Cell Therapy For Neurodegenerative Diseases Research Articles

Neural cell engraftment therapy for sporadic Creutzfeldt-Jakob disease restores neuroelectrophysiological parameters in a cerebral organoid model

BackgroundSporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is a fatal neurodegenerative disease with currently no treatment options. Stem cell therapy for neurodegenerative diseases is emerging as a possible treatment option. However, while there are a few clinical trials for other neurodegenerative disorders such as Parkinson’s disease, prion disease cell therapy research has so far been confined to animal models.MethodsHere, we use a novel approach to study cell therapies in sCJD using a human cerebral organoid model. Cerebral organoids can be infected with sCJD prions allowing us to assess how neural precursor cell (NPC) therapy impacts the progression of sCJD. After 90 days of sCJD or mock infection, organoids were either seeded with NPCs or left unseeded and monitored for cellular composition changes, prion infection parameters and neuroelectrophysiological function at 180 days post-infection.ResultsOur results showed NPCs integrated into organoids leading to an increase in neuronal markers and changes in cell signaling irrespective of sCJD infection. Although a small, but significant, decrease in protease-resistant PrP deposition was observed in the CJD-infected organoids that received the NPCs, other disease-associated parameters showed minimal changes. However, the NPCs had a beneficial impact on organoid function following infection. sCJD infection caused reduction in neuronal spike rate and mean burst spike rate, indicative of reduced action potentials. NPC seeding restored these electrophysiological parameters to the uninfected control level.ConclusionsTogether with the previous animal studies, our results support that cell therapy may have some functional benefit for the treatment of human prion diseases.

Somatic Cell-Fusion and/or Co-Culturing: A Mechanism for Cell Re-Programming Prior to Cell Therapy of Neurodegenerative Diseases

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most prevalent neurodegenerative diseases which generally start after 50-55 ages of life where the brain neural cell gets destroyed. Transplantation of the dopaminergic (DA-ergic) neuronal cells, though, could help the diseases but the most obstacle is the availability of a sufficient number of such cells for replacement therapy. Neural stem cells (NSCs) are able to produce DA-ergic neurons and also have the capacity to act as a useful vehicle for genetic and molecular therapies within the central system (CNS), however, the sustainability of slowly and senescence NSCs must be ensured through genetic manipulation both in vitro and in vivo. NSCs grow very occurs after a few passages. Here we'll discuss many options to modify the NSC cells for a better growth, and increased survival length, as well as their ability to control the release of dopamine within the neural synaptic cleft. Cell-Cell interactions in terms of co-culturing or cell fusion are commonly known to change the cells’ fate by genetic reprogramming, and thus discussed here for evaluation of their use in the transplantation process.

Neural progenitor cells derived from fibroblasts induced by small molecule compounds under hypoxia for treatment of Parkinson's disease in rats.

Neural progenitor cells (NPCs) capable of self-renewal and differentiation into neural cell lineages offer broad prospects for cell therapy for neurodegenerative diseases. However, cell therapy based on NPC transplantation is limited by the inability to acquire sufficient quantities of NPCs. Previous studies have found that a chemical cocktail of valproic acid, CHIR99021, and Repsox (VCR) promotes mouse fibroblasts to differentiate into NPCs under hypoxic conditions. Therefore, we used VCR (0.5 mM valproic acid, 3 μM CHIR99021, and 1 μM Repsox) to induce the reprogramming of rat embryonic fibroblasts into NPCs under a hypoxic condition (5%). These NPCs exhibited typical neurosphere-like structures that can express NPC markers, such as Nestin, SRY-box transcription factor 2, and paired box 6 (Pax6), and could also differentiate into multiple types of functional neurons and astrocytes in vitro. They had similar gene expression profiles to those of rat brain-derived neural stem cells. Subsequently, the chemically-induced NPCs (ciNPCs) were stereotactically transplanted into the substantia nigra of 6-hydroxydopamine-lesioned parkinsonian rats. We found that the ciNPCs exhibited long-term survival, migrated long distances, and differentiated into multiple types of functional neurons and glial cells in vivo. Moreover, the parkinsonian behavioral defects of the parkinsonian model rats grafted with ciNPCs showed remarkable functional recovery. These findings suggest that rat fibroblasts can be directly transformed into NPCs using a chemical cocktail of VCR without introducing exogenous factors, which may be an attractive donor material for transplantation therapy for Parkinson's disease.

Human neural stem cell-derived extracellular vesicles protect against Parkinson\u2019s disease pathologies

BackgroundNeural stem cells (NSCs) have the ability to generate a variety of functional neural cell types and have a high potential for neuronal cell regeneration and recovery. Thus, they been recognized as the best source of cell therapy for neurodegenerative diseases, such as Parkinson’s disease (PD). Owing to the possibility of paracrine effect-based therapeutic mechanisms and easier clinical accessibility, extracellular vesicles (EVs), which possess very similar bio-functional components from their cellular origin, have emerged as potential alternatives in regenerative medicine.Material and methodsEVs were isolated from human fibroblast (HFF) and human NSC (F3 cells). The supernatant of the cells was concentrated by a tangential flow filtration (TFF) system. Then, the final EVs were isolated using a total EV isolation kit.ResultsIn this study, we demonstrate the potential protective effect of human NSC-derived EVs, showing the prevention of PD pathologies in 6-hydroxydopamine (6-OHDA)-induced in vitro and in vivo mouse models. Human NSC and F3 cell (F3)-derived EVs reduced the intracellular reactive oxygen species (ROS) and associated apoptotic pathways. In addition, F3-derived EVs induced downregulation of pro-inflammatory factors and significantly decreased 6-OHDA-induced dopaminergic neuronal loss in vivo. F3 specific microRNAs (miRNAs) such as hsa-mir-182-5p, hsa-mir-183-5p, hsa-mir-9, and hsa-let-7, which are involved in cell differentiation, neurotrophic function, and immune modulation, were found in F3-derived EVs.ConclusionsWe report that human NSC-derived EVs show an effective neuroprotective property in an in vitro transwell system and in a PD model. The EVs clearly decreased ROS and pro-inflammatory cytokines. Taken together, these results indicate that NSC-derived EVs could potentially help prevent the neuropathology and progression of PD.Graphical

Regulation of Neural Differentiation of ADMSCs using Graphene-Mediated Wireless-Localized Electrical Signals Driven by Electromagnetic Induction.

Although adipose‐derived mesenchymal stem cells (ADMSCs) isolated from patients’ fat are considered as the most important autologous stem cells for tissue repair, significant difficulties in the neural differentiation of ADMSCs still impede stem cell therapy for neurodegenerative diseases. Herein, a wireless‐electrical stimulation method is proposed to direct the neural differentiation of ADMSCs based on the electromagnetic effect using a graphene film as a conductive scaffold. By placing a rotating magnet on the top of a culture system without any inducer, the ADMSCs cultured on graphene differentiate into functional neurons within 15 days. As a conductive biodegradable nanomaterial, graphene film acts as a wireless electrical signal generator driven by the electromagnetic induction, and millivolt‐level voltage generated in situ provokes ADMSCs to differentiate into neurons, proved by morphological variation, extremely high levels of neuron‐specific genes, and proteins. Most importantly, Ca2+ intracellular influx is observed in these ADMSC‐derived neurons once exposure to neurotransmitters, indicating that these cells are functional neurons. This research enhances stem cell therapy for neurodegenerative diseases using autologous ADMSCs and overcomes the lack of neural stem cells. This nanostructure‐mediated physical‐signal simulation method is inexpensive, safe, and localized, and has a significant impact on neural regeneration.

Review: Neuronal Differentiation Protocols of Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) are self-renewing cells found in almost all postnatal organs and tissues in the perivascular region. These cells present multiple characteristics that make them candidates to be applied in cell therapy for neurodegenerative diseases, such as their secretory action, migration to the lesion area, and immunomodulatory potential. These cells have a high capacity for mesodermal differentiation; however, numerous studies have shown that MSCs can also differentiate into neurons. However, despite positive results in multiple trials in which undifferentiated MSCs transplanted into animal models of neurodegenerative diseases, some studies suggest that the therapeutic effects obtained are enhanced by the use of MSCs differentiated towards the neuronal lineage before transplant. In this sense, there are several methods to induce in vitro reprogramming of MSCs towards the neuronal lineage, including chemical substances, growth factors, cocultures with neural lineage cells, transfection of genes, miRNAs, etc., and small molecules stand out. Therefore, this article compares multiple experimental tests in which these inducers promote neuronal differentiation of MSCs and identify those methods that originate an optimal neuronal differentiation. The analysis includes the percentage of differentiation, maturation, expression of neuronal markers, functionality, and cell survival considering the intrinsic characteristics of the MSCs used as the tissue of origin and the species from which they were isolated.

Cell-derived extracellular matrix enhanced by collagen-binding domain-decorated exosomes to promote neural stem cells neurogenesis

Enhancing neurogenesis of neural stem cells (NSCs) is crucial in stem cell therapy for neurodegenerative diseases. Within the extracellular microenvironment, extracellular matrix (ECM) plays a pivotal role in modulating cell behaviors. However, a single ECM biomaterial is not sufficient to establish an ideal microenvironment. As multifunctional nanocarriers, exosomes display tremendous advantages for the treatments of various diseases. Herein, collagen binding domain peptide-modified exosomes (CBD-Exo) were obtained from the SH-SY5Y cell line infected with lentivirus particles encoding CBD-lysosome associated membrane glycoprotein 2b (CBD-Lamp2b) to improve the binding efficiency of exosomes and ECM. An exosomes-functionalized ECM (CBD-Exo/ECM) was then constructed via the interaction between CBD and collagen in ECM. Then, CBD-Exo/ECM was employed as a carrier for NSCs culture. The results showed that CBD-Exo/ECM can support the neurogenesis of NSCs with the percentage of proliferation marker EdU-positive (35.8% ± 0.47% vs 21.9% ± 2.32%) and neuron maker Tuj-1-positive (55.8% ± 0.47% vs 30.6% ± 2.62%) were both significantly increased in the exosomes-functionalized ECM system. This exosomes-functionalized ECM was capable to promote the cell proliferation and accelerate neuronal differentiation of NSCs, providing a potential biomedical material for stem cell application in tissue engineering and regenerative medicine.

Safety and Effectiveness of Cell Therapy in Neurodegenerative Diseases: Take-Home Messages From a Pilot Feasibility Phase I Study of Progressive Supranuclear Palsy.

Mesenchymal stromal cells (MSCs) are multipotent cells with anti-inflammatory properties. Here we tested the safety of MSCs in patients with progressive supranuclear palsy (PSP; ClinicalTrials.gov: NCT01824121; Eudract No. 2011-004051-39). Seven patients were treated. To improve the safety, protocol adjustments were made during the performance of the study. The objectives of our work were: (1) to assess the safety of MSCs and (2) to identify critical issues in cell therapies for neurodegenerative diseases. Autologous MSCs from the bone marrow of PSP patients were administered through the internal carotid arteries. 1-year survival and number of severe adverse events were considered as safety endpoints. Clinical rating scales, neuropsychological assessments, gait and posture analysis, single-photon emission computed tomography, positron emission tomography, and brain magnetic resonance (BMR) were performed at different follow-up times. Peripheral blood levels of inflammatory cytokines were measured before and after cell infusion. Six of the seven treated patients were living 1 year after cell infusion. Asymptomatic spotty lesions were observed at BMR after 24 h in six of the seven treated patients. The last patient in the preliminary cohort (Case 5) exhibited transiently symptomatic BMR ischemic alterations. No severe adverse events were recorded in the last two treated patients. Interleukin-8 serum concentrations decreased in three patients (Case 2, 3, and 4). An adaptive study design, appropriate and up-to-date efficacy measures, adequate sample size estimation, and, possibly, the use of a cellular and/or allogeneic cell sources may help in performing phase II trials in the field.

Therapeutic Potential of Human Stem Cell Implantation in Alzheimer's Disease.

Alzheimer’s disease (AD) is a progressive debilitating neurodegenerative disease and the most common form of dementia in the older population. At present, there is no definitive effective treatment for AD. Therefore, researchers are now looking at stem cell therapy as a possible treatment for AD, but whether stem cells are safe and effective in humans is still not clear. In this narrative review, we discuss both preclinical studies and clinical trials on the therapeutic potential of human stem cells in AD. Preclinical studies have successfully differentiated stem cells into neurons in vitro, indicating the potential viability of stem cell therapy in neurodegenerative diseases. Preclinical studies have also shown that stem cell therapy is safe and effective in improving cognitive performance in animal models, as demonstrated in the Morris water maze test and novel object recognition test. Although few clinical trials have been completed and many trials are still in phase I and II, the initial results confirm the outcomes of the preclinical studies. However, limitations like rejection, tumorigenicity, and ethical issues are still barriers to the advancement of stem cell therapy. In conclusion, the use of stem cells in the treatment of AD shows promise in terms of effectiveness and safety.

Biomaterial Cues Regulated Differentiation of Neural Stem Cells into GABAergic Neurons through Ca2+/c-Jun/TLX3 Signaling Promoted by Hydroxyapatite Nanorods

Directed differentiation enables the production of a specific cell type by manipulating signals in development. However, there is a lack of effective means to accelerate the regeneration of neurons of particular subtypes for pathogenesis and clinical therapy. In this study, we find that hydroxyapatite (HAp) nanorods promote neural differentiation of neural stem cells due to their chemical compositions. Lysosome-mediated degradation of HAp nanorods elevates intracellular calcium concentrations and accelerates GABAergic neurogenesis. As a mechanism, the enhanced activity of a Ca2+ peak initiated by HAp nanorods leads to the activation of c-Jun and thus suppresses the expression of GABAergic/glutamatergic selection gene TLX3. We demonstrate the capability of HAp nanorods in promoting the differentiation into GABAergic neurons at both molecular and cellular function levels. Given that GABAergic neurons are responsible for various physiological and pathological processes, our findings open up enormous opportunities in efficient and precise stem cell therapy of neurodegenerative diseases.

MESENCHYMAL STROMAL CELLS PROTECT THE BLOOD-BRAIN BARRIER, REDUCE ASTROGLIOSIS, AND PREVENT COGNITIVE AND BEHAVIORAL IMPAIRMENTS IN EXPERIMENTAL SEPSIS

<h3>Background</h3> Sepsis is a systemic inflammatory host-response against a pathogen; it is the largest cause of admission to intensive care units (ICUs) in the United States. Sepsis-associated encephalopathies (SAEs) are neurological complications that occur during or after sepsis events. SAE causes long-term neurological consequences affecting memory, cognition and mood. Currently, there is no prevention or treatment for neurological damage resulting from SAEs. Thus, investigating new therapies is necessary. Both clinical and experimental studies have been show the effects of cell therapy in neurodegenerative diseases. Indeed, the immunomodulatory capacity of mesenchymal stromal cells (MSCs) is well established. Considering that, the aim of the present study was to evaluate the effects of MSC therapy on blood-brain barrier (BBB) maintenance, astrocyte activation, cognitive and behavioral damage in an experimental model of sepsis. <h3>Methods</h3> Male adult Swiss mice underwent cecal ligation and puncture (CLP) surgery for sepsis induction and sham-operated animals were used as control. Six hours after surgery, mice were treated with MSC intravenously (1 × 10⁵ cells in 0.05 mL of saline/mouse) or saline. For in vitro, analysis cultured astrocytes were stimulated with lipopolysaccharide (LPS) (1μg/ ml). After 24 hours, cells were washed to eliminated residual LPS and then treated with conditioned media from MSCs (CM-MSCs). <h3>Results</h3> MSC therapy led to a reduction in systemic levels of IL-1β, IL-6, and MCP-1, a decrease in cortical and hippocampal cytokine levels, a reduction in astrogliosis (evaluated by immunofluorescence) and BBB protection (evaluated by Evans Blue Dye Assay). In cultured astrocytes stimulated with LPS, CM-MSCs reduced astrogliosis at 24h, suggesting a paracrine mechanism of action. These results might be associated with an improvement in spatial memory (Morris Water Maze test), aversive memory (fear-conditioned test) and anxiety-like behavior (Elevated plus maze test). <h3>Conclusion</h3> A single dose- therapy with MSC led to an improvement in cognitive damage, behavioral impairments, protection of the BBB, reduction in local levels of cytokines and astrogliosis and these effects might be associated with a decrease in systemic levels of inflammatory mediators.

Recovery potential of transplanted oligoprogenitor cells derived from human dental pulp stem cells in Lysophosphatidyl choline demyelination mode.

The cells were cultured in DMEM-F12 medium containing 1M Retinoic acid and were treated with 5ng/ml platelet-derived growth factor, 10 ng/ml basic fibroblast growth factor for 8-10 days. The differentiation cells were examined via the expression of specific glial markers: Olig2 and O4. Cells were transplanted in to a demylinated rat corpus callosum. The alteration of the demyelination extension as well as remyelination intensity was examined via a specific myelin staining: Luxol Fast Blue and immunohistochemistry. Differentiated oligoprogenitor cells were confirmed via immunofluorescence staining with specific glial markers: Olig2 and O4. Also, the amount of demyelination was decreased and intensity of remyelination showed an increase after an engraftment of differentiated cells. Immunohistochemistry for evaluation of PLP expression proved the mature myelinating oligodendrocytes. hDPSCs can be induced to transdifferentiate into oligoprogenitor cells and respond to the routinely applied regents for glial differentiation of Mesenchymal stem cells. hDPSCs may be a valuable source for cell therapy in neurodegenerative diseases (Fig. 4, Ref. 30). Text in PDF www.elis.sk Keywords: dental pulp stem cells, lysophosphatidylcholine, corpus callosum, oligodendrocyte, differentiation.

Defining the role of 17β-estradiol in human endometrial stem cells differentiation into neuron-like cells.

Human endometrial stem cells (hEnSCs) that can be differentiated into various neural cell types have been regarded as a suitable cell population for neural tissue engineering and regenerative medicine. Considering different interactions between hormones, growth factors, and other factors in the neural system, several differentiation protocols have been proposed to direct hEnSCs towards specific neural cells. The 17β-estradiol plays important roles in the processes of development, maturation, and function of nervous system. In the present research, the impact of 17β-estradiol (estrogen, E2) on the neural differentiation of hEnSCs was examined for the first time, based on the expression levels of neural genes and proteins. In this regard, hEnSCs were differentiated into neuron-like cells after exposure to retinoic acid (RA), epidermal growth factor (EGF), and also fibroblast growth factor-2 (FGF2) in the absence or presence of 17β-estradiol. The majority of cells showed a multipolar morphology. In all groups, the expression levels of nestin, Tuj-1 and NF-H (neurofilament heavy polypeptide) (as neural-specific markers) increased during 14 days. According to the outcomes of immunofluorescence (IF) and real-time PCR analyses, the neuron-specific markers were more expressed in the estrogen-treated groups, in comparison with the estrogen-free ones. These findings suggest that 17β-estradiol along with other growth factors can stimulate and upregulate the expression of neural markers during the neuronal differentiation of hEnSCs. Moreover, our findings confirm that hEnSCs can be an appropriate cell source for cell therapy of neurodegenerative diseases and neural tissue engineering.

Stem Cell Therapy for Neurodegenerative Diseases: How Do Stem Cells Bypass the Blood-Brain Barrier and Home to the Brain?

Blood-brain barrier (BBB) is a term describing the highly selective barrier formed by the endothelial cells (ECs) of the central nervous system (CNS) homeostasis by restricting movement across the BBB. An intact BBB is critical for normal brain functions as it maintains brain homeostasis, modulates immune cell transport, and provides protection against pathogens and other foreign substances. However, it also prevents drugs from entering the CNS to treat neurodegenerative diseases. Stem cells, on the other hand, have been reported to bypass the BBB and successfully home to their target in the brain and initiate repair, making them a promising approach in cellular therapy, especially those related to neurodegenerative disease. This review article discusses the mechanism behind the successful homing of stem cells to the brain, their potential role as a drug delivery vehicle, and their applications in neurodegenerative diseases.

Is the Immunological Response a Bottleneck for Cell Therapy in Neurodegenerative Diseases?

Neurodegenerative disorders such as Parkinson’s (PD) and Huntington’s disease (HD) are characterized by a selective detrimental impact on neurons in a specific brain area. Currently, these diseases have no cures, although some promising trials of therapies that may be able to slow the loss of brain cells are underway. Cell therapy is distinguished by its potential to replace cells to compensate for those lost to the degenerative process and has shown a great potential to replace degenerated neurons in animal models and in clinical trials in PD and HD patients. Fetal-derived neural progenitor cells, embryonic stem cells or induced pluripotent stem cells are the main cell sources that have been tested in cell therapy approaches. Furthermore, new strategies are emerging, such as the use of adult stem cells, encapsulated cell lines releasing trophic factors or cell-free products, containing an enriched secretome, which have shown beneficial preclinical outcomes. One of the major challenges for these potential new treatments is to overcome the host immune response to the transplanted cells. Immune rejection can cause significant alterations in transplanted and endogenous tissue and requires immunosuppressive drugs that may produce adverse effects. T-, B-lymphocytes and microglia have been recognized as the main effectors in striatal graft rejection. This review aims to summarize the preclinical and clinical studies of cell therapies in PD and HD. In addition, the precautions and strategies to ensure the highest quality of cell grafts, the lowest risk during transplantation and the reduction of a possible immune rejection will be outlined. Altogether, the wide-ranging possibilities of advanced therapy medicinal products (ATMPs) could make therapeutic treatment of these incurable diseases possible in the near future.

Characteristics and Therapeutic Potential of Dental Pulp Stem Cells on Neurodegenerative Diseases.

To evaluate the therapeutic potential of stem cells for neurodegenerative diseases, emphasis should be placed on clarifying the characteristics of the various types of stem cells. Among stem cells, dental pulp stem cells (DPSCs) are a cell population that is rich in cell proliferation and multipotency. It has been reported that transplantation of DPSCs has protective effects against models of neurodegenerative diseases. The protective effects are not only through differentiation into the target cell type for the disease but are also related to trophic factors released from DPSCs. Recently, it has been reported that serum-free culture supernatant of dental pulp stem cell-conditioned medium (DPCM) contains various trophic factors and cytokines and that DPCM is effective for models of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic Lateral Sclerosis (ALS). Moreover, the use of stem cells from human exfoliated deciduous teeth (SHEDs) has been considered. SHEDs are derived from deciduous teeth that have been disposed of as medical waste. SHEDs have higher differentiation capacity and proliferation ability than DPSCs. In addition, the serum-free culture supernatant of SHEDs (SHED-CM) contains more trophic factors, cytokines, and biometals than DPCM and also promotes neuroprotection. The neuroprotective effect of DPSCs, including those from deciduous teeth, will be used as the seeds of therapeutic drugs for neurodegenerative diseases. SHEDs will be used for further cell therapy of neurodegenerative diseases in the future. In this paper, we focused on the characteristics of DPSCs and their potential for neurodegenerative diseases.

Stem cells and vascular dementia: from basic science to the clinic.

Vascular dementia (VD) is the second most common cause of dementia following Alzheimer's disease (AD). The major symptoms of VD including memory loss, language deficits and impairment of executive functions. Its specific etiology and pathogenesis remain unknown. Currently, treatment options of VD are still limited. The therapeutic strategies aim to control the vascular risk factors and improve the cognitive function. In recent years, cell therapy for neurodegenerative diseases has attracted a great deal of attention. Evidence suggested that stem cell transplantation could improve the symptoms of cerebral infarction and AD. Therefore, it may serve as a potential therapy for VD. We summarized the latest research results both in vitro and in vivo. Further, the clinical trial of stem cell transplantation in VD patients was also reviewed. Finally, the limitations and future directions of cell therapy in VD treatment were discussed.

Future Challenges and Perspectives for Stem Cell Therapy of Neurodegenerative Diseases.

Stem cell-based therapy has shown exciting efficacy in pre-clinical studies on different neurodegenerative diseases (NDs). However, no clinically applicable stem-cell-derived neurons are available to the patients with NDs. There exist some obstacles associated with stem cell therapy, which need to be overcome in future clinical studies. In this chapter, more challenges and new strategies will be explored to accelerate the clinical translation of a human embryonic stem cell (hESC)/induced pluripotent stem cell (iPSC)-derived neural cell product to patients with NDs.

Transplantation of Mesenchymal Stem Cells Improves Amyloid-β Pathology by Modifying Microglial Function and Suppressing Oxidative Stress

Mesenchymal stem cells (MSC) are increasingly being studied as a source of cell therapy for neurodegenerative diseases, and several groups have reported their beneficial effects on Alzheimer’s disease (AD). In this study using AD model mice (APdE9), we found that transplantation of MSC via the tail vein improved spatial memory in the Morris water maze test. Using electron paramagnetic resonance imaging to evaluate the in vivo redox state of the brain, we found that MSC transplantation suppressed oxidative stress in AD model mice. To elucidate how MSC treatment ameliorates oxidative stress, we focused on amyloid-β (Aβ) pathology and microglial function. MSC transplantation reduced Aβ deposition in the cortex and hippocampus. Transplantation of MSC also decreased Iba1-positive area in the cortex and reduced activated ameboid shaped microglia. On the other hand, MSC transplantation accelerated accumulation of microglia around Aβ deposits and prompted microglial Aβ uptake and clearance as shown by higher frequency of Aβ-containing microglia. MSC transplantation also increased CD14-positive microglia in vivo, which play a critical role in Aβ uptake. To confirm the effects of MSC on microglia, we co-cultured the mouse microglial cell line MG6 with MSC. Co-culture with MSC enhanced Aβ uptake by MG6 cells accompanied by upregulation of CD14 expression. Additionally, co-culture of MG6 cells with MSC induced microglial phenotype switching from M1 to M2 and suppressed production of proinflammatory cytokines. These data indicate that MSC treatment has the potential to ameliorate oxidative stress through modification of microglial functions, thereby improving Aβ pathology in AD model mice.

A critical role for miR-184 in the fate determination of oligodendrocytes

BackgroundNew insights on cellular and molecular aspects of both oligodendrocyte (OL) differentiation and myelin synthesis pathways are potential avenues for developing a cell-based therapy for demyelinating disorders comprising multiple sclerosis. MicroRNAs (miRNA) have broad implications in all aspects of cell biology including OL differentiation. MiR-184 has been identified as one of the most highly enriched miRNAs in oligodendrocyte progenitor cells (OPCs). However, the exact molecular mechanism of miR-184 in OL differentiation is yet to be elucidated.Methods and resultsBased on immunochemistry assays, qRT-PCR, and western blotting findings, we hypothesized that overexpression of miR-184 in either neural progenitor cells (NPCs) or embryonic mouse cortex stimulated the differentiation of OL lineage efficiently through regulating crucial developmental genes. Luciferase assays demonstrated that miR-184 directly represses positive regulators of neural and astrocyte differentiation, i.e., SOX1 and BCL2L1, respectively, including the negative regulator of myelination, LINGO1. Moreover, blocking the function of miR-184 reduced the number of committed cells to an OL lineage.ConclusionsOur data highlighted that miR-184 could promote OL differentiation even in the absence of exogenous growth factors and propose a novel strategy to improve the efficacy of OL differentiation, with potential applications in cell therapy for neurodegenerative diseases.