Mesenchymal stem cells’“garbage bags”at work:Treating radial nerve injury with mesenchymal stem cell-derived exosomes

Unlike central nervous system injuries,peripheral nerve injuries(PNIs)are often characterized by more or less successful axonal regeneration.However,structural and functional recovery is a senile process involving multifaceted cellular and molecular processes.The contemporary treatment options are limited,with surgical intervention as the gold-standard method;however,each treatment option has its associated limitations,especially when the injury is severe with a large gap.Recent advancements in cell-based therapy and cell-free therapy approaches using stem cell-derived soluble and insoluble components of the cell secretome are fast-emerging therapeutic approaches to treating acute and chronic PNI.The recent pilot study is a leap forward in the field,which is expected to pave the way for more enormous,systematic,and well-designed clinical trials to assess the therapeutic efficacy of mesenchymal stem cell-derived exosomes as a bio-drug either alone or as part of a combinatorial approach,in an attempt synergize the best of novel treatment approaches to address the complexity of the neural repair and regeneration.

Etanercept-synthesizing adipose-derived stem cell secretome:A promising therapeutic option for inflammatory bowel disease

BACKGROUND Inflammatory bowel disease(IBD)is a chronic inflammatory condition of the gastrointestinal tract,with tumor necrosis factor(TNF)-αplaying a key role in its pathogenesis.Etanercept,a decoy receptor for TNF,is used to treat inflammatory conditions.The secretome derived from adipose-derived stem cells(ASCs)has anti-inflammatory effects,making it a promising therapeutic option for IBD.AIM To investigate the anti-inflammatory effects of the secretome obtained from ASCs synthesizing etanercept on colon cells and in a dextran sulfate sodium(DSS)-induced IBD mouse model.METHODS ASCs were transfected with etanercept-encoding mini-circle plasmids to create etanercept-producing cells.The secretory material from these cells was then tested for anti-inflammatory effects both in vitro and in a DSS-induced IBD mouse model.RESULTS This study revealed promising results indicating that the group treated with the secretome derived from etanercept-synthesizing ASCs[Etanercept-Secretome(Et-Sec)group]had significantly lower expression levels of inflammatory mediators,such as interleukin-6,Monocyte Chemoattractant Protein-1,and TNF-α,when compared to the control secretome(Ct-Sec).Moreover,the Et-Sec group exhibited a marked therapeutic effect in terms of preserving the architecture of intestinal tissue compared to the Ct-Sec.CONCLUSION These results suggest that the secretome derived from ASCs that synthesize etanercept has potential as a therapeutic agent for the treatment of IBD,potentially enhancing treatment efficacy by merging the anti-inflam-matory qualities of the ASC secretome with etanercept's targeted approach to better address the multifaceted pathophysiology of IBD.

Mechanism of spinal cord injury regeneration and the effect of human neural stem cells-secretome treatment in rat model

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.

Cell-based therapeutic strategies for treatment of spinocerebellar ataxias:an update

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.

Advances in microfluidic chips based on islet hormone-sensing techniques

Diabetes mellitus is a global health problem resulting from islet dysfunction or insulin resistance.The mechanisms of islet dysfunction are still under investigation.Islet hormone secretion is the main function of islets,and serves an important role in the homeostasis of blood glucose.Elucidating the detailed mechanism of islet hormone secretome distortion can provide clues for the treatment of diabetes.Therefore,it is crucial to develop accurate,real-time,laborsaving,high-throughput,automated,and cost-effective techniques for the sensing of islet secretome.Microfluidic chips,an elegant platform that combines biology,engineering,computer science,and biomaterials,have attracted tremendous interest from scientists in the field of diabetes worldwide.These tiny devices are miniatures of traditional experimental systems with more advantages of timesaving,reagent-minimization,automation,high-throughput,and online detection.These features of microfluidic chips meet the demands of islet secretome analysis and a variety of chips have been designed in the past 20 years.In this review,we present a brief introduction of microfluidic chips,and three microfluidic chipsbased islet hormone sensing techniques.We focus mainly on the theory of these techniques,and provide detailed examples based on these theories with the hope of providing some insights into the design of future chips or whole detection systems.

Human retinal secretome:A cross-link between mesenchymal and retinal cells

In recent years,mesenchymal stem cells(MSC)have been considered the most effective source for regenerative medicine,especially due to released soluble paracrine bioactive components and extracellular vesicles.These factors,collectively called the secretome,play crucial roles in immunomodulation and in improving survival and regeneration capabilities of injured tissue.Recently,there has been a growing interest in the secretome released by retinal cytotypes,especially retinal pigment epithelium and Müller glia cells.The latter trophic factors represent the key to preserving morphofunctional integrity of the retina,regulating biological pathways involved in survival,function and responding to injury.Furthermore,these factors can play a pivotal role in onset and progression of retinal diseases after damage of cell secretory function.In this review,we delineated the importance of cross-talk between MSCs and retinal cells,focusing on common/induced secreted factors,during experimental therapy for retinal diseases.The cross-link between the MSC and retinal cell secretomes suggests that the MSC secretome can modulate the retinal cell secretome and vice versa.For example,the MSC secretome can protect retinal cells from degeneration by reducing oxidative stress,autophagy and programmed cell death.Conversely,the retinal cell secretome can influence the MSC secretome by inducing changes in MSC gene expression and phenotype.

The secretome of endothelial progenitor cells: a potential therapeutic strategy for ischemic stroke

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.

Mesenchymal stem cells secretome:The cornerstone of cell-free regenerative medicine

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.

Structural and functional aspects of the Helicobacter pylori secretome

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.

Stem cell-derived biofactors fight against coronavirus infection

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.

From regenerative strategies to pharmacological approaches:can we fine-tune treatment for Parkinson's disease?

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.

Perspectives on mesenchymal stem/progenitor cells and their derivates as potential therapies for lung damage caused by COVID-19

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.

Estimation of the density of neural,glial,and endothelial lineage cells in the adult mouse dentate gyrus

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.

Ameliorating liver fibrosis in an animal model using the secretome released from miR-122-transfected adipose-derived stem cells

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.

Conditioned secretome of adipose-derived stem cells improves dextran sulfate sodium-induced colitis in mice

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.

Generation of induced secretome from adipose-derived stem cells specialized for disease-specific treatment:An experimental mouse model

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.

Mesenchymal stem cells,secretome and biomaterials in in-vivo animal models:Regenerative medicine application in cutaneous wound healing

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.

Disagreements in the therapeutic use of mesenchymal stem cellderived secretome

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.

Controversies in therapeutic application of mesenchymal stem cell-derived secretome

Though mesenchymal stem cells(MSCs)are considered as an important pillar of regenerative medicine,their regenerative potential has been shown to be limited in several pathological conditions.The adverse properties of MSCbased cell therapy have drawn attention to the therapeutic use of MSC-derived secretome.However,MSC-originated exosomes and microvesicles can also possess a significant impact on disease development,including cancer.By interchanging secretome,MSCs can interact with tumor cells and promote mutual exchange/induction of cellular markers.In addition,enzymes secreted into and activated within exosomes can result in the acquisition of new tumor cell properties.Therefore,therapeutic applications of MSC-derived secretome require much caution.

Dental-derived stem cells and biowaste biomaterials:What’s next in bone regenerative medicine applications

The human teeth and oral cavity harbor various populations of mesenchymal stem cells(MSCs),so called dental-derived stem cells(D-dSCs)with self-renewing and multilineage differentiation capabilities.D-dSCs properties involves a strong paracrine component resulting from the high levels of bioactive molecules they secrete in response to the local microenvironment.Altogether,this viewpoint develops a general picture of current innovative strategies to employ D-dSCs combined with biomaterials and bioactive factors for regenerative medicine purposes,and offers information regarding the available scientific data and possible applications.