation potential of control and neural-induced keratinocytes by grafting them in the developing CNS of rats, through ultrasound-guided injection. For this purpose, keratinocytes were transduced with lentivirus that contained the coding sequence of green fluorescent protein. Cell sorting was employed to select cells with high fluorescence. Unexpectedly, 4 days after grafting these cells in the ventricles, both control and neural-induced cells expressed green fluorescent protein together with the neuronal proteins βIII-Tubulin and Microtubule-Associated Protein 2. These results support the notion that in vivo environment provides appropriate signals to evaluate the neuronal differentiation potential of keratinocytes or other non-neural cell populations.
Mesenchymal stem cell (MSC) treatment is an effective strategy to reduce brain damage after neonatal hypoxia-ischemia (HI) in mice. We recently showed that a single injection with MSC at either 3 or 10 days after HI (MSC-3 or MSC-10) increases neurogenesis. In case of two injections (MSC-3+10), the second MSC application does not increase neurogenesis, but promotes corticospinal tract remodeling. Here we investigated GFP(+)-MSC engraftment level in the brain using quantitative-PCR analysis. We show for the first time that in the neonatal ischemic brain survival of transplanted MSC is very limited. At 3 days after injection ∼22% of transplanted MSC were still detectable and 18 days after the last administration barely ∼1%. These findings indicate that engraftment of MSC is not likely the underlying mechanism of the efficient regenerative process. Therefore, we tested the hypothesis that the effects of MSC-treatment on regenerative processes are related to specific changes in the gene expression of growth factors and cytokines in the damaged area of the brain using PCR-array analysis. We compared the effect of one (MSC-10) or two (MSC-3+10) injections of 10(5) MSC on gene expression in the brain. Our data show that MSC-10 induced expression of genes regulating proliferation/survival. In response to MSC-3+10-treatment a pattern functionally categorized as growth stimulating genes was increased. Collectively, our data indicate that specific regulation of the endogenous growth factor milieu rather than replacement of damaged tissue by exogenous MSC mediates regeneration of the damaged neonatal brain by MSC-treatment.
Ischemic stroke is a leading cause of morbidity and mortality, with limited treatments that can facilitate brain regeneration. Neural progenitor cells (NPCs) hold promise for replacing tissue lost to stroke, and biomaterial approaches may improve their efficacy to overcome hurdles in clinical translation. The immune response and its role in stroke pathogenesis and regeneration may interplay with critical mechanisms of stem cell and biomaterial therapies. Cellular therapy can modulate the immune response to reduce toxic neuroinflammation early after ischemia. However, few studies have attempted to harness the regenerative effects of neuroinflammation to augment recovery. Our previous studies demonstrated that intracerebrally transplanted NPCs encapsulated in a chondroitin sulfate-A hydrogel (CS-A + NPCs) can improve vascular regeneration after stroke. In this paper, we found that CS-A + NPCs affect the microglia/macrophage response to promote a regenerative phenotype following stroke in mice. Following transplantation, PPARγ-expressing microglia/macrophages, and MCP-1 and IL-10 protein levels are enhanced. Secreted immunomodulatory factor expression of other factors was altered compared to NPC transplantation alone. Post-stroke depression-like behavior was reduced following cellular and material transplantation. Furthermore, we showed in cultures that microglia/macrophages encapsulated in CS-A had increased expression of angiogenic and arteriogenic mediators. Neutralization with anti-IL-10 antibody negated these effects in vitro. Cumulatively, this work provides a framework for understanding the mechanisms by which immunomodulatory biomaterials can enhance the regenerative effects of cellular therapy for ischemic stroke and other brain injuries.
Ischemic stroke, and the consequent brain cell death, is a common cause of death and disability worldwide. Current treatments that primarily aim to relieve symptoms are relatively inefficient in achieving brain tissue regeneration and functional recovery, and thus novel therapeutic options are urgently needed. Although cell-based therapies have shown promise for treating the infarcted brain, a recurring challenge is the inadequate retention and engraftment of transplanted cells at the target tissue, thereby limiting the ultimate therapeutic efficacy. Here, we show that transplantation of preassembled three-dimensional (3D) spheroids of mesenchymal stem cells (MSCs) and vascular endothelial cells (ECs) results in significantly improved cell retention and survival compared with conventional mixed-cell suspensions. The transplanted 3D spheroids exhibit notable neuroprotective, proneurogenic, proangiogenic and anti-scarring potential as evidenced by clear extracellular matrix structure formation and paracrine factor expression and secretion; this ultimately results in increased structural and motor function recovery in the brain of an ischemic stroke mouse model. Therefore, transplantation of MSCs and ECs using the 3D cell spheroid configuration not only reduces cell loss during cell harvesting/administration but also enhances the resultant therapeutic benefit, thus providing important proof-of-concept for future clinical translation.
Microglia appear activated in the vicinity of amyloid beta (Aβ) plaques, but whether microglia contribute to Aβ propagation into unaffected brain regions remains unknown. Using transplantation of wild-type (WT) neurons, we show that Aβ enters WT grafts, and that this is accompanied by microglia infiltration. Manipulation of microglia function reduced Aβ deposition within grafts. Furthermore, in vivo imaging identified microglia as carriers of Aβ pathology in previously unaffected tissue. Our data thus argue for a hitherto unexplored mechanism of Aβ propagation.
Nerve tissue engineering is an important strategy for the treatment of brain injuries. Mesenchymal stem cell (MSC) transplantation has been proven to be able to promote repair and functional recovery of brain damage, and poly (lactic-co-glycolic acid) (PLGA) has also been found to have the capability of bearing cells. In the present study, to observe the ability of PLGA scaffold in supporting the adherent growth of MSCs and neurons in vivo and vitro and to assess the effects of PLGA scaffold on proliferation and neural differentiation of MSCs, this study undertakes the following steps. First, MSCs and neurons were cultured and labeled with green fluorescent protein (GFP) or otherwise identified and the PLGA scaffold was synthesized. Next, MSCs and neurons were inoculated on PLGA scaffolds and their adhesion rates were investigated and the proliferation of MSCs was evaluated by using MTT assay. After MSCs were induced by a neural induction medium, the morphological change and neural differentiation of MSCs were detected using scanning electron microscopy (SEM) and immunocytochemistry, respectively. Finally, cell migration and adhesion in the PLGA scaffold in vivo were examined by immunohistochemistry, nuclear staining, and SEM. The experimental results demonstrated that PLGA did not interfere with the proliferation and neural differentiation of MSCs and that MSCs and neuron could grow and migrate in PLGA scaffold. These data suggest that the MSC-PLGA complex may be used as tissue engineering material for brain injuries.
Bone marrow stromal cells (BMSCs) are heterogeneous and their therapeutic effect is pleiotropic. Multilineage-differentiating stress enduring (Muse) cells are recently identified to comprise several percentages of BMSCs, being able to differentiate into triploblastic lineages including neuronal cells and act as tissue repair cells. This study was aimed to clarify how Muse and non-Muse cells in BMSCs contribute to functional recovery after ischemic stroke.
Reestablishment of functional networks after traumatic brain injury (TBI) has been proffered as one of the goals of neural stem cell (NSC) transplantation therapeutics. Gap junctions provide essential means for direct cellular communication by transferring small molecules and ions, which may provide insights into the interplay between grafted NSCs and host cells.
Neural tissue engineering has been introduced as a novel therapeutic strategy for traumatic brain injury (TBI). Transplantation of mesenchymal stem cells (MSCs) has been demonstrated to improve functional outcome of brain injury, and RADA4GGSIKVAV (R-GSIK), a self-assembling nano-peptide scaffold, has been suggested to promote the behavior of stem cells. This study was designed to determine the ability of the R-GSIK scaffold in supporting the effects of MSCs on motor function activity and inflammatory responses in an experimental TBI model. A significant recovery of motor function was observed in rats that received MSCs+R-GSIK compared with the control groups. Further analysis showed a reduction in the number of reactive astrocytes and microglial cells in the MSCs and MSCs+R-GSIK groups compared with the control groups. Furthermore, western blot analysis indicated a significant reduction in pro-inflammatory cytokines, such as TLR4, TNF, and IL6, in the MSCs and MSCs+R-GSIK groups compared with the TBI, vehicle, and R-GSIK groups. Overall, this study strengthens the idea that the co-transplantation of MSCs with R-GSIK can increase functional outcomes by preparing a beneficial environment. This improvement may be explained by the immunomodulatory effects of MSCs and the self-assembling nano-scaffold peptide.
There is growing evidence that type 2 diabetes or insulin resistance is linked to cognitive impairment. We recently confirmed altered lipid composition, down-regulation of insulin receptor expression and impaired basal synaptic transmission in the hippocampus of our transgenic murine model of adipocyte insulin resistance (AtENPP1-Tg). Here we evaluated whether the correction of adipose tissue dysfunction [via the subcutaneous transplantation of mesenchymal stem cells (MSC)] can improve the hippocampal synaptic transmission in AtENPP1-Tg mice versus their wildtype littermates. Animals were simply randomized to receive MSC, then weighed weekly for 12 weeks. At euthanasia, we assessed leptin in the collected serum and hippocampal synaptic high-frequency stimulation long-term potentiation (HFS-LTP) using brain slices. MSC transplantation normalized AtENPP1-Tg body and epididymal fat weights and was associated with increased leptin levels, a sign of adipocyte maturation. More importantly, transplantation restored the deficiency observed in AtENPP1-Tg HFS-LTP, the cellular readout of memory. Our results further corroborate the role of adipocyte maturation arrest in adipose tissue and highlight a role for the adipose tissue in modulating hippocampal cellular mechanisms. Further studies are warranted to explore the mechanisms for the MSC-induced improvement of hippocampal HFS-LTP.
Traumatic brain injury (TBI) in humans can result in permanent tissue damage and has been linked to cognitive impairment that lasts years beyond the initial insult. Clinically effective treatment strategies have yet to be developed. Transplantation of human neural stem cells (hNSCs) has the potential to restore cognition lost due to injury, however, the vast majority of rodent TBI/hNSC studies to date have evaluated cognition only at early time points, typically <1month post-injury and cell transplantation. Additionally, human cell engraftment and long-term survival in rodent models of TBI has been difficult to achieve due to host immunorejection of the transplanted human cells, which confounds conclusions pertaining to transplant-mediated behavioral improvement. To overcome these shortfalls, we have developed a novel TBI xenotransplantation model that utilizes immunodeficient athymic nude (ATN) rats as the host recipient for the post-TBI transplantation of human embryonic stem cell (hESC) derived NSCs and have evaluated cognition in these animals at long-term (≥2months) time points post-injury. We report that immunodeficient ATN rats demonstrate hippocampal-dependent spatial memory deficits (Novel Place, Morris Water Maze), but not non-spatial (Novel Object) or emotional/anxiety-related (Elevated Plus Maze, Conditioned Taste Aversion) deficits, at 2-3months post-TBI, confirming that ATN rats recapitulate some of the cognitive deficits found in immunosufficient animal strains. Approximately 9-25% of transplanted hNSCs survived for at least 5months post-transplantation and differentiated into mature neurons (NeuN, 18-38%), astrocytes (GFAP, 13-16%), and oligodendrocytes (Olig2, 11-13%). Furthermore, while this model of TBI (cortical impact) targets primarily cortex and the underlying hippocampus and generates a large lesion cavity, hNSC transplantation facilitated cognitive recovery without affecting either lesion volume or total spared cortical or hippocampal tissue volume. Instead, we have found an overall increase in host hippocampal neuron survival in hNSC transplanted animals and demonstrate that a correlation exists between hippocampal neuron survival and cognitive performance. Together, these findings support the use of immunodeficient rodents in models of TBI that involve the transplantation of human cells, and suggest that hNSC transplantation may be a viable, long-term therapy to restore cognition after brain injury.
Transplantation of neural progenitor cells (NPCs) may be a potential treatment strategy for traumatic brain injury (TBI) due to their intrinsic advantages, including the secretion of neurotrophins. Neurotrophins are critical for neuronal survival and repair, but their clinical use is limited. In this study, we hypothesized that pericontusional transplantation of NPCs genetically modified to secrete a synthetic, human multineurotrophin (MNTS1) would overcome some of the limitations of traditional neurotrophin therapy. MNTS1 is a multifunctional neurotrophin that binds all three tropomyosin-related kinase (Trk) receptors, recapitulating the prosurvival activity of 3 endogenous mature neurotrophins. NPCs obtained from rat fetuses at E15 were transduced with lentiviral vectors containing MNTS1 and GFP constructs (MNTS1-NPCs) or fluorescent constructs alone (control GFP-NPCs). Adult rats received fluid percussion-induced TBI or sham surgery. Animals were transplanted 1week later with control GFP-NPCs, MNTS1-NPCs, or injected with saline (vehicle). At five weeks, animals were evaluated for hippocampal-dependent spatial memory. Six weeks post-surgery, we observed significant survival and neuronal differentiation of MNTS1-NPCs and injury-activated tropism toward contused regions. NPCs displayed processes that extended into several remote structures, including the hippocampus and contralateral cortex. Both GFP- and MNTS1-NPCs conferred significant preservation of pericontusional host tissues and enhanced hippocampal neurogenesis. NPC transplantation improved spatial memory capacity on the Morris water maze (MWM) task. Transplant recipients exhibited escape latencies approximately half that of injured vehicle controls. While we observed greater transplant survival and neuronal differentiation of MNTS1-NPCs, our collective findings suggest that MNTS1 may be superfluous in terms of preserving the cytoarchitecture and rescuing behavioral deficits given the lack of significant difference between MNTS1- and GFP-control transplanted groups. Nevertheless, our overall findings support the potential of syngeneic NPC transplantation to enhance endogenous neuroreparative responses and may therefore be an effective treatment for TBI.
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