The rapid increasing number of completed bacterial genomes provides a good opportunity to compare their proteomes. This study was undertaken to specifically compare and contrast their secretomes--the fraction of the p...The rapid increasing number of completed bacterial genomes provides a good opportunity to compare their proteomes. This study was undertaken to specifically compare and contrast their secretomes--the fraction of the proteome with predicted N-terminal signal sequences, both type Ⅰ and type Ⅱ. A total of 176 theoretical bacterial proteomes were examined using the ExProt program. Compared with the Gram-positives, the Gram-negative bacteria were found, on average, to contain a larger number of potential Sec-dependent sequences. In the Gram-negative bacteria but not in the others, there was a positive correlation between proteome size and secretome size, while there was no correlation between secretome size and pathogenicity. Within the Gram-negative bacteria, intracellular pathogens were found to have the smallest secretomes. However, the secretomes of certain bacteria did not fit into the observed pattern. Specifically, the secretome of Borrelia burgdoferi has an unusually large number of putative lipoproteins, and the signal peptides of mycoplasmas show closer sequence similarity to those of the Gramnegative bacteria. Our analysis also suggests that even for a theoretical minimal genome of 300 open reading frames, a fraction of this gene pool （up to a maximum of 20%） may code for proteins with Sec-dependent signal sequences.展开更多
BACKGROUND Exosome-based therapies represent a promising approach for hair regeneration.Unlike conventional treatments such as minoxidil and finasteride,exosomes deliver bioactive cargo that can stimulate dermal papil...BACKGROUND Exosome-based therapies represent a promising approach for hair regeneration.Unlike conventional treatments such as minoxidil and finasteride,exosomes deliver bioactive cargo that can stimulate dermal papilla cells,enhance angiogenesis,and modulate inflammatory pathways.However,variability in exosome sources,isolation techniques,and dosing protocols limits their clinical translation.AIM To synthesize findings from in vitro,preclinical and clinical studies,and to evaluate the efficacy,mechanisms,and challenges associated with exosome-based hair restoration therapies.METHODS A literature search was conducted using multiple databases(PubMed/Medline,Embase,Scopus,and Web of Science)employing terms for exosomes and hair regeneration for articles published in English to February 2025,following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.RESULTS A total of 27 studies(three in vitro,three pre-clinical,18 with both in vitro and preclinical component and three clinical)met the pre-defined search and inclusion criteria and were included in this review.CONCLUSION Exosome-based therapies hold immense promise for hair regeneration by leveraging their ability to modulate key signaling pathways and enhance hair follicle regeneration.While in vitro and preclinical studies demonstrate consistent efficacy across diverse exosome sources,methodological heterogeneity and a limited number of clinical studies warrant further clinical research to realize their full clinical potential for hair regeneration.展开更多
Intervertebral disc degeneration(IDD)results from an imbalance within the intervertebral disc,leading to alterations in extracellular matrix composition,loss of nucleus pulposus cells,increased oxidative stress,and in...Intervertebral disc degeneration(IDD)results from an imbalance within the intervertebral disc,leading to alterations in extracellular matrix composition,loss of nucleus pulposus cells,increased oxidative stress,and inflammatory cascade.While IDD naturally progresses with age,some factors such as mechanical trauma,lifestyle choices,and genetic abnormalities can elevate the risk of symptomatic disease progression.Current treatments,including pharmacological and surgical interventions,fail to halt disease progression or restore IDD function.Although biological therapies have been evaluated,their effectiveness in reversing long-term disc degeneration remains inconsistent.Mesenchymal stem cellbased therapies have demonstrated potential for IDD regeneration but are hindered by biological limitations,ethical issues,etc.To date,mesenchymal stem cell-derived extracellular vesicles(EVs)have emerged as promising therapeutic agents for regeneration and anti-inflammation.Their therapeutic effects are attributed to several mechanisms,such as the induction of regenerative phenotype,apoptosis mitigation,and immunomodulation.In addition,the abundance of microRNAs within EVs play a crucial role in modulating the disc degeneration.Due to the problems in clinical use,however,the efficiency of the EVs should be overcome further by optimizing cell culture conditions,engineering them to deliver drugs and targeting molecules,etc.展开更多
BACKGROUND Acute kidney injury is characterized by a sudden decline in renal function,often due to ischemia or nephrotoxins,leading to increased oxidative stress and inflam-mation.AIM To investigate the protective eff...BACKGROUND Acute kidney injury is characterized by a sudden decline in renal function,often due to ischemia or nephrotoxins,leading to increased oxidative stress and inflam-mation.AIM To investigate the protective effects of adipose-derived mesenchymal stromal cell(ADMSC)secretome on renal tubular epithelial cells(NRK-52E)as an in vitro model of oxidative stress-associated kidney injury.METHODS ADMSCs were isolated from human adipose tissue and characterized for mesenchymal markers and differentiation potential.Conditioned media(CM)was collected after 48-hour serum-free culture and applied to serum-deprived NRK-52E cells for 48 hours.Cell viability was assessed using the MTT assay,apoptosis was assessed by Annexin V-FITC/PI staining and flow cytometry,reactive oxygen species(ROS)levels via H2DCFDA staining,and mitochondrial membrane potential by the tetramethylrhodamine ethyl ester assay.The expression of heme oxygenase-1(HO-1),nuclear factor erythroid 2-related factor 2(Nrf2),and NAD(P)H quinone dehydrogenase 1(Nqo1)genes was quantified by quantitative polymerase chain reaction.Comparative transcriptomic analysis was performed on ADMSCs and bone marrow-derived MSCs(BM-MSCs)using publicly available microarray data(GSE108511).RESULTS ADMSC secretome significantly reduced ROS production and enhanced mitochondrial membrane potential in NRK cells.Gene expression analysis revealed a significant upregulation of HO-1 mRNA levels in ADMSC-CM treated cells.However,no significant changes were observed in Nrf2 and Nqo1 mRNA levels.Transcriptome analysis of ADMSCs against BM-MSCs revealed significant differences in the expression of genes related to oxidative stress response,antioxidant activity,and mitochondrial function.CONCLUSION The results of this study suggest that the ADMSC secretome exerts multifaceted protective effects on NRK cells by reducing oxidative stress and enhancing mitochondrial function.The study demonstrates the potential beneficial applications of the ADMSC secretome in treating oxidative stress-related kidney injuries.展开更多
Stem cells have moved from lab to bedside, and many initial studies showed promising results. Therefore big companies are entering the business. However, most initial studies did not used controls to make sure of the ...Stem cells have moved from lab to bedside, and many initial studies showed promising results. Therefore big companies are entering the business. However, most initial studies did not used controls to make sure of the efficacy of stem cells. Many phase-1 studies showed safety of stem cell therapies, when precaution measures were adapted. However, efficacy needs to be proven by randomized controlled trials (RCT) to exclude placebo effects. Recently, various RCTs for various conditions have been done with various contradictory results. Therefore, a meta-analysis is very useful to know whether a stem cell therapy really work for a certain condition. As various centres used various type of stem cells, various dose, and route of application, as well as different outcome measures with various results for one certain condition, sometimes it is difficult to conduct a meta-analysis when there is high heterogeneity, which is like pooling “apples” with “oranges” and “avocado” that will lead to a misleading conclusion. In many cases, where the studies are highly heterogeneous, and the heterogeneity can’t be identified, then a descriptive systematic review is the best solution to take a conclusion which protocol is the best and valuable to be standardized. Formerly it was believed that stem cells that are given to patients work by differentiating into the needed cells, and thus replacing damaged cell. However, recent evidence showed that only a few stem cells homed to the desired area, while a large amount went to various areas that were remote from the damaged area. Even though they were trapped in remote areas, the stem cells still exerted beneficial effects by remote signalling and secretion of various beneficial factors. Therefore, there are attempts to produce stem cell secretomes/metabolites to replace the stem cells, as metabolites are easier to handle and transported compared to the cells themselves. In addition, various studies worked on substitute tissue/organs “ex vivo” to be transplanted to replace a damaged organ. There are various means to produce a tissue/an organ/organoid “ex vivo” (tissue engineering) by using various stem cells, scaffold, and soluble factors, in various vessels from static vessel to bioreactors, and “on chips”. Though these attempts are in the initial stage, but some translational animal studies have been done. A more usual use of these “ex vivo” developed tissues/organs/organoids is for drug testing, such as toxicity testing, and for studying the mechanism of certain diseases that is directed toward the development of a cure of the diseases. In conclusion, many stem cell therapies have entered RCTs, but no standardized and approved protocol has been established, while organoids are usually used for drug testing and studying the mechanism of certain diseases.展开更多
The regeneration of peripheral nerves comprises complicated steps involving a set of cellular and molecular events in distal nerve stumps with axonal sprouting and remyelination. Stem cell isolation and expansion for ...The regeneration of peripheral nerves comprises complicated steps involving a set of cellular and molecular events in distal nerve stumps with axonal sprouting and remyelination. Stem cell isolation and expansion for peripheral nerve repair(PNR) can be achieved using a wide diversity of prenatal and adult tissues, such as bone marrow or brain tissues. The ability to obtain stem cells for cell-based therapy(CBT) is limited due to donor site morbidity and the invasive nature of the harvesting process. Dental pulp stem cells(DPSCs) can be relatively and simply isolated from the dental pulps of permanent teeth, extracted for surgical or orthodontic reasons. DPSCs are of neural crest origin with an outstanding ability to differentiate into multiple cell lineages. They have better potential to differentiate into neural and glial cells than other stem cell sources through the expression and secretion of certain markers and a range of neurotropic factors;thus, they should be considered a good choice for PNR using CBT. In addition,these cells have paracrine effects through the secretion of neurotrophic growth factors and extracellular vesicles, which can enhance axonal growth and remyelination by decreasing the number of dying cells and activating local inhabitant stem cell populations, thereby revitalizing dormant or blocked cells,modulating the immune system and regulating inflammatory responses. The use of DPSC-derived secretomes holds great promise for controllable and manageable therapy for peripheral nerve injury. In this review, up-to-date information about the neurotrophic and neurogenic properties of DPSCs and their secretomes is provided.展开更多
Mesenchymal stem cells(MSCs)are the most frequently used stem cells in clinical trials due to their easy isolation from various adult tissues,their ability of homing to injury sites and their potential to differentiat...Mesenchymal stem cells(MSCs)are the most frequently used stem cells in clinical trials due to their easy isolation from various adult tissues,their ability of homing to injury sites and their potential to differentiate into multiple cell types.However,the realization that the beneficial effect of MSCs relies mainly on their paracrine action,rather than on their engraftment in the recipient tissue and subsequent differentiation,has opened the way to cell-free therapeutic strategies in regenerative medicine.All the soluble factors and vesicles secreted by MSCs are commonly known as secretome.MSCs secretome has a key role in cell-to-cell communication and has been proven to be an active mediator of immunemodulation and regeneration both in vitro and in vivo.Moreover,the use of secretome has key advantages over cell-based therapies,such as a lower immunogenicity and easy production,handling and storage.Importantly,MSCs can be modulated to alter their secretome composition to better suit specific therapeutic goals,thus,opening a large number of possibilities.Altogether these advantages now place MSCs secretome at the center of an important number of investigations in different clinical contexts,enabling rapid scientific progress in this field.展开更多
Ischemic stroke continues to be a leading cause of mortality and morbidity in the world. Despite recent advances in the field of stroke medicine, thrombolysis with recombinant tissue plasminogen activator remains as t...Ischemic stroke continues to be a leading cause of mortality and morbidity in the world. Despite recent advances in the field of stroke medicine, thrombolysis with recombinant tissue plasminogen activator remains as the only pharmacological therapy for stroke patients. However, due to short therapeutic window(4.5 hours of stroke onset) and increased risk of hemorrhage beyond this point, each year globally less than 1% of stroke patients receive this therapy which necessitate the discovery of safe and efficacious therapeutics that can be used beyond the acute phase of stroke. Accumulating evidence indicates that endothelial progenitor cells(EPCs), equipped with an inherent capacity to migrate, proliferate and differentiate, may be one such therapeutics. However, the limited availability of EPCs in peripheral blood and early senescence of few isolated cells in culture conditions adversely affect their application as effective therapeutics. Given that much of the EPC-mediated reparative effects on neurovasculature is realized by a wide range of biologically active substances released by these cells, it is possible that EPC-secretome may serve as an important therapeutic after an ischemic stroke. In light of this assumption, this review paper firstly discusses the main constituents of EPC-secretome that may exert the beneficial effects of EPCs on neurovasculature, and then reviews the currently scant literature that focuses on its therapeutic capacity.展开更多
Proteins secreted by Helicobacter pylori (H. pylori), an important human pathogen responsible for severe gastric diseases, are reviewed from the point of view of their biochemical characterization, both functional and...Proteins secreted by Helicobacter pylori (H. pylori), an important human pathogen responsible for severe gastric diseases, are reviewed from the point of view of their biochemical characterization, both functional and structural. Despite the vast amount of experimental data available on the proteins secreted by this bacterium, the precise size of the secretome remains unknown. In this review, we consider as secreted both proteins that contain a secretion signal for the periplasm and proteins that have been detected in the external medium in in vitro experiments. In this way, H. pylori’s secretome appears to be composed of slightly more than 160 proteins, but this number must be considered very cautiously, not only because the definition of secretome itself is ambiguous but also because the included proteins were observed as secreted in in vitro experiments that were not representative of the environmental situation in vivo. The proteins that appear to be secreted can be grouped into different classes: enzymes (48 proteins), outer membrane proteins (43), components of flagella (11), members of the cytotoxic-associated genes pathogenicity island or other toxins (8 and 5, respectively), binding and transport proteins (9), and others (11). A final group, which includes 28 members, is represented by hypothetical uncharacterized proteins. Despite the large amount of data accumulated on the H. pylori secretome, a considerable amount of work remains to reach a full comprehension of the system at the molecular level.展开更多
Parkinson's disease is the second most prevalent neurodegenerative disorder worldwide.Clinically,it is characterized by severe motor complications caused by progressive degeneration of dopaminergic neurons.Current...Parkinson's disease is the second most prevalent neurodegenerative disorder worldwide.Clinically,it is characterized by severe motor complications caused by progressive degeneration of dopaminergic neurons.Current treatment is focused on mitigating the symptoms through the administration of levodopa,rather than on preventing dopaminergic neuronal damage.Therefore,the use and development of neuroprotective/disease-modifying strategies is an absolute need that can lead to promising gains on translational research of Parkinson's disease.For instance,N-acetylcysteine,a natural compound with strong antioxidant effects,has been shown to modulate oxidative stress,preventing dopamine-induced cell death.Despite the evidence of neuroprotective and modulatory effects of this drug,as far as we know,it does not induce per se any regenerative process.Therefore,it would be of interest to combine the latter with innovative therapies that induce dopaminergic neurons repair or even differentiation,as stem cell-based strategies.Stem cells secretome has been proposed as a promising therapeutic approach for Parkinson's disease,given its ability to modulate cell viability/preservation of dopaminergic neurons.Such approach represents a shift in the paradigm,showing that cell-transplantation free therapies based on the use of stem cells secretome may represent a potential alternative for regenerative medicine of Parkinson's disease.Thus,in this review,we address the current understanding of the potential combination of stem cell free-based strategies and neuroprotective/disease-modifying strategies as a new paradigm for the treatment of central nervous system neurodegenerative diseases,like Parkinson's disease.展开更多
Despite various treatment protocols and newly recognized therapeutics,there are no effective treatment approaches against coronavirus disease.New therapeutic strategies including the use of stem cells-derived secretom...Despite various treatment protocols and newly recognized therapeutics,there are no effective treatment approaches against coronavirus disease.New therapeutic strategies including the use of stem cells-derived secretome as a cell-free therapy have been recommended for patients with critical illness.The pro-regenerative,pro-angiogenic,anti-inflammatory,anti-apoptotic,immunomodulatory,and trophic properties of stem cells-derived secretome,extracellular vesicles(EVs),and bioactive factors have made them suitable candidates for respiratory tract regeneration in coronavirus disease 2019(COVID-19)patients.EVs including microvesicles and exosomes can be applied for communication at the intercellular level due to their abilities in the long-distance transfer of biological messages such as mRNAs,growth factors,transcription factors,microRNAs,and cytokines,and therefore,simulate the specifications of the parent cell,influencing target cells upon internalization and/or binding.EVs exhibit both anti-inflammatory and tolerogenic immune responses by regulation of proliferation,polarization,activation,and migration of different immune cells.Due to effective immunomodulatory and high safety including a minimum risk of immunogenicity and tumorigenicity,mesenchymal stem cell(MSC)-EVs are more preferable to MSC-based therapies.Thus,as an endogenous repair and inflammation-reducing agent,MSCEVs could be used against COVID-19 induced morbidity and mortality after further mechanistic and preclinical/clinical investigations.This review is focused on the therapeutic perspective of the secretome of stem cells in alleviating the cytokine storm and organ injury in COVID-19 patients.展开更多
Spinocerebellar ataxias are heritable neurodegenerative diseases caused by a cytosine-adenine-guanine expansion,which encodes a long glutamine tract(polyglutamine)in the respective wild-type protein causing misfolding...Spinocerebellar ataxias are heritable neurodegenerative diseases caused by a cytosine-adenine-guanine expansion,which encodes a long glutamine tract(polyglutamine)in the respective wild-type protein causing misfolding and protein aggregation.Clinical features of polyglutamine spinocerebellar ataxias include neuronal aggregation,mitochondrial dysfunction,decreased proteasomal activity,and autophagy impairment.Mutant polyglutamine protein aggregates accumulate within neurons and cause neural dysfunction and death in specific regions of the central nervous system.Spinocerebellar ataxias are mostly characterized by progressive ataxia,speech and swallowing problems,loss of coordination and gait deficits.Over the past decade,efforts have been made to ameliorate disease symptoms in patients,yet no cure is available.Previous studies have been proposing the use of stem cells as promising tools for central nervous system tissue regeneration.So far,pre-clinical trials have shown improvement in various models of neurodegenerative diseases following stem cell transplantation,including animal models of spinocerebellar ataxia types 1,2,and 3.However,contrasting results can be found in the literature,depending on the animal model,cell type,and route of administration used.Nonetheless,clinical trials using cellular implants into degenerated brain regions have already been applied,with the expectation that these cells would be able to differentiate into the specific neuronal subtypes and re-populate these regions,reconstructing the affected neural network.Meanwhile,the question of how feasible it is to continue such treatments remains unanswered,with long-lasting effects being still unknown.To establish the value of these advanced therapeutic tools,it is important to predict the actions of the transplanted cells as well as to understand which cell type can induce the best outcomes for each disease.Further studies are needed to determine the best route of administration,without neglecting the possible risks of repetitive transplantation that these approaches so far appear to demand.Despite the challenges ahead of us,cell-transplantation therapies are reported to have transient but beneficial outcomes in spinocerebellar ataxias,which encourages efforts towards their improvement in the future.展开更多
BACKGROUND Globally,complete neurological recovery of spinal cord injury(SCI)is still less than 1%,and 90%experience permanent disability.The key issue is that a pharmacological neuroprotective-neuroregenerative agent...BACKGROUND Globally,complete neurological recovery of spinal cord injury(SCI)is still less than 1%,and 90%experience permanent disability.The key issue is that a pharmacological neuroprotective-neuroregenerative agent and SCI regeneration mechanism have not been found.The secretomes of stem cell are an emerging neurotrophic agent,but the effect of human neural stem cells(HNSCs)secretome on SCI is still unclear.AIM To investigate the regeneration mechanism of SCI and neuroprotective-neuroregenerative effects of HNSCs-secretome on subacute SCI post-laminectomy in rats.METHODS An experimental study was conducted with 45 Rattus norvegicus,divided into 15 normal,15 control(10 mL physiologic saline),and 15 treatment(30μL HNSCssecretome,intrathecal T10,three days post-traumatic).Locomotor function was evaluated weekly by blinded evaluators.Fifty-six days post-injury,specimens were collected,and spinal cord lesion,free radical oxidative stress(F2-Isoprostanes),nuclear factor-kappa B(NF-κB),matrix metallopeptidase 9(MMP9),tumor necrosis factor-alpha(TNF-α),interleukin-10(IL-10),transforming growth factor-beta(TGF-β),vascular endothelial growth factor(VEGF),B cell lymphoma-2(Bcl-2),nestin,brain-derived neurotrophic factor(BDNF),glial cell line-derived neurotrophic factor(GDNF)were analyzed.The SCI regeneration mechanism was analyzed using partial least squares structural equation modeling(PLS SEM).RESULTS HNSCs-secretome significantly improved locomotor recovery according to Basso,Beattie,Bresnahan(BBB)scores and increased neurogenesis(nestin,BDNF,and GDNF),neuroangiogenesis(VEGF),anti-apoptotic(Bcl-2),anti-inflammatory(IL-10 and TGF-β),but decreased proinflammatory(NF-κB,MMP9,TNF-α),F2-Isoprostanes,and spinal cord lesion size.The SCI regeneration mechanism is valid by analyzed outer model,inner model,and hypothesis testing in PLS SEM,started with pro-inflammation followed by anti-inflammation,anti-apoptotic,neuroangiogenesis,neurogenesis,and locomotor function.CONCLUSION HNSCs-secretome as a potential neuroprotective-neuroregenerative agent for the treatment of SCI and uncover the SCI regeneration mechanism.展开更多
The new coronavirus,severe acute respiratory syndrome coronavirus-2(SARSCoV-2),which emerged in December 2019 in Wuhan,China,has reached worldwide pandemic proportions,causing coronavirus disease 2019(COVID-19).The cl...The new coronavirus,severe acute respiratory syndrome coronavirus-2(SARSCoV-2),which emerged in December 2019 in Wuhan,China,has reached worldwide pandemic proportions,causing coronavirus disease 2019(COVID-19).The clinical manifestations of COVID-19 vary from an asymptomatic disease course to clinical symptoms of acute respiratory distress syndrome and severe pneumonia.The lungs are the primary organ affected by SARS-CoV-2,with a very slow turnover for renewal.SARS-CoV-2 enters the lungs via angiotensinconverting enzyme 2 receptors and induces an immune response with the accumulation of immunocompetent cells,causing a cytokine storm,which leads to target organ injury and subsequent dysfunction.To date,there is no effective antiviral therapy for COVID-19 patients,and therapeutic strategies are based on experience treating previously recognized coronaviruses.In search of new treatment modalities of COVID-19,cell-based therapy with mesenchymal stem cells(MSCs)and/or their secretome,such as soluble bioactive factors and extracellular vesicles,is considered supportive therapy for critically ill patients.Multipotent MSCs are able to differentiate into different types of cells of mesenchymal origin,including alveolar epithelial cells,lung epithelial cells,and vascular endothelial cells,which are severely damaged in the course of COVID-19 disease.Moreover,MSCs secrete a variety of bioactive factors that can be applied for respiratory tract regeneration in COVID-19 patients thanks to their trophic,anti-inflammatory,immunomodulatory,anti-apoptotic,pro-regenerative,and proangiogenic properties.展开更多
The dentate gyrus subregion of the mammalian hippocampus is an adult neural stem cell niche and site of lifelong neurogenesis.Hypotheses regarding the role of adult-born neuron synaptic integration in hippocampal circ...The dentate gyrus subregion of the mammalian hippocampus is an adult neural stem cell niche and site of lifelong neurogenesis.Hypotheses regarding the role of adult-born neuron synaptic integration in hippocampal circuit function are framed by robust estimations of adultborn versus pre/perinatally-born neuron number.In contrast,the non-neurogenic functions of adult neural stem cells and their immediate progeny,such as secretion of bioactive growth factors and expression of extracellular matrix-modifying proteins,lack similar framing due to few estimates of their number versus other prominent secretory cells.Here,we apply immunohistochemical methods to estimate cell density of neural stem/progenitor cells versus other major classes of glial and endothelial cell types that are potentially secretory in the dentate gyrus of adult mice.Of the cell types quantified,we found that GFAP^(+)SOX2^(+)stellate astrocytes were the most numerous,followed by CD31^(+)endothelia,GFAP-SOX2^(+)intermediate progenitors,Olig2^(+)oligodendrocytes,Iba1+microglia,and GFAP^(+)SOX2^(+)radial glia-like neural stem cells.We did not observe any significant sex differences in density of any cell population.Notably,neural stem/progenitor cells were present at a similar density as several cell types known to have potent functional roles via their secretome.These findings may be useful for refining hypotheses regarding the contributions of these cell types to regulating hippocampal function and their potential therapeutic uses.All experimental protocols were approved by the Ohio State University Institutional Animal Care and Use Committee(protocol#2016A00000068)on July 14,2016.展开更多
BACKGROUND Recently,the exclusive use of mesenchymal stem cell(MSC)-secreted molecules,called secretome,rather than cells,has been evaluated for overcoming the limitations of cell-based therapy,while maintaining its a...BACKGROUND Recently,the exclusive use of mesenchymal stem cell(MSC)-secreted molecules,called secretome,rather than cells,has been evaluated for overcoming the limitations of cell-based therapy,while maintaining its advantages.However,the use of na?ve secretome may not fully satisfy the specificity of each disease.Therefore,it appears to be more advantageous to use the functionally reinforced secretome through a series of processes involving physico-chemical adjustments or genetic manipulation rather than to the use na?ve secretome.AIM To determine the therapeutic potential of the secretome released from miR-122-transfected adipose-derived stromal cells(ASCs).METHODS We collected secretory materials released from ASCs that had been transfected with antifibrotic miR-122(MCM)and compared their antifibrotic effects with those of the na?ve secretome(CM).MCM and CM were intravenously administered to the mouse model of thioacetamide-induced liver fibrosis,and their therapeutic potentials were compared.RESULTS MCM infusion provided higher therapeutic potential in terms of:(A)Reducing collagen content in the liver;(B)Inhibiting proinflammatory cytokines;and(C)Reducing abnormally elevated liver enzymes than the infusion of the na?ve secretome.The proteomic analysis of MCM also indicated that the contents of antifibrotic proteins were significantly elevated compared to those in the na?ve secretome.CONCLUSION We could,thus,conclude that the secretome released from miR-122-transfected ASCs has higher antifibrotic and anti-inflammatory properties than the na?ve secretome.Because miR-122 transfection into ASCs provides a specific way of potentiating the antifibrotic properties of ASC secretome,it could be considered as an enhanced method for reinforcing secretome effectiveness.展开更多
BACKGROUND Inflammatory bowel diseases(IBD)is related to uncontrolled immune response.Currently,there is no successful treatment for significant improvement in IBD.Stem cells display their therapeutic effects through ...BACKGROUND Inflammatory bowel diseases(IBD)is related to uncontrolled immune response.Currently,there is no successful treatment for significant improvement in IBD.Stem cells display their therapeutic effects through their repopulating capacity or secreting factors.AIM To investigate the effects of conditioned mouse adipose-derived stem cells(mADSCs)secretome on colitis-induced mice.METHODS mADSCs were isolated from adipose tissue of C57BL/6 mice.Conditioned mADSCs secrectome was obtained by culturing of mADSCs with lipopolysaccharides(LPS,1μg/mL)for 24 h.Acute colitis was induced by 2%dextran sulfate sodium(DSS)drinking water for 7 d and then normal drinking water for 4 d.The mice were treated with normal culture medium(NM group),conditioned mADSCs secretome(CM group)or mADSCs(SC group).The length of colon and histopatholgy of colon tissues were evaluated.The mRNA expression levels of inflammatory cytokines in colon tissue and the serum interleukin(IL)-6 levels were determined.RESULTS The isolated mADSCs maintained the mADSCs specific gene expression profiles during experiment.The conditioned mADSCs secretome released by the treatment of mADSCs with LPS contained mainly inflammatory chemokines,colony-stimulating factors and inflammatory cytokines.The loss of body weight and reduction in colon length were ameliorated in the CM group.The conditioned mADSCs secretome reduced the histological score in colon tissue.The expression of IL-1b and IL-6 mRNAs in colon tissues significantly inhibited in the CM group compared to SC group and NM group,respectively.The elevation of serum IL-6 levels was also ameliorated in the CM group.These results indicate that the conditioned mADSCs secretome suppressed the synthesis of inflammatory cytokines in damaged colon tissue and the elevation of serum IL-6 concentration in DSS-induced mice CONCLUSION Conditioned mADSCs secretome might play regenerative roles by the suppression of IL-6 in serum and tissue during acute colitis,and may be more effective than stem cells themselves in the regeneration of colon tissue.展开更多
BACKGROUND Recently,the exclusive use of mesenchymal stem cell(MSC)-secreted molecules,named as the secretome,have been evaluated for overcoming the limitations of cell-based therapy while maintaining its advantages.A...BACKGROUND Recently,the exclusive use of mesenchymal stem cell(MSC)-secreted molecules,named as the secretome,have been evaluated for overcoming the limitations of cell-based therapy while maintaining its advantages.AIM To improve cell-free therapy by adding disease-specificity through stimulation of MSCs using disease-causing materials.METHODS We collected the secretory materials(named as inducers)released from AML12 hepatocytes that had been pretreated with thioacetamide(TAA)and generated the TAA-induced secretome(TAA-isecretome)after stimulating adipose-derived stem cells with the inducers.The TAA-isecretome was intravenously administered to mice with TAA-induced hepatic failure and those with partial hepatectomy.RESULTS TAA-isecretome infusion showed higher therapeutic potential in terms of(1)restoring disorganized hepatic tissue to normal tissue;(2)inhibiting proinflammatory cytokines(interleukin-6 and tumor necrosis factor-α);and(3)reducing abnormally elevated liver enzymes(aspartate aminotransferase and alanine aminotransferase)compared to the naïve secretome infusion in mice with TAA-induced hepatic failure.However,the TAA-isecretome showed inferior therapeutic potential for restoring hepatic function in partially hepatectomized mice.Proteomic analysis of TAA-isecretome identified that antioxidant processes were the most predominant enriched biological networks of the proteins exclusively identified in the TAA-isecretome.In addition,peroxiredoxin-1,a potent antioxidant protein,was found to be one of representative components of TAA-isecretome and played a central role in the protection of TAA-induced hepatic injury.CONCLUSION Appropriate stimulation of adipose-derived stem cells with TAA led to the production of a secretome enriched with proteins,especially peroxiredoxin-1,with higher antioxidant activity.Our results suggest that appropriate stimulation of MSCs with pathogenic agents can lead to the production of a secretome specialized for protecting against the pathogen.This approach is expected to open a new way of developing various specific therapeutics based on the high plasticity and responsiveness of MSCs.展开更多
The treatment of nonhealing and chronic cutaneous wounds still needs a clinical advancement to be effective.Both mesenchymal stem cells(MSCs),obtained from different sources,and their secretome derived thereof(especia...The treatment of nonhealing and chronic cutaneous wounds still needs a clinical advancement to be effective.Both mesenchymal stem cells(MSCs),obtained from different sources,and their secretome derived thereof(especially exosomes)can activate signaling pathways related to promotion of cell migration,vascularization,collagen deposition,and inflammatory response demonstrating prohealing,angiogenetic and anti-scarring capacities.On the other hand,biodegradable biomimetic scaffolds can facilitate endogenous cell attachment and proliferation as well as extracellular matrix production.In this Review,we revise the complex composites made by biomimetic scaffolds,mainly hydrogels,and MSC-derived exosomes constructed for cutaneous wound healing.Studies demonstrate that there exists a synergistic action of scaffolds with encapsulated exosomes,displaying a sustained release profiles to facilitate longlasting healing effects.It can be envisioned that dressings made by biomimetic hydrogels and MSC-derived exosomes will be clinically applied in the near future for the effective treatment of nonhealing and chronic wounds.展开更多
In a recent article,the authors provide a detailed summary of the characteristics and biological functions of mesenchymal stem cells(MSCs),as well as a discussion on the potential mechanisms of action of MSC-based the...In a recent article,the authors provide a detailed summary of the characteristics and biological functions of mesenchymal stem cells(MSCs),as well as a discussion on the potential mechanisms of action of MSC-based therapies.They describe the morphology,biogenesis,and current isolation techniques of exosomes,one of the most important fractions of the MSC-derived secretome.They also summarize the characteristics of MSC-derived exosomes and highlight their functions and therapeutic potential for tissue/organ regeneration and for kidney,liver,cardiovascular,neurological,and musculoskeletal diseases,as well as cutaneous wound healing.Despite the fact that MSCs are regarded as an important pillar of regenerative medicine,their regenerative potential has been demonstrated to be limited in a number of pathological conditions.The negative effects of MSC-based cell therapy have heightened interest in the therapeutic use of MSC-derived secretome.On the other hand,MSC-derived exosomes and microvesicles possess the potential to have a significant impact on disease development,including cancer.MSCs can interact with tumor cells and promote mutual exchange and induction of cellular markers by exchanging secretome.Furthermore,enzymes secreted into and activated within exosomes can result in tumor cells acquiring new properties.As a result,therapeutic applications of MSC-derived secretomes must be approached with extreme caution.展开更多
文摘The rapid increasing number of completed bacterial genomes provides a good opportunity to compare their proteomes. This study was undertaken to specifically compare and contrast their secretomes--the fraction of the proteome with predicted N-terminal signal sequences, both type Ⅰ and type Ⅱ. A total of 176 theoretical bacterial proteomes were examined using the ExProt program. Compared with the Gram-positives, the Gram-negative bacteria were found, on average, to contain a larger number of potential Sec-dependent sequences. In the Gram-negative bacteria but not in the others, there was a positive correlation between proteome size and secretome size, while there was no correlation between secretome size and pathogenicity. Within the Gram-negative bacteria, intracellular pathogens were found to have the smallest secretomes. However, the secretomes of certain bacteria did not fit into the observed pattern. Specifically, the secretome of Borrelia burgdoferi has an unusually large number of putative lipoproteins, and the signal peptides of mycoplasmas show closer sequence similarity to those of the Gramnegative bacteria. Our analysis also suggests that even for a theoretical minimal genome of 300 open reading frames, a fraction of this gene pool （up to a maximum of 20%） may code for proteins with Sec-dependent signal sequences.
文摘BACKGROUND Exosome-based therapies represent a promising approach for hair regeneration.Unlike conventional treatments such as minoxidil and finasteride,exosomes deliver bioactive cargo that can stimulate dermal papilla cells,enhance angiogenesis,and modulate inflammatory pathways.However,variability in exosome sources,isolation techniques,and dosing protocols limits their clinical translation.AIM To synthesize findings from in vitro,preclinical and clinical studies,and to evaluate the efficacy,mechanisms,and challenges associated with exosome-based hair restoration therapies.METHODS A literature search was conducted using multiple databases(PubMed/Medline,Embase,Scopus,and Web of Science)employing terms for exosomes and hair regeneration for articles published in English to February 2025,following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.RESULTS A total of 27 studies(three in vitro,three pre-clinical,18 with both in vitro and preclinical component and three clinical)met the pre-defined search and inclusion criteria and were included in this review.CONCLUSION Exosome-based therapies hold immense promise for hair regeneration by leveraging their ability to modulate key signaling pathways and enhance hair follicle regeneration.While in vitro and preclinical studies demonstrate consistent efficacy across diverse exosome sources,methodological heterogeneity and a limited number of clinical studies warrant further clinical research to realize their full clinical potential for hair regeneration.
基金Supported by 2024 Yeungnam University Grant,No.224A480005.
文摘Intervertebral disc degeneration(IDD)results from an imbalance within the intervertebral disc,leading to alterations in extracellular matrix composition,loss of nucleus pulposus cells,increased oxidative stress,and inflammatory cascade.While IDD naturally progresses with age,some factors such as mechanical trauma,lifestyle choices,and genetic abnormalities can elevate the risk of symptomatic disease progression.Current treatments,including pharmacological and surgical interventions,fail to halt disease progression or restore IDD function.Although biological therapies have been evaluated,their effectiveness in reversing long-term disc degeneration remains inconsistent.Mesenchymal stem cellbased therapies have demonstrated potential for IDD regeneration but are hindered by biological limitations,ethical issues,etc.To date,mesenchymal stem cell-derived extracellular vesicles(EVs)have emerged as promising therapeutic agents for regeneration and anti-inflammation.Their therapeutic effects are attributed to several mechanisms,such as the induction of regenerative phenotype,apoptosis mitigation,and immunomodulation.In addition,the abundance of microRNAs within EVs play a crucial role in modulating the disc degeneration.Due to the problems in clinical use,however,the efficiency of the EVs should be overcome further by optimizing cell culture conditions,engineering them to deliver drugs and targeting molecules,etc.
基金Supported by Abdul Hameed Shoman Foundation,No.6/2018.
文摘BACKGROUND Acute kidney injury is characterized by a sudden decline in renal function,often due to ischemia or nephrotoxins,leading to increased oxidative stress and inflam-mation.AIM To investigate the protective effects of adipose-derived mesenchymal stromal cell(ADMSC)secretome on renal tubular epithelial cells(NRK-52E)as an in vitro model of oxidative stress-associated kidney injury.METHODS ADMSCs were isolated from human adipose tissue and characterized for mesenchymal markers and differentiation potential.Conditioned media(CM)was collected after 48-hour serum-free culture and applied to serum-deprived NRK-52E cells for 48 hours.Cell viability was assessed using the MTT assay,apoptosis was assessed by Annexin V-FITC/PI staining and flow cytometry,reactive oxygen species(ROS)levels via H2DCFDA staining,and mitochondrial membrane potential by the tetramethylrhodamine ethyl ester assay.The expression of heme oxygenase-1(HO-1),nuclear factor erythroid 2-related factor 2(Nrf2),and NAD(P)H quinone dehydrogenase 1(Nqo1)genes was quantified by quantitative polymerase chain reaction.Comparative transcriptomic analysis was performed on ADMSCs and bone marrow-derived MSCs(BM-MSCs)using publicly available microarray data(GSE108511).RESULTS ADMSC secretome significantly reduced ROS production and enhanced mitochondrial membrane potential in NRK cells.Gene expression analysis revealed a significant upregulation of HO-1 mRNA levels in ADMSC-CM treated cells.However,no significant changes were observed in Nrf2 and Nqo1 mRNA levels.Transcriptome analysis of ADMSCs against BM-MSCs revealed significant differences in the expression of genes related to oxidative stress response,antioxidant activity,and mitochondrial function.CONCLUSION The results of this study suggest that the ADMSC secretome exerts multifaceted protective effects on NRK cells by reducing oxidative stress and enhancing mitochondrial function.The study demonstrates the potential beneficial applications of the ADMSC secretome in treating oxidative stress-related kidney injuries.
文摘Stem cells have moved from lab to bedside, and many initial studies showed promising results. Therefore big companies are entering the business. However, most initial studies did not used controls to make sure of the efficacy of stem cells. Many phase-1 studies showed safety of stem cell therapies, when precaution measures were adapted. However, efficacy needs to be proven by randomized controlled trials (RCT) to exclude placebo effects. Recently, various RCTs for various conditions have been done with various contradictory results. Therefore, a meta-analysis is very useful to know whether a stem cell therapy really work for a certain condition. As various centres used various type of stem cells, various dose, and route of application, as well as different outcome measures with various results for one certain condition, sometimes it is difficult to conduct a meta-analysis when there is high heterogeneity, which is like pooling “apples” with “oranges” and “avocado” that will lead to a misleading conclusion. In many cases, where the studies are highly heterogeneous, and the heterogeneity can’t be identified, then a descriptive systematic review is the best solution to take a conclusion which protocol is the best and valuable to be standardized. Formerly it was believed that stem cells that are given to patients work by differentiating into the needed cells, and thus replacing damaged cell. However, recent evidence showed that only a few stem cells homed to the desired area, while a large amount went to various areas that were remote from the damaged area. Even though they were trapped in remote areas, the stem cells still exerted beneficial effects by remote signalling and secretion of various beneficial factors. Therefore, there are attempts to produce stem cell secretomes/metabolites to replace the stem cells, as metabolites are easier to handle and transported compared to the cells themselves. In addition, various studies worked on substitute tissue/organs “ex vivo” to be transplanted to replace a damaged organ. There are various means to produce a tissue/an organ/organoid “ex vivo” (tissue engineering) by using various stem cells, scaffold, and soluble factors, in various vessels from static vessel to bioreactors, and “on chips”. Though these attempts are in the initial stage, but some translational animal studies have been done. A more usual use of these “ex vivo” developed tissues/organs/organoids is for drug testing, such as toxicity testing, and for studying the mechanism of certain diseases that is directed toward the development of a cure of the diseases. In conclusion, many stem cell therapies have entered RCTs, but no standardized and approved protocol has been established, while organoids are usually used for drug testing and studying the mechanism of certain diseases.
文摘The regeneration of peripheral nerves comprises complicated steps involving a set of cellular and molecular events in distal nerve stumps with axonal sprouting and remyelination. Stem cell isolation and expansion for peripheral nerve repair(PNR) can be achieved using a wide diversity of prenatal and adult tissues, such as bone marrow or brain tissues. The ability to obtain stem cells for cell-based therapy(CBT) is limited due to donor site morbidity and the invasive nature of the harvesting process. Dental pulp stem cells(DPSCs) can be relatively and simply isolated from the dental pulps of permanent teeth, extracted for surgical or orthodontic reasons. DPSCs are of neural crest origin with an outstanding ability to differentiate into multiple cell lineages. They have better potential to differentiate into neural and glial cells than other stem cell sources through the expression and secretion of certain markers and a range of neurotropic factors;thus, they should be considered a good choice for PNR using CBT. In addition,these cells have paracrine effects through the secretion of neurotrophic growth factors and extracellular vesicles, which can enhance axonal growth and remyelination by decreasing the number of dying cells and activating local inhabitant stem cell populations, thereby revitalizing dormant or blocked cells,modulating the immune system and regulating inflammatory responses. The use of DPSC-derived secretomes holds great promise for controllable and manageable therapy for peripheral nerve injury. In this review, up-to-date information about the neurotrophic and neurogenic properties of DPSCs and their secretomes is provided.
基金Supported by Spanish Ministerio de Economía y competitividad,No.RTI2018-097324Predoctoral program in Biomedicine from the University of Cantabria and the Instituto de Investigación Valdecilla(IDIVAL),No.PREVAL 19/02 and PREVAL 20/01.
文摘Mesenchymal stem cells(MSCs)are the most frequently used stem cells in clinical trials due to their easy isolation from various adult tissues,their ability of homing to injury sites and their potential to differentiate into multiple cell types.However,the realization that the beneficial effect of MSCs relies mainly on their paracrine action,rather than on their engraftment in the recipient tissue and subsequent differentiation,has opened the way to cell-free therapeutic strategies in regenerative medicine.All the soluble factors and vesicles secreted by MSCs are commonly known as secretome.MSCs secretome has a key role in cell-to-cell communication and has been proven to be an active mediator of immunemodulation and regeneration both in vitro and in vivo.Moreover,the use of secretome has key advantages over cell-based therapies,such as a lower immunogenicity and easy production,handling and storage.Importantly,MSCs can be modulated to alter their secretome composition to better suit specific therapeutic goals,thus,opening a large number of possibilities.Altogether these advantages now place MSCs secretome at the center of an important number of investigations in different clinical contexts,enabling rapid scientific progress in this field.
文摘Ischemic stroke continues to be a leading cause of mortality and morbidity in the world. Despite recent advances in the field of stroke medicine, thrombolysis with recombinant tissue plasminogen activator remains as the only pharmacological therapy for stroke patients. However, due to short therapeutic window(4.5 hours of stroke onset) and increased risk of hemorrhage beyond this point, each year globally less than 1% of stroke patients receive this therapy which necessitate the discovery of safe and efficacious therapeutics that can be used beyond the acute phase of stroke. Accumulating evidence indicates that endothelial progenitor cells(EPCs), equipped with an inherent capacity to migrate, proliferate and differentiate, may be one such therapeutics. However, the limited availability of EPCs in peripheral blood and early senescence of few isolated cells in culture conditions adversely affect their application as effective therapeutics. Given that much of the EPC-mediated reparative effects on neurovasculature is realized by a wide range of biologically active substances released by these cells, it is possible that EPC-secretome may serve as an important therapeutic after an ischemic stroke. In light of this assumption, this review paper firstly discusses the main constituents of EPC-secretome that may exert the beneficial effects of EPCs on neurovasculature, and then reviews the currently scant literature that focuses on its therapeutic capacity.
基金Supported by the University of Padua grant "Progetto di Ateneo 2011" and by PRIN 2010-2011 "Unraveling structural and functional determinants behind Helicobacter pylori pathogen-esis and persistence"
文摘Proteins secreted by Helicobacter pylori (H. pylori), an important human pathogen responsible for severe gastric diseases, are reviewed from the point of view of their biochemical characterization, both functional and structural. Despite the vast amount of experimental data available on the proteins secreted by this bacterium, the precise size of the secretome remains unknown. In this review, we consider as secreted both proteins that contain a secretion signal for the periplasm and proteins that have been detected in the external medium in in vitro experiments. In this way, H. pylori’s secretome appears to be composed of slightly more than 160 proteins, but this number must be considered very cautiously, not only because the definition of secretome itself is ambiguous but also because the included proteins were observed as secreted in in vitro experiments that were not representative of the environmental situation in vivo. The proteins that appear to be secreted can be grouped into different classes: enzymes (48 proteins), outer membrane proteins (43), components of flagella (11), members of the cytotoxic-associated genes pathogenicity island or other toxins (8 and 5, respectively), binding and transport proteins (9), and others (11). A final group, which includes 28 members, is represented by hypothetical uncharacterized proteins. Despite the large amount of data accumulated on the H. pylori secretome, a considerable amount of work remains to reach a full comprehension of the system at the molecular level.
基金the financial support from Prémios Santa Casa Neurociências Prize Mantero Belard for Neurodegenerative Diseases Research(MB-28-2019)supported by the European Regional Development Fund(FEDER)+8 种基金through the Competitiveness Internationalization Operational Programme(POCI)by National fundsthrough the Foundation for Science and Technology(FCT)under the scope of projects UIDB/50026/2020UIDP/50026/2020 and POCI-01-0145-FEDER-029751developed under the scope of the project NORTE-01-0145-FEDER-000023supported by the Northern Portugal Regional Operational Programme(NORTE 2020)under the Portugal 2020 Partnership Agreement,through the European Regional Development Fund(FEDER)funded by ICVS Scientific Microscopy Platform,member of the national infrastructure PPBI-Portuguese Platform of Bioimaging(PPBI-POCI-01-0145-FEDER-022122)(to FGT)。
文摘Parkinson's disease is the second most prevalent neurodegenerative disorder worldwide.Clinically,it is characterized by severe motor complications caused by progressive degeneration of dopaminergic neurons.Current treatment is focused on mitigating the symptoms through the administration of levodopa,rather than on preventing dopaminergic neuronal damage.Therefore,the use and development of neuroprotective/disease-modifying strategies is an absolute need that can lead to promising gains on translational research of Parkinson's disease.For instance,N-acetylcysteine,a natural compound with strong antioxidant effects,has been shown to modulate oxidative stress,preventing dopamine-induced cell death.Despite the evidence of neuroprotective and modulatory effects of this drug,as far as we know,it does not induce per se any regenerative process.Therefore,it would be of interest to combine the latter with innovative therapies that induce dopaminergic neurons repair or even differentiation,as stem cell-based strategies.Stem cells secretome has been proposed as a promising therapeutic approach for Parkinson's disease,given its ability to modulate cell viability/preservation of dopaminergic neurons.Such approach represents a shift in the paradigm,showing that cell-transplantation free therapies based on the use of stem cells secretome may represent a potential alternative for regenerative medicine of Parkinson's disease.Thus,in this review,we address the current understanding of the potential combination of stem cell free-based strategies and neuroprotective/disease-modifying strategies as a new paradigm for the treatment of central nervous system neurodegenerative diseases,like Parkinson's disease.
文摘Despite various treatment protocols and newly recognized therapeutics,there are no effective treatment approaches against coronavirus disease.New therapeutic strategies including the use of stem cells-derived secretome as a cell-free therapy have been recommended for patients with critical illness.The pro-regenerative,pro-angiogenic,anti-inflammatory,anti-apoptotic,immunomodulatory,and trophic properties of stem cells-derived secretome,extracellular vesicles(EVs),and bioactive factors have made them suitable candidates for respiratory tract regeneration in coronavirus disease 2019(COVID-19)patients.EVs including microvesicles and exosomes can be applied for communication at the intercellular level due to their abilities in the long-distance transfer of biological messages such as mRNAs,growth factors,transcription factors,microRNAs,and cytokines,and therefore,simulate the specifications of the parent cell,influencing target cells upon internalization and/or binding.EVs exhibit both anti-inflammatory and tolerogenic immune responses by regulation of proliferation,polarization,activation,and migration of different immune cells.Due to effective immunomodulatory and high safety including a minimum risk of immunogenicity and tumorigenicity,mesenchymal stem cell(MSC)-EVs are more preferable to MSC-based therapies.Thus,as an endogenous repair and inflammation-reducing agent,MSCEVs could be used against COVID-19 induced morbidity and mortality after further mechanistic and preclinical/clinical investigations.This review is focused on the therapeutic perspective of the secretome of stem cells in alleviating the cytokine storm and organ injury in COVID-19 patients.
基金funded by national fundsthrough the Foundation for Science and Technology(FCT)-project UIDB/50026/2020 and UIDP/50026/2020by the National Ataxia Foundation(NAF)
文摘Spinocerebellar ataxias are heritable neurodegenerative diseases caused by a cytosine-adenine-guanine expansion,which encodes a long glutamine tract(polyglutamine)in the respective wild-type protein causing misfolding and protein aggregation.Clinical features of polyglutamine spinocerebellar ataxias include neuronal aggregation,mitochondrial dysfunction,decreased proteasomal activity,and autophagy impairment.Mutant polyglutamine protein aggregates accumulate within neurons and cause neural dysfunction and death in specific regions of the central nervous system.Spinocerebellar ataxias are mostly characterized by progressive ataxia,speech and swallowing problems,loss of coordination and gait deficits.Over the past decade,efforts have been made to ameliorate disease symptoms in patients,yet no cure is available.Previous studies have been proposing the use of stem cells as promising tools for central nervous system tissue regeneration.So far,pre-clinical trials have shown improvement in various models of neurodegenerative diseases following stem cell transplantation,including animal models of spinocerebellar ataxia types 1,2,and 3.However,contrasting results can be found in the literature,depending on the animal model,cell type,and route of administration used.Nonetheless,clinical trials using cellular implants into degenerated brain regions have already been applied,with the expectation that these cells would be able to differentiate into the specific neuronal subtypes and re-populate these regions,reconstructing the affected neural network.Meanwhile,the question of how feasible it is to continue such treatments remains unanswered,with long-lasting effects being still unknown.To establish the value of these advanced therapeutic tools,it is important to predict the actions of the transplanted cells as well as to understand which cell type can induce the best outcomes for each disease.Further studies are needed to determine the best route of administration,without neglecting the possible risks of repetitive transplantation that these approaches so far appear to demand.Despite the challenges ahead of us,cell-transplantation therapies are reported to have transient but beneficial outcomes in spinocerebellar ataxias,which encourages efforts towards their improvement in the future.
文摘BACKGROUND Globally,complete neurological recovery of spinal cord injury(SCI)is still less than 1%,and 90%experience permanent disability.The key issue is that a pharmacological neuroprotective-neuroregenerative agent and SCI regeneration mechanism have not been found.The secretomes of stem cell are an emerging neurotrophic agent,but the effect of human neural stem cells(HNSCs)secretome on SCI is still unclear.AIM To investigate the regeneration mechanism of SCI and neuroprotective-neuroregenerative effects of HNSCs-secretome on subacute SCI post-laminectomy in rats.METHODS An experimental study was conducted with 45 Rattus norvegicus,divided into 15 normal,15 control(10 mL physiologic saline),and 15 treatment(30μL HNSCssecretome,intrathecal T10,three days post-traumatic).Locomotor function was evaluated weekly by blinded evaluators.Fifty-six days post-injury,specimens were collected,and spinal cord lesion,free radical oxidative stress(F2-Isoprostanes),nuclear factor-kappa B(NF-κB),matrix metallopeptidase 9(MMP9),tumor necrosis factor-alpha(TNF-α),interleukin-10(IL-10),transforming growth factor-beta(TGF-β),vascular endothelial growth factor(VEGF),B cell lymphoma-2(Bcl-2),nestin,brain-derived neurotrophic factor(BDNF),glial cell line-derived neurotrophic factor(GDNF)were analyzed.The SCI regeneration mechanism was analyzed using partial least squares structural equation modeling(PLS SEM).RESULTS HNSCs-secretome significantly improved locomotor recovery according to Basso,Beattie,Bresnahan(BBB)scores and increased neurogenesis(nestin,BDNF,and GDNF),neuroangiogenesis(VEGF),anti-apoptotic(Bcl-2),anti-inflammatory(IL-10 and TGF-β),but decreased proinflammatory(NF-κB,MMP9,TNF-α),F2-Isoprostanes,and spinal cord lesion size.The SCI regeneration mechanism is valid by analyzed outer model,inner model,and hypothesis testing in PLS SEM,started with pro-inflammation followed by anti-inflammation,anti-apoptotic,neuroangiogenesis,neurogenesis,and locomotor function.CONCLUSION HNSCs-secretome as a potential neuroprotective-neuroregenerative agent for the treatment of SCI and uncover the SCI regeneration mechanism.
文摘The new coronavirus,severe acute respiratory syndrome coronavirus-2(SARSCoV-2),which emerged in December 2019 in Wuhan,China,has reached worldwide pandemic proportions,causing coronavirus disease 2019(COVID-19).The clinical manifestations of COVID-19 vary from an asymptomatic disease course to clinical symptoms of acute respiratory distress syndrome and severe pneumonia.The lungs are the primary organ affected by SARS-CoV-2,with a very slow turnover for renewal.SARS-CoV-2 enters the lungs via angiotensinconverting enzyme 2 receptors and induces an immune response with the accumulation of immunocompetent cells,causing a cytokine storm,which leads to target organ injury and subsequent dysfunction.To date,there is no effective antiviral therapy for COVID-19 patients,and therapeutic strategies are based on experience treating previously recognized coronaviruses.In search of new treatment modalities of COVID-19,cell-based therapy with mesenchymal stem cells(MSCs)and/or their secretome,such as soluble bioactive factors and extracellular vesicles,is considered supportive therapy for critically ill patients.Multipotent MSCs are able to differentiate into different types of cells of mesenchymal origin,including alveolar epithelial cells,lung epithelial cells,and vascular endothelial cells,which are severely damaged in the course of COVID-19 disease.Moreover,MSCs secrete a variety of bioactive factors that can be applied for respiratory tract regeneration in COVID-19 patients thanks to their trophic,anti-inflammatory,immunomodulatory,anti-apoptotic,pro-regenerative,and proangiogenic properties.
基金a R00 Pathway to Independence Award from NIH/NINDS(R00NS089938to EDK).
文摘The dentate gyrus subregion of the mammalian hippocampus is an adult neural stem cell niche and site of lifelong neurogenesis.Hypotheses regarding the role of adult-born neuron synaptic integration in hippocampal circuit function are framed by robust estimations of adultborn versus pre/perinatally-born neuron number.In contrast,the non-neurogenic functions of adult neural stem cells and their immediate progeny,such as secretion of bioactive growth factors and expression of extracellular matrix-modifying proteins,lack similar framing due to few estimates of their number versus other prominent secretory cells.Here,we apply immunohistochemical methods to estimate cell density of neural stem/progenitor cells versus other major classes of glial and endothelial cell types that are potentially secretory in the dentate gyrus of adult mice.Of the cell types quantified,we found that GFAP^(+)SOX2^(+)stellate astrocytes were the most numerous,followed by CD31^(+)endothelia,GFAP-SOX2^(+)intermediate progenitors,Olig2^(+)oligodendrocytes,Iba1+microglia,and GFAP^(+)SOX2^(+)radial glia-like neural stem cells.We did not observe any significant sex differences in density of any cell population.Notably,neural stem/progenitor cells were present at a similar density as several cell types known to have potent functional roles via their secretome.These findings may be useful for refining hypotheses regarding the contributions of these cell types to regulating hippocampal function and their potential therapeutic uses.All experimental protocols were approved by the Ohio State University Institutional Animal Care and Use Committee(protocol#2016A00000068)on July 14,2016.
基金Supported by the National Research Foundation of Korea(NRF)grant funded by the Korea government(MSIT),No.NRF-2015R1D1A1A01060721
文摘BACKGROUND Recently,the exclusive use of mesenchymal stem cell(MSC)-secreted molecules,called secretome,rather than cells,has been evaluated for overcoming the limitations of cell-based therapy,while maintaining its advantages.However,the use of na?ve secretome may not fully satisfy the specificity of each disease.Therefore,it appears to be more advantageous to use the functionally reinforced secretome through a series of processes involving physico-chemical adjustments or genetic manipulation rather than to the use na?ve secretome.AIM To determine the therapeutic potential of the secretome released from miR-122-transfected adipose-derived stromal cells(ASCs).METHODS We collected secretory materials released from ASCs that had been transfected with antifibrotic miR-122(MCM)and compared their antifibrotic effects with those of the na?ve secretome(CM).MCM and CM were intravenously administered to the mouse model of thioacetamide-induced liver fibrosis,and their therapeutic potentials were compared.RESULTS MCM infusion provided higher therapeutic potential in terms of:(A)Reducing collagen content in the liver;(B)Inhibiting proinflammatory cytokines;and(C)Reducing abnormally elevated liver enzymes than the infusion of the na?ve secretome.The proteomic analysis of MCM also indicated that the contents of antifibrotic proteins were significantly elevated compared to those in the na?ve secretome.CONCLUSION We could,thus,conclude that the secretome released from miR-122-transfected ASCs has higher antifibrotic and anti-inflammatory properties than the na?ve secretome.Because miR-122 transfection into ASCs provides a specific way of potentiating the antifibrotic properties of ASC secretome,it could be considered as an enhanced method for reinforcing secretome effectiveness.
基金National Research Foundation of Korea(NRF)grants funded by the Korea Government(MSIT),No.2017R1A2B2011956 and No.2019R1F1A1061453.
文摘BACKGROUND Inflammatory bowel diseases(IBD)is related to uncontrolled immune response.Currently,there is no successful treatment for significant improvement in IBD.Stem cells display their therapeutic effects through their repopulating capacity or secreting factors.AIM To investigate the effects of conditioned mouse adipose-derived stem cells(mADSCs)secretome on colitis-induced mice.METHODS mADSCs were isolated from adipose tissue of C57BL/6 mice.Conditioned mADSCs secrectome was obtained by culturing of mADSCs with lipopolysaccharides(LPS,1μg/mL)for 24 h.Acute colitis was induced by 2%dextran sulfate sodium(DSS)drinking water for 7 d and then normal drinking water for 4 d.The mice were treated with normal culture medium(NM group),conditioned mADSCs secretome(CM group)or mADSCs(SC group).The length of colon and histopatholgy of colon tissues were evaluated.The mRNA expression levels of inflammatory cytokines in colon tissue and the serum interleukin(IL)-6 levels were determined.RESULTS The isolated mADSCs maintained the mADSCs specific gene expression profiles during experiment.The conditioned mADSCs secretome released by the treatment of mADSCs with LPS contained mainly inflammatory chemokines,colony-stimulating factors and inflammatory cytokines.The loss of body weight and reduction in colon length were ameliorated in the CM group.The conditioned mADSCs secretome reduced the histological score in colon tissue.The expression of IL-1b and IL-6 mRNAs in colon tissues significantly inhibited in the CM group compared to SC group and NM group,respectively.The elevation of serum IL-6 levels was also ameliorated in the CM group.These results indicate that the conditioned mADSCs secretome suppressed the synthesis of inflammatory cytokines in damaged colon tissue and the elevation of serum IL-6 concentration in DSS-induced mice CONCLUSION Conditioned mADSCs secretome might play regenerative roles by the suppression of IL-6 in serum and tissue during acute colitis,and may be more effective than stem cells themselves in the regeneration of colon tissue.
基金Supported by National Research Foundation of Korea,No.NRF-2015R1C1A1A02036931
文摘BACKGROUND Recently,the exclusive use of mesenchymal stem cell(MSC)-secreted molecules,named as the secretome,have been evaluated for overcoming the limitations of cell-based therapy while maintaining its advantages.AIM To improve cell-free therapy by adding disease-specificity through stimulation of MSCs using disease-causing materials.METHODS We collected the secretory materials(named as inducers)released from AML12 hepatocytes that had been pretreated with thioacetamide(TAA)and generated the TAA-induced secretome(TAA-isecretome)after stimulating adipose-derived stem cells with the inducers.The TAA-isecretome was intravenously administered to mice with TAA-induced hepatic failure and those with partial hepatectomy.RESULTS TAA-isecretome infusion showed higher therapeutic potential in terms of(1)restoring disorganized hepatic tissue to normal tissue;(2)inhibiting proinflammatory cytokines(interleukin-6 and tumor necrosis factor-α);and(3)reducing abnormally elevated liver enzymes(aspartate aminotransferase and alanine aminotransferase)compared to the naïve secretome infusion in mice with TAA-induced hepatic failure.However,the TAA-isecretome showed inferior therapeutic potential for restoring hepatic function in partially hepatectomized mice.Proteomic analysis of TAA-isecretome identified that antioxidant processes were the most predominant enriched biological networks of the proteins exclusively identified in the TAA-isecretome.In addition,peroxiredoxin-1,a potent antioxidant protein,was found to be one of representative components of TAA-isecretome and played a central role in the protection of TAA-induced hepatic injury.CONCLUSION Appropriate stimulation of adipose-derived stem cells with TAA led to the production of a secretome enriched with proteins,especially peroxiredoxin-1,with higher antioxidant activity.Our results suggest that appropriate stimulation of MSCs with pathogenic agents can lead to the production of a secretome specialized for protecting against the pathogen.This approach is expected to open a new way of developing various specific therapeutics based on the high plasticity and responsiveness of MSCs.
文摘The treatment of nonhealing and chronic cutaneous wounds still needs a clinical advancement to be effective.Both mesenchymal stem cells(MSCs),obtained from different sources,and their secretome derived thereof(especially exosomes)can activate signaling pathways related to promotion of cell migration,vascularization,collagen deposition,and inflammatory response demonstrating prohealing,angiogenetic and anti-scarring capacities.On the other hand,biodegradable biomimetic scaffolds can facilitate endogenous cell attachment and proliferation as well as extracellular matrix production.In this Review,we revise the complex composites made by biomimetic scaffolds,mainly hydrogels,and MSC-derived exosomes constructed for cutaneous wound healing.Studies demonstrate that there exists a synergistic action of scaffolds with encapsulated exosomes,displaying a sustained release profiles to facilitate longlasting healing effects.It can be envisioned that dressings made by biomimetic hydrogels and MSC-derived exosomes will be clinically applied in the near future for the effective treatment of nonhealing and chronic wounds.
基金Supported by Startup Program of Semmelweis University Faculty of Medicine,No.SE10332470.
文摘In a recent article,the authors provide a detailed summary of the characteristics and biological functions of mesenchymal stem cells(MSCs),as well as a discussion on the potential mechanisms of action of MSC-based therapies.They describe the morphology,biogenesis,and current isolation techniques of exosomes,one of the most important fractions of the MSC-derived secretome.They also summarize the characteristics of MSC-derived exosomes and highlight their functions and therapeutic potential for tissue/organ regeneration and for kidney,liver,cardiovascular,neurological,and musculoskeletal diseases,as well as cutaneous wound healing.Despite the fact that MSCs are regarded as an important pillar of regenerative medicine,their regenerative potential has been demonstrated to be limited in a number of pathological conditions.The negative effects of MSC-based cell therapy have heightened interest in the therapeutic use of MSC-derived secretome.On the other hand,MSC-derived exosomes and microvesicles possess the potential to have a significant impact on disease development,including cancer.MSCs can interact with tumor cells and promote mutual exchange and induction of cellular markers by exchanging secretome.Furthermore,enzymes secreted into and activated within exosomes can result in tumor cells acquiring new properties.As a result,therapeutic applications of MSC-derived secretomes must be approached with extreme caution.
