• Alzheimer's disease
• Anti-neuronal senescence therapy
• Neural microenvironment
• Neuronal senescence
• Pathogenesis

• Alzheimer Disease/therapy
• Alzheimer Disease/metabolism
• Alzheimer Disease/pathology
• Humans
• Cellular Senescence/physiology
• Neurons/pathology
• Neurons/metabolism
• Animals
• Aging/physiology
• Aging/pathology
• Brain/pathology
• Brain/metabolism

• Curcumin
• Extracellular vesicles-mimetics
• Liver fibrosis
• Mesenchymal stem cells

• Bilobalide
• MPTP-PD model
• astrocytes
• neuroregeneration

• Humans
• Male
• Animals
• Mice
• Mice, Inbred C57BL
• Bilobalides
• Astrocytes
• Neurodegenerative Diseases
• Parkinson Disease/drug therapy
• Cyclopentanes
• Furans
• Ginkgolides

• Excitotoxicity
• Neurodegeneration
• Oxidative Stress, Neurogenesis
• Thiamine deficiency
• Vitamin B1
• Wernicke’s encephalopathy
• blood-brain Barrier
• stem cell

• Humans
• Thiamine Deficiency/therapy
• Thiamine Deficiency/complications
• Animals
• Wernicke Encephalopathy/etiology
• Wernicke Encephalopathy/therapy
• Stem Cell Transplantation/methods
• Brain/pathology
• Brain/metabolism

• CSF1R
• Cuprizone
• inflammatory cytokines
• mesenchymal stem cell
• multiple sclerosis

• IR.SUMS.REC.1398.662 Shiraz University of Medical Sciences, shiraz, Iran

• anti-inflammatory
• dental pulp stem cells
• immune regulation
• inflammation
• regeneration

• Animals
• Cell Differentiation
• Dental Pulp
• Stem Cells
• Inflammation
• Anti-Inflammatory Agents/pharmacology
• Anti-Inflammatory Agents/therapeutic use

• Amyotrophic lateral sclerosis
• Exosomes
• Mesenchymal stem cells
• Neurodegeneration

• Mice
• Humans
• Animals
• Amyotrophic Lateral Sclerosis/metabolism
• Exosomes/metabolism
• Antioxidants/pharmacology
• Motor Neurons/metabolism
• Mesenchymal Stem Cells/metabolism

• Alzheimer's disease
• Gene therapy
• Genetic phenotypes
• Molecular mechanism

• the Key Project of the National Natural Science Foundation of China
• Beijing Brain Initiative from Beijing Municipal Science & Technology Commission
• National major R&D projects of China-Scientific technological innovation 2030
• the National Key Scientific Instrument and Equipment Development Projectthe National Key Scientific Instrument and Equipment Development Projectthe National Key Scientific Instrument and Equipment Development Project
• Youth Program of National Natural Science Foundation of China
• Beijing Postdoctoral Research Foundation

• Alzheimer’s disease
• advances
• treatment

• Bone Marrow-Derived Mesenchymal Stem Cells
• Enteric Nervous System
• Enteric Neural Precursor Cells
• Glial Cell-Derived Neurotrophic Factor

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and its prevalence is increasing. Nowadays, very few drugs effectively reduce AD symptoms and thus, a better understanding of its pathophysiology is vital to design new effective schemes. Presymptomatic neuronal damage caused by the accumulation of Amyloid β peptide and Tau protein abnormalities remains a challenge, despite recent efforts in drug development. Importantly, therapeutic targets, biomarkers, and diagnostic techniques have emerged to detect and treat AD. Of note, the compromised blood-brain barrier (BBB) and peripheral inflammation in AD are becoming more evident, being harmful factors that contribute to the development of the disease. Perspectives from different pre-clinical and clinical studies link peripheral inflammation with the onset and progression of AD. This review aims to analyze the main factors and the contribution of impaired BBB in AD development. Additionally, we describe the potential therapeutic strategies using stem cells for AD treatment.

• Alzheimer’s disease
• MSCs
• NSCs
• blood-brain barrier

• Alzheimer Disease/metabolism
• Amyloid beta-Peptides/metabolism
• Blood-Brain Barrier/metabolism
• Humans
• Inflammation/metabolism
• Stem Cells/metabolism

Parkinson’s disease is the second most common neurodegenerative disease. Insidious and progressive, this disorder is secondary to the gradual loss of dopaminergic signaling and worsening neuroinflammation, affecting patients’ motor capabilities. Gold standard treatment includes exogenous dopamine therapy in the form of levodopa–carbidopa, or surgical intervention with a deep brain stimulator to the subcortical basal ganglia. Unfortunately, these therapies may ironically exacerbate the already pro-inflammatory environment. An alternative approach may involve cell-based therapies. Cell-based therapies, whether endogenous or exogenous, often have anti-inflammatory properties. Alternative strategies, such as exercise and diet modifications, also appear to play a significant role in facilitating endogenous and exogenous stem cells to induce an anti-inflammatory response, and thus are of unique interest to neuroinflammatory conditions including Parkinson’s disease. Treating patients with current gold standard therapeutics and adding adjuvant stem cell therapy, alongside the aforementioned lifestyle modifications, may ideally sequester inflammation and thus halt neurodegeneration.

• Parkinson’s disease
• neuroinflammation
• stem cell

• Cell- and Tissue-Based Therapy
• Dopamine
• Humans
• Inflammation/therapy
• Neurodegenerative Diseases
• Parkinson Disease/therapy

• Parkinson disease
• ROS
• STAT3
• neuron death
• stem cells

Bone marrow-derived mesenchymal stem cells (BMSCs) have therapeutic potential for spinal cord injury (SCI). We have shown that insulin-like growth factor 1 (IGF-1) enhances the cellular proliferation and survivability of BMSCs-derived neural progenitor cells (NPCs) by downregulating miR-22-3p. However, the functional application of BMSCs-derived NPCs has not been investigated fully. In this study, we demonstrate that knockdown of endogenous miR-22-3p in BMSCs-derived NPCs upregulates Akt1 expression, leading to enhanced cellular proliferation. RNASeq analysis reveals 3,513 differentially expressed genes in NPCs. The upregulated genes in NPCs enrich the gene ontology term associated with nervous system development. Terminally differentiated NPCs generate cells with neuronal-like morphology and phenotypes. Transplantation of NPCs in the SCI rat model results in better recovery in locomotor and sensory functions 4 weeks after transplantation. Altogether, the result of this study demonstrate that NPCs derived with IGF-1 supplementation could be differentiated into functional neural lineage cells and are optimal for stem cell therapy in SCI.

• Enteric nervous system
• Enteric neuropathy
• Inflammatory bowel disease
• Intestinal inflammation
• Mesenchymal stem cells
• Spontaneous chronic colitis

• basal cognition
• bioelectricity
• bioengineering
• gap junctions
• regeneration
• synthetic morphology

• Paul G. Allen Frontiers Group
• Templeton World Charity Foundation
• John Templeton Foundation

Exosomes are naturally occurring nanoscale vesicles that are released and received by almost all cells in the body. Exosomes can be transferred between cells and contain various molecular constitutes closely related to their origin and function, including proteins, lipids, and RNAs. The importance of exosomes in cellular communication makes them important vectors for delivering a variety of drugs throughout the body. Exosomes are ubiquitous in the circulatory system and can reach the site of injury or disease through a variety of biological barriers. Due to its unique structure and rich inclusions, it can be used for the diagnosis and treatment of diseases. Mesenchymal stem-cell-derived exosomes (MSCs-Exo) inherit the physiological functions of MSCs, including repairing and regenerating tissues, suppressing inflammatory responses, and regulating the body’s immunity; therefore, MSCs-Exo can be used as a natural drug delivery carrier with therapeutic effects, and has been increasingly used in the treatment of cardiovascular diseases and neurodegenerative diseases. Here, we summarize the research progress of MSCs-Exo as drug delivery vectors and their application for various drug deliveries, providing ideas and references for the study of MSCs-Exo in recent years.

• Alzheimer’s disease
• Amyotrophic lateral sclerosis
• Gene therapy
• Neurological disorders
• Parkinson’s disease
• Spinal muscular atrophy

• Genetic Therapy
• Genetic Vectors
• Humans
• Intercellular Signaling Peptides and Proteins/genetics
• Neurodegenerative Diseases/genetics
• Neurodegenerative Diseases/therapy
• Treatment Outcome

• Conditioned medium
• Dravet syndrome
• Electrophysiology
• Neuronal differentiation
• Oxidative stress

• Cell Differentiation
• Child
• Epilepsies, Myoclonic/genetics
• Epilepsies, Myoclonic/metabolism
• Humans
• Induced Pluripotent Stem Cells
• Mesenchymal Stem Cells/metabolism
• Umbilical Cord/metabolism

• Amyotrophic lateral sclerosis
• Mesenchymal stem cells
• Metaanalysis
• Neurodegenerative disorder

• Animals
• Amyotrophic Lateral Sclerosis/therapy
• Disease Models, Animal
• Disease Progression
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) have been demonstrated to have a great potential in the treatment of several diseases due to their differentiation and immunomodulatory capabilities and their ability to be easily cultured and manipulated. Recent investigations revealed that their therapeutic effect is largely mediated by the secretion of paracrine factors including exosomes. Exosomes reflect biophysical features of MSCs and are considered more effective than MSCs themselves. Alternative approaches based on MSC-derived exosomes can offer appreciable promise in overcoming the limitations and practical challenges observed in cell-based therapy. Furthermore, MSC-derived exosomes may provide a potent therapeutic strategy for various diseases and are promising candidates for cell-based and cell-free regenerative medicine. This review briefly summarizes the development of MSCs as a treatment for human diseases as well as describes our current knowledge about exosomes: their biogenesis and molecular composition, and how they exert their effects on target cells. Particularly, the therapeutic potential of MSC-derived exosomes in experimental models and recent clinical trials to evaluate their safety and efficacy are summarized in this study. Overall, this paper provides a current overview of exosomes as a new cell-free therapeutic agent.

• Cell-free therapy
• Exosomes
• Mesenchymal stem cells
• Therapeutic potential

• Spinal cord injury
• cell-based therapies
• devastating disease
• mesenchymal stem cells
• somatic stem cells
• stem cells.

Oxidative stress associated with neuroinflammation is a key process involved in the pathophysiology of neurodegenerative diseases, and therefore, has been proposed as a crucial target for new therapies. Recently, the therapeutic potential of human adipose-derived stem cells (hASCs) has been investigated as a novel strategy for neuroprotection. These cells can be preconditioned by exposing them to mild stress in order to improve their response to oxidative stress. In this study, we evaluate the therapeutic potential of hASCs preconditioned with low doses of H₂O₂ (called HC016 cells) to overcome the deleterious effect of oxidative stress in an in vitro model of oligodendrocyte-like cells (HOGd), through two strategies: i, the culture of oxidized HOGd with HC016 cell-conditioned medium (CM), and ii, the indirect co-culture of oxidized HOGd with HC016 cells, which had or had not been exposed to oxidative stress. The results demonstrated that both strategies had reparative effects, oxidized HC016 cell co-culture being the one associated with the greatest recovery of the damaged HOGd, increasing their viability, reducing their intracellular reactive oxygen species levels and promoting their antioxidant capacity. Taken together, these findings support the view that HC016 cells, given their reparative capacity, might be considered an important breakthrough in cell-based therapies.

• H2O2 preconditioning
• antioxidant capacity
• cell therapy
• human adipose-derived stem cells
• oligodendrocyte-like cells
• oxidative stress

• Alzheimer's disease
• Mitochondria
• Mitochondrial transplant
• Neurodegenerative diseases
• Parkinson's disease
• Treatment

Several treatments have been attempted in amyotrophic lateral sclerosis (ALS) animal models and patients. Recently, transplantation of bone marrow-derived mononuclear cells (MNCs) was investigated as a regenerative therapy for ALS, but satisfactory treatments remain to be established. To develop an effective treatment, we focused on mesenchymal stem cells (MSCs) expressing hepatocyte growth factor, glial cell line-derived neurotrophic factor, and insulin-like growth factor using human artificial chromosome vector (HAC-MSCs). Here, we demonstrated the transplantation of MNCs with HAC-MSCs in ALS mice. As per our results, the progression of motor dysfunction was significantly delayed, and their survival was prolonged dramatically. Additional analysis revealed preservation of motor neurons, suppression of gliosis, engraftment of numerous MNCs, and elevated chemotaxis-related cytokines in the spinal cord of treated mice. Therefore, growth factor-expressing MSCs enhance the therapeutic effects of bone marrow-derived MNCs for ALS and have a high potential as a novel cell therapy for patients with ALS.

•

MNCs with growth factor-expressing MSCs is an effective cell therapy for ALS mice

• Cellular Neuroscience
• Molecular Neuroscience
• Stem Cells Research

• cell-based therapies
• mesenchymal stem cell-derived exosomes
• neurodegenerative diseases

• Alzheimer Disease/metabolism
• Alzheimer Disease/pathology
• Alzheimer Disease/therapy
• Animals
• Biological Transport
• Brain Injuries, Traumatic/metabolism
• Brain Injuries, Traumatic/pathology
• Brain Injuries, Traumatic/therapy
• Disease Models, Animal
• Exosomes/chemistry
• Exosomes/metabolism
• Exosomes/transplantation
• Humans
• Inflammation/prevention & control
• Injections, Intravenous
• Mesenchymal Stem Cells/metabolism
• Mice
• Multiple Sclerosis/metabolism
• Multiple Sclerosis/pathology
• Multiple Sclerosis/therapy
• Nervous System/metabolism
• Nervous System/pathology
• Neurons/metabolism
• Neurons/pathology
• Spinal Cord Injuries/metabolism
• Spinal Cord Injuries/pathology
• Spinal Cord Injuries/therapy
• Status Epilepticus/metabolism
• Status Epilepticus/pathology
• Status Epilepticus/therapy
• Stroke/metabolism
• Stroke/pathology
• Stroke/therapy

• GCV
• HSV-TK
• Mesenchymal stem cells
• bystander effect
• glioblastoma
• local gene therapy
• umbilical cord.

Canine inflammatory brain disease (IBD) is a severe inflammatory disorder characterized by infiltration of activated immune cell subsets into the brain and spinal cord. Multipotent mesenchymal stromal cells (MSCs) are a promising therapy for IBD, based on their potent pro-angiogenic, neuroprotective, and immunomodulatory properties. The aims of this study were to compare the immunomodulatory attributes of canine adipose-derived MSCs (ASCs) and placenta-derived MSCs (PMSCs) in vitro. These data will serve as potency information to help inform the optimal MSC cell source to treat naturally occurring canine IBD.

Indoleamine 2,3 dioxygenase (IDO) activity and prostaglandin E₂ (PGE₂) concentration at baseline and after stimulation with interferon gamma (IFNγ) and/or tumor necrosis factor alpha (TNFα) were measured from canine ASC and PMSC cultures. Leukocyte suppression assays (LSAs) were performed to compare the ability of ASCs and PMSCs to inhibit activated peripheral blood mononuclear cell (PBMC) proliferation. IDO activity and PGE₂; interleukin (IL)-2, IL-6, and IL-8; TNFα; and vascular endothelial growth factor (VEGF) concentrations were also measured from co-culture supernatants. Cell cycle analysis was performed to determine how ASCs and PMSCs altered lymphocyte proliferation.

Activated canine MSCs from both tissue sources secreted high concentrations of IDO and PGE₂, after direct stimulation with IFNγ and TNFα, or indirect stimulation by activated PBMCs. Both ASCs and PMSCs inhibited activated PBMC proliferation in LSA assays; however, PMSCs inhibited PBMC proliferation significantly more than ASCs. Blocking PGE₂ and IDO in LSA assays determined that PGE₂ is important only for ASC inhibition of PBMC proliferation. Activated ASCs increased IL-6 and VEGF secretion and decreased TNFα secretion, while activated PMSCs increased IL-6, IL-8, and VEGF secretion. ASCs inhibited lymphocyte proliferation via cell cycle arrest in the G0/G1 and PMSCs inhibited lymphocyte proliferation via induction of lymphocyte apoptosis.

Our results demonstrate that ASCs and PMSCs have substantial in vitro potential as a cell-based therapy for IBD; however, PMSCs more potently inhibited lymphocyte proliferation by inducing apoptosis of activated lymphocytes. These data suggest that the mechanism by which ASCs and PMSCs downregulate PBMC proliferation differs. Additional studies may elucidate additional mechanisms by which canine MSCs modulate neuroinflammatory responses.

• Adipose tissue
• Animal model
• Canine
• Immunomodulation
• Inflammatory brain disease
• Mesenchymal stromal cell
• Multiple sclerosis
• Multipotent progenitor cell
• Placenta
• Translational research

• Diabetes mellitus
• diabetic foot
• diabetic nephropathy
• diabetic neuropathies
• diabetic retinopathy
• platelet-derived growth factor
• platelet-derived growth factor-targeted therapy

• Animals
• Diabetes Complications/diagnosis
• Diabetes Complications/drug therapy
• Diabetes Complications/etiology
• Diabetes Complications/metabolism
• Diabetes Mellitus, Type 2/complications
• Diabetes Mellitus, Type 2/diagnosis
• Diabetes Mellitus, Type 2/drug therapy
• Diabetes Mellitus, Type 2/metabolism
• Humans
• Hypoglycemic Agents/therapeutic use
• Platelet-Derived Growth Factor/antagonists & inhibitors
• Platelet-Derived Growth Factor/metabolism
• Platelet-Derived Growth Factor/therapeutic use
• Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors
• Receptors, Platelet-Derived Growth Factor/metabolism
• Signal Transduction

• Cell therapy
• Expansion
• Immunomodulatory properties
• Mesenchymal stromal cells (MSCs)
• Neurodegenerative diseases
• Source

Trimethyltin Chloride (TMT) is a neurotoxin that can kill neurons in the nervous system and activate astrocytes. This neurotoxin mainly damages the hippocampal neurons. After TMT injection, behavioral changes such as aggression and hyperactivity have been reported in animals along with impaired spatial and learning memory. Hence, TMT is a suitable tool for an experimental model of neurodegeneration. The present study aims to determine the palliative effects of Bone Marrow-derived Mesenchymal Stem Cells (BM-MSCs) on the hippocampi of rats damaged from TMT exposure.

We assigned 28 male Wistar rats to the following groups: control, model, vehicle, and treatment. The groups received Intraperitoneal (IP) injections of 8 mg/kg TMT. After one week, stem cells were stereotactically injected into the CA1 of the right rats’ hippocampi. Spatial memory was determined by the Morris Water Maze (MWM) test 6 weeks after cell transplantation. Finally, the rats’ brains were perfused and stained by cresyl violet to determine the numbers of cells in the Cornus Ammonis (CA1) section of the hippocampus. We assessed the expressions of Glial Fibrillary Acidic Protein (GFAP) and Neuronal-specific Nuclear (NeuN) proteins in the right hippocampus by Western blot.

The MWM test showed that the treatment group had significantly higher traveled distances in the target quarter compared with the model and vehicle groups (P<0.05). Based on the result of cell count (Nissl staining), the number of cells increased in the treatment group compared with the model and vehicle groups (P<0.05). Western blot results showed up-regulation of GFAP and NeuN proteins in the model, vehicle, and treatment groups compared with the control group.

Injection of BM-MSCs may lead to a behavioral and histological improvement in TMT-induced neurotoxicity by increasing the number of pyramidal neurons and improving memory.

• Hippocampus
• Mesenchymal Stem Cells (MSCs)
• Spatial Memory
• Trimethyltin Chloride (TMT)

• Alzheimer’s disease
• Mesenchymal stem cells
• mTOR, AMPK, GSK-3β, and Wnt3/β-catenin signaling pathways
• stem-cell-based therapy

• blood-brain barrier
• parkinson's disease
• mesenchymal stem cells
• stem-cell research

• Animals
• Autophagy
• Blood-Brain Barrier/physiopathology
• Cell Differentiation
• Exosomes/metabolism
• Humans
• Mesenchymal Stem Cells/metabolism
• Mice
• Parkinson Disease/genetics
• Parkinson Disease/physiopathology

• Natural Science Foundation of Hebei Province (Hebei Provincial Natural Science Foundation)
• National Natural Science Foundation of China (National Science Foundation of China)

• Adipose-derived stem cells
• Extracellular nanovesicles
• Liver fibrosis

• mesenchymal stromal cells
• neurons
• secretome
• tissue repair
• traumatic brain injury

• Brain Injuries, Traumatic/genetics
• Brain Injuries, Traumatic/therapy
• Cellular Microenvironment
• Humans
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/metabolism
• Nerve Regeneration/genetics
• Neurogenesis/genetics
• Neuroprotective Agents/therapeutic use

• Adipose-derived stem cells
• Cryopreservation
• Differentiation
• Multipotency
• Stemness

• Mesenchymal stem cells (MSCs)
• genetic manipulation
• potential risks
• preconditioning

Immune cell trafficking into the CNS is considered to contribute to pathogenesis in MS and its animal model, EAE. Disruption of the blood–brain barrier (BBB) is a hallmark of these pathologies and a potential target of therapeutics. Human embryonic stem cell-derived mesenchymal stem/stromal cells (hES-MSCs) have shown superior therapeutic efficacy, compared to bone marrow-derived MSCs, in reducing clinical symptoms and neuropathology of EAE. However, it has not yet been reported whether hES-MSCs inhibit and/or repair the BBB damage associated with neuroinflammation that accompanies EAE.

BMECs were cultured on Transwell inserts as a BBB model for all the experiments. Disruption of BBB models was induced by TNF-α, a pro-inflammatory cytokine that is a hallmark of acute and chronic neuroinflammation.

Results indicated that hES-MSCs reversed the TNF-α-induced changes in tight junction proteins, permeability, transendothelial electrical resistance, and expression of adhesion molecules, especially when these cells were placed in direct contact with BMEC.

hES-MSCs and/or products derived from them could potentially serve as novel therapeutics to repair BBB disturbances in MS.

The online version of this article (10.1186/s12987-019-0138-5) contains supplementary material, which is available to authorized users.

• Blood brain barrier
• Brain endothelial cells
• MS and EAE
• Mesenchymal stem/stromal cells
• Tight junction

• Huntington disease
• R6/2 mice
• cell therapy
• dopamine transmission
• intranasal
• mesenchymal stem cells
• microglia
• neuroinflammation

• Administration, Intranasal
• Animals
• Brain/pathology
• Brain/physiopathology
• Cell Tracking
• Circadian Rhythm
• Disease Models, Animal
• Dopamine/metabolism
• Dopamine and cAMP-Regulated Phosphoprotein 32/metabolism
• Gene Expression Regulation
• Humans
• Huntington Disease/genetics
• Huntington Disease/physiopathology
• Huntington Disease/therapy
• Inflammation/genetics
• Inflammation/pathology
• Male
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/cytology
• Mice, Inbred C57BL
• Mice, Transgenic
• Microglia/metabolism
• Microglia/pathology
• Motor Activity
• Nerve Growth Factors/metabolism
• Sleep
• Survival Analysis
• Synaptic Transmission
• Tyrosine 3-Monooxygenase/metabolism

• Adipose-derived stem cells
• Conditioned medium
• N-acetyl cysteine
• Neurodegenerative diseases
• Oxidative stress
• SH-SY5Y cells

• Fibroblast growth factor 2
• GABRB1
• Human dental pulp cells
• Spinal cord injury

• Animals
• Dental Pulp/cytology
• Disease Models, Animal
• Electrophysiological Phenomena/drug effects
• Fibroblast Growth Factor 2/pharmacology
• Gene Expression Regulation/drug effects
• Humans
• Motor Activity/drug effects
• Rats
• Rats, Sprague-Dawley
• Recovery of Function
• Spinal Cord Injuries/genetics
• Spinal Cord Injuries/physiopathology
• Spinal Cord Injuries/therapy

• Atherosclerosis
• Exosome
• Macrophage
• Mesenchymalstem cells
• Polarization
• microRNA

Introduction: Induced neural stem cells (iNSCs) have the ability of differentiation into neurons, astrocytes and oligodendrocytes. iNSCs are very useful in terms of research and treatment. The present study offers an idea that biomaterials could be one of the tools that could modulate reprogramming process in the fibroblasts.

Methods: Gelatin biomaterials were fabricated into 3 types, including (i) gelatin, (ii) gelatin with 1 mg/mL hydroxyapatite, and (iii) gelatin with hydroxyapatite and pig brain. NIH/3T3 fibroblasts were cultured on each type of biomaterial for 7, 9 and 14 days. RT-PCR was performed to investigate the gene expression of the fibroblasts on biomaterials compared to the fibroblasts on tissue culture plates. PI3K/Akt signaling was performed by flow cytometry after 24 hours seeding on the biomaterials. The biomaterials were also tested with the human APCs and PDL cells.

Results: The fibroblasts exhibited changes in the expression of the reprogramming factor; Klf‫4 and the neural transcription factors; NFIa, NFIb and Ptbp1 after 9 days culture. The cultivation of fibroblasts on the biomaterials for 7 days showed a higher expression of the transcription factor SOX9. The expression of epigenetic genes; Kat2a and HDAC3 were changed upon the cultivation on the biomaterials for 9 days. The fibroblasts cultured on the biomaterials showed an activation of PI3K/Akt signaling. The human APCs and human PDL cells developed mineralization process on biomaterials

Conclusion: Changes in the expression of Klf4, NFIa, NFIb, Ptbp1 and SOX9 indicated that fibroblasts were differentiated into an astrocytic lineage. It is possible that the well-designed biomaterials could work as powerful tools in the reprogramming process of fibroblasts into iNSCs.

• Cell reprogramming
• Fibroblasts
• Induced neuronal stem cells

Widespread death of transplanted mesenchymal stem cells (MSCs) hampers the development of stem cell therapy for Alzheimer disease (AD). Cell pre-conditioning might help cope with this challenge. We tested whether let-7f-5p-modified MSCs could prolong the survival of MSCs after transplantation. When exposed to Aβ₂₅₋₃₅in vitro, MSCs showed significant early apoptosis with decrease in the let-7f-5p levels and increased caspase-3 expression. Upregulating microRNA let-7f-5p in MSCs alleviated Aβ₂₅₋₃₅-induced apoptosis by decreasing the caspase-3 levels. After computerized analysis and the luciferase reporter assay, we identified that caspases-3 was the target gene of let-7f-5p. In vivo, hematoxylin and eosin staining confirmed the success of MSCs transplantation into the lateral ventricles, and the let-7f-5p upregulation group showed the lowest apoptotic rate of MSCs detected by TUNEL immunohistochemistry analysis and immunofluorescence. Similarly, bioluminescent imaging showed that let-7f-5p upregulation moderately prolonged the retention of MSCs in brain. In summary, we identified the anti-apoptotic role of let-7f-5p in Aβ₂₅₋₃₅-induced cytotoxicity, as well as the protective effect of let-7f-5p on survival of grafted MSCs by targeting caspase-3 in AD models. These findings show a promising approach of microRNA-modified MSCs transplantation as a therapy for neurodegenerative diseases.

• Alzheimer disease
• bone marrow mesenchymal stem cells
• cell apoptosis
• cell transplantation
• let-7f