Apoptotic vesicles are required to repair DNA damage and suppress premature cellular senescence.

It is well known that DNA damage can cause apoptosis. However, whether apoptosis and its metabolites contribute to DNA repair is largely unknown. In this study, we found that apoptosis-deficient Fasmut and Bim- /- mice show significantly elevated DNA damage and premature cellular senescence, along with a significantly reduced number of 16,000 g apoptotic vesicles (apoVs). Intravenous infusion of mesenchymal stromal cell (MSC)-derived 16,000 g apoVs rescued the DNA damage and premature senescence in Fasmut and Bim-/- mice. Moreover, a sublethal dose of radiation exposure caused more severe DNA damage, reduced survival rate, and loss of body weight in Fasmut mice than in wild-type mice, which can be recovered by the infusion of MSC-apoVs. Mechanistically, we showed that apoptosis can assemble multiple nuclear DNA repair enzymes, such as the full-length PARP1, into 16,000 g apoVs. These DNA repair components are directly transferred by 16,000 g apoVs to recipient cells, leading to the rescue of DNA damage and elimination of senescent cells. Finally, we showed that embryonic stem cell-derived 16,000 g apoVs have superior DNA repair capacity due to containing a high level of nuclear DNA repair enzymes to rescue lethal dose-irradiated mice. This study uncovers a previously unknown role of 16,000 g apoVs in safeguarding tissues from DNA damage and demonstrates a strategy for using stem cell-derived apoVs to ameliorate irradiation-induced DNA damage.

Apoptotic Vesicular Metabolism Contributes to Organelle Assembly and Safeguards Liver Homeostasis and Regeneration.

BACKGROUND & AIMS: Apoptosis generates plenty of membrane-bound nanovesicles, the apoptotic vesicles (apoVs), which show promise for biomedical applications. The liver serves as a significant organ for apoptotic material removal. Whether and how the liver metabolizes apoptotic vesicular products and contributes to liver health and disease is unrecognized. METHODS: apoVs were labeled and traced after intravenous infusion. Apoptosis-deficient mice by Fas mutant (Fasmut) and Caspase-3 knockout (Casp3-/-) were used with apoV replenishment to evaluate the physiological apoV function. Combinations of morphologic, biochemical, cellular, and molecular assays were applied to assess the liver while hepatocyte analysis was performed. Partial hepatectomy and acetaminophen liver failure models were established to investigate liver regeneration and disease recovery. RESULTS: We discovered that the liver is a major metabolic organ of circulatory apoVs, in which apoVs undergo endocytosis by hepatocytes via a sugar recognition system. Moreover, apoVs play an indispensable role to counteract hepatocellular injury and liver impairment in apoptosis-deficient mice upon replenishment. Surprisingly, apoVs form a chimeric organelle complex with the hepatocyte Golgi apparatus through the soluble N-ethylmaleimide-sensitive factor attachment protein receptor machinery, which preserves Golgi integrity, promotes microtubule acetylation by regulating α-tubulin N-acetyltransferase 1, and consequently facilitates hepatocyte cytokinesis for liver recovery. The assembly of the apoV-Golgi complex is further revealed to contribute to liver homeostasis, regeneration, and protection against acute liver failure. CONCLUSIONS: These findings establish a previously unrecognized functional and mechanistic framework that apoptosis through vesicular metabolism safeguards liver homeostasis and regeneration, which holds promise for hepatic disease therapeutics.

ASC-expressing pyroptotic extracellular vesicles alleviate sepsis by protecting B cells.

Pyroptosis is an inflammatory programmed cell death process characterized by membrane rupture. Interestingly, pyroptotic cells can generate plenty of nanosized vesicles. Non-inflammatory apoptotic cell death-derived apoptotic vesicles (apoVs) were systemically characterized and displayed multiple physiological functions and therapeutic potentials. However, the characteristics of pyroptotic cell-generated extracellular vesicles (EVs) are largely unknown. Here, we identified a group of pyroptotic EVs (pyroEVs) from in vitro cultured pyroptotic mesenchymal stem cells (MSCs), as well as from septic mouse blood. Compared with apoVs, pyroEVs express similar levels of annexin V, calreticulin, and common EV markers, but express a decreased level of apoptotic marker cleave caspase-3. PyroEVs, but not apoVs and exosomes, specifically express pyroptotic maker apoptosis-associated speck-like protein containing CARD (ASC). More importantly, MSC-derived pyroEVs protect B cells in the spleen and bone marrow to relieve inflammatory responses and enhance the survival rate of the septic mice. Mechanistically, pyroEV membrane-expressed ASC binds to B cells to repress cell death by repressing Toll-like receptor 4. This study uncovered the characteristics of pyroEVs and their therapeutic role in sepsis and B cell-mediated immune response.

Apoptosis releases hydrogen sulfide to inhibit Th17 cell differentiation.

Over 50 billion cells undergo apoptosis each day in an adult human to maintain immune homeostasis. Hydrogen sulfide (H2S) is also required to safeguard the function of immune response. However, it is unknown whether apoptosis regulates H2S production. Here, we show that apoptosis-deficient MRL/lpr (B6.MRL-Faslpr/J) and Bim-/- (B6.129S1-Bcl2l11tm1.1Ast/J) mice exhibit significantly reduced H2S levels along with aberrant differentiation of Th17 cells, which can be rescued by the additional H2S. Moreover, apoptotic cells and vesicles (apoVs) express key H2S-generating enzymes and generate a significant amount of H2S, indicating that apoptotic metabolism is an important source of H2S. Mechanistically, H2S sulfhydrates selenoprotein F (Sep15) to promote signal transducer and activator of transcription 1 (STAT1) phosphorylation and suppress STAT3 phosphorylation, leading to the inhibition of Th17 cell differentiation. Taken together, this study reveals a previously unknown role of apoptosis in maintaining H2S homeostasis and the unique role of H2S in regulating Th17 cell differentiation via sulfhydration of Sep15C38.

Lyophilized apoptotic vesicle-encapsulated adhesive hydrogel sponge as a rapid hemostat for traumatic hemorrhage in coagulopathy.

Rapid hemostasis of uncontrolled bleeding following traumatic injuries, especially accompanied by coagulopathies, remains a significant clinical challenge. Extracellular vesicles (EVs) show therapeutic effects for fast clotting. However, low yield, specific storage conditions, and lack of proper carriers have hindered EVs' clinical application. Herein, we establish an optimized procedure method to generate lyophilized mesenchymal stem cell-derived apoptotic vesicles (apoVs) with adhesive hydrogel sponge to show superior procoagulant activity for traumatic hemorrhage. Mechanistically, apoVs' procoagulant ability stems from their high tissue factor (TF) and phosphatidylserine (PS) expression independent of hemocytes and circulating procoagulant microparticles (cMPs). Their stable hemostatic capability was maintained after 2-month room temperature storage. Subsequently, we mixed apoVs with both phenylboronic acid grafted oxidized hyaluronic acid (PBA-HA) and poly(vinyl alcohol) (PVA) simultaneously, followed by lyophilization to construct a novel apoV-encapsulated hydrogel sponge (apoV-HS). Compared to commercial hemostats, apoV-HS exhibits rapid procoagulant ability in liver-laceration and femoral artery hemorrhage in rat and rabbit models of coagulopathies. The combination of high productivity, physiological stability, injectability, plasticity, excellent adhesivity, biocompatibility, and rapid coagulant property indicates that apoV-HS is a promising therapeutic approach for heavy hemorrhage in civilian and military populations.

Inducing the "re-development state" of periodontal ligament cells via tuning macrophage mediated immune microenvironment.

INTRODUCTION: Periodontal regeneration, specifically the restoration of the cementum-periodontal ligament (PDL)-alveolar bone complex, remains a formidable challenge in the field of regenerative dentistry. In light of periodontal development, harnessing the multi-tissue developmental capabilities of periodontal ligament cells (PDLCs) and reinitiating the periodontal developmental process hold great promise as an effective strategy to foster the regeneration of the periodontal complex. OBJECTIVES: This study aims to delve into the potential effects of the macrophage-mediated immune microenvironment on the "developmental engineering" regeneration strategy and its underlying molecular mechanisms. METHODS: In this study, we conducted a comprehensive examination of the periodontium developmental process in the rat mandibular first molar using histological staining. Through the induction of diverse immune microenvironments in macrophages, we evaluated their potential effects on periodontal re-development events using a cytokine array. Additionally, we investigated PDLC-mediated periodontal re-development events under these distinct immune microenvironments through transcriptome sequencing and relevant functional assays. Furthermore, the underlying molecular mechanism was also performed. RESULTS: The activation of development-related functions in PDLCs proved challenging due to their declined activity. However, our findings suggest that modulating the macrophage immune response can effectively regulate PDLCs-mediated periodontium development-related events. The M1 type macrophage immune microenvironment was found to promote PDLC activities associated with epithelial-mesenchymal transition, fiber degradation, osteoclastogenesis, and inflammation through the Wnt, IL-17, and TNF signaling pathways. Conversely, the M2 type macrophage immune microenvironment demonstrated superiority in inducing epithelium induction, fibers formation, and mineralization performance of PDLCs by upregulating the TGFß and PI3K-Akt signaling pathway. CONCLUSION: The results of this study could provide some favorable theoretical bases for applying periodontal development engineering strategy in resolving the difficulties in periodontal multi-tissue regeneration.

Encapsulation of Nano-Bortezomib in Apoptotic Stem Cell-Derived Vesicles for the Treatment of Multiple Myeloma.

Extracellular vesicles (EVs) are lipid bilayer nanovesicles released from living or apoptotic cells that can transport DNA, RNA, protein, and lipid cargo. EVs play critical roles in cell-cell communication and tissue homeostasis, and have numerous therapeutic uses including serving as carriers for nanodrug delivery. There are multiple ways to load EVs with nanodrugs, such as electroporation, extrusion, and ultrasound. However, these approaches may have limited drug-loading rates, poor EV membrane stability, and high cost for large-scale production. Here, it is shown that apoptotic mesenchymal stem cells (MSCs) can encapsulate exogenously added nanoparticles into apoptotic vesicles (apoVs) with a high loading efficiency. When nano-bortezomib is incorporated into apoVs in culture-expanded apoptotic MSCs, nano-bortezomib-apoVs show a synergistic combination effect of bortezomib and apoVs to ameliorate multiple myeloma (MM) in a mouse model, along with significantly reduced side effects of nano-bortezomib. Moreover, it is shown that Rab7 regulates the nanoparticle encapsulation efficiency in apoptotic MSCs and that activation of Rab7 can increase nanoparticle-apoV production. In this study, a previously unknown mechanism to naturally synthesize nano-bortezomib-apoVs to improve MM therapy is revealed.

Extracellular vesicles and their indispensable roles in pathogenesis and treatment of inflammatory bowel disease: A comprehensive review.

Inflammatory bowel disease (IBD) is a global disease with rising incidence worldwide, and its debilitating symptoms and dissatisfactory therapies have brought heavy burdens for patients. Extracellular vesicles (EVs), a heterogeneous population of lipid bilayer membranes containing abundant bioactive molecules, have been indicated to play important roles in the pathogenesis and treatment of many diseases. However, to our knowledge, comprehensive reviews summarizing the various roles of diverse source-derived EVs in the pathogenesis and treatment of IBD are still lacking. This review, not only summarizes the EV characteristics, but also focuses on the multiple roles of diverse EVs in IBD pathogenesis and their treatment potential. In addition, hoping to push forward the research frontiers, we point out several challenges that the researchers are faced, about EVs in current IBD research and future therapeutic applications. We also put forward our prospects on future exploration regarding EVs in IBD treatment, including developing IBD vaccines and paying more attention on apoptotic vesicles. This review is aimed to enrich the knowledge on the indispensable roles of EVs in IBD pathogenesis and treatment, providing ideas and reference for future therapeutic strategy for IBD treatment.

Apoptotic vesicles ameliorate lupus and arthritis via phosphatidylserine-mediated modulation of T cell receptor signaling.

Mesenchymal stem cells (MSCs) influence T cells in health, disease and therapy through messengers of intercellular communication including extracellular vesicles (EVs). Apoptosis is a mode of cell death that tends to promote immune tolerance, and a large number of apoptotic vesicles (apoVs) are generated from MSCs during apoptosis. In an effort to characterize these apoVs and explore their immunomodulatory potential, here we show that after replenishing them systemically, the apoV deficiency in Fas mutant mice and pathological lymphoproliferation were rescued, leading to the amelioration of inflammation and lupus activity. ApoVs directly interacted with CD4+ T cells and inhibited CD25 expression and IL-2 production in a dose-dependent manner. A broad range of Th1/2/17 subsets and cytokines including IFNγ, IL17A and IL-10 were suppressed while Foxp3+ cells were maintained. Mechanistically, exposed phosphatidylserine (PtdSer/PS) on apoVs mediated the interaction with T cells to disrupt proximal T cell receptor signaling transduction. Remarkably, administration of apoVs prevented Th17 differentiation and memory formation, and ameliorated inflammation and joint erosion in murine arthritis. Collectively, our findings unveil a previously unrecognized crosstalk between MSC apoVs and CD4+ T cells and suggest a promising therapeutic use of apoVs for autoimmune diseases.

Apoptotic vesicles resist oxidative damage in noise-induced hearing loss through activation of FOXO3a-SOD2 pathway.

BACKGROUND: Mesenchymal stem cell (MSC) transplantation is a promising therapeutic approach for noise-induced hearing loss (NIHL). As the indispensable role of apoptosis in MSC transplantation was raised, the benefits of MSC-derived apoptotic vesicles (apoVs) in several disease models have been proved. However, whether apoVs benefit in NIHL have not been studied yet. METHODS: Female CBA/J mice and HEI-OC1 cells were used in this study. Flow cytometry, nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM) were used to characterize apoVs. Proteomic analysis was used to identify function proteins in apoVs. Immunofluorescence was used to reveal distribution pattern. Auditory brainstem response (ABR) test was used to measure the effect of apoVs treatment. DCFH-DA staining and MitoSOX staining were used to indicate oxidative damage. Western-blot and qRT-PCR were used to study the signaling pathways. RESULTS: We found that apoVs can be endocytosed by hair cells through systemic administration. Importantly, apoVs administration effectively attenuated NIHL and reduced hair cell loss by resisting oxidative damage in vivo. Further, apoVs application activated forkhead box o3 (FOXO3a)-mitochondrial superoxide dismutase 2(SOD2) pathway, which may relate to signal transduction and activators of transcription 3 (STAT3) in apoVs. CONCLUSIONS: These findings uncovered the role of apoVs in preventing NIHL and resisting oxidative damage, indicating that apoVs is a promising way for inner ear delivery and a prospective cell-free therapy for NIHL.

Extracellular vesicles in osteoarthritis of peripheral joint and temporomandibular joint.

Osteoarthritis (OA) is a disabling disease with significant morbidity worldwide. OA attacks the large synovial joint, including the peripheral joints and temporomandibular joint (TMJ). As a representative of peripheral joint OA, knee OA shares similar symptoms with TMJ OA. However, these two joints also display differences based on their distinct development, anatomy, and physiology. Extracellular vesicles (EVs) are phospholipid bilayer nanoparticles, including exosomes, microvesicles, and apoptotic bodies. EVs contain proteins, lipids, DNA, micro-RNA, and mRNA that regulate tissue homeostasis and cell-to-cell communication, which play an essential role in the progression and treatment of OA. They are likely to partake in mechanical response, extracellular matrix degradation, and inflammatory regulation during OA. More evidence has shown that synovial fluid and synovium-derived EVs may serve as OA biomarkers. More importantly, mesenchymal stem cell-derived EV shows a therapeutic effect on OA. However, the different function of EVs in these two joints is largely unknown based on their distinct biological characteristic. Here, we reviewed the effects of EVs in OA progression and compared the difference between the knee joint and TMJ, and summarized their potential therapeutic role in the treatment of OA.

Dual Role of Interleukin-20 in Different Stages of Osteoclast Differentiation and Its Osteoimmune Regulation during Alveolar Bone Remodeling.

Osteoimmunology mediators are critical to balance osteoblastogenesis and osteoclastogenesis to maintain bone homeostasis. A lot of the osteoimmunology mediators are regulated by interleukin-20 (IL-20). However, little is known about the role of IL-20 in bone remodeling. Here, we showed that IL-20 expression was correlated with osteoclast (OC) activity in remodeled alveolar bone during orthodontic tooth movement (OTM). Ovariectomize (OVX) in rats promoted OC activity and enhanced IL-20 expression, while blocking OC inhibited IL-20 expression in osteoclasts. In vitro, IL-20 treatment promoted survival, inhibited apoptosis of the preosteoclast at the early stages of osteoclast differentiation, and boosted the formation of osteoclasts and their bone resorption function at the late stages. More importantly, anti-IL-20 antibody treatment blocked IL-20-induced osteoclastogenesis and the subsequent bone resorption function. Mechanistically, we showed that IL-20 synergistically acts with RANKL to activate the NF-κB signaling pathway to promote the expression of c-Fos and NFATc1 to promote osteoclastogenesis. Moreover, we found that local injection of IL-20 or anti-IL-20 antibody enhanced osteoclast activity and accelerated OTM in rats, while blocking IL-20 reversed this phenomenon. This study revealed a previously unknown role of IL-20 in regulating alveolar bone remodeling and implies the application of IL-20 to accelerated OTM.

Extracellular Vesicles for Dental Pulp and Periodontal Regeneration.

Extracellular vesicles (EVs) are lipid bound particles derived from their original cells, which play critical roles in intercellular communication through their cargoes, including protein, lipids, and nucleic acids. According to their biogenesis and release pathway, EVs can be divided into three categories: apoptotic vesicles (ApoVs), microvesicles (MVs), and small EVs (sEVs). Recently, the role of EVs in oral disease has received close attention. In this review, the main characteristics of EVs are described, including their classification, biogenesis, biomarkers, and components. Moreover, the therapeutic mechanism of EVs in tissue regeneration is discussed. We further summarize the current status of EVs in pulp/periodontal tissue regeneration and discuss the potential mechanisms. The therapeutic potential of EVs in pulp and periodontal regeneration might involve the promotion of tissue regeneration and immunomodulatory capabilities. Furthermore, we highlight the current challenges in the translational use of EVs. This review would provide valuable insights into the potential therapeutic strategies of EVs in dental pulp and periodontal regeneration.

Apoptotic extracellular vesicles are metabolized regulators nurturing the skin and hair.

Over 300 billion of cells die every day in the human body, producing a large number of endogenous apoptotic extracellular vesicles (apoEVs). Also, allogenic stem cell transplantation, a commonly used therapeutic approach in current clinical practice, generates exogenous apoEVs. It is well known that phagocytic cells engulf and digest apoEVs to maintain the body's homeostasis. In this study, we show that a fraction of exogenous apoEVs is metabolized in the integumentary skin and hair follicles. Mechanistically, apoEVs activate the Wnt/ß-catenin pathway to facilitate their metabolism in a wave-like pattern. The migration of apoEVs is enhanced by treadmill exercise and inhibited by tail suspension, which is associated with the mechanical force-regulated expression of DKK1 in circulation. Furthermore, we show that exogenous apoEVs promote wound healing and hair growth via activation of Wnt/ß-catenin pathway in skin and hair follicle mesenchymal stem cells. This study reveals a previously unrecognized metabolic pathway of apoEVs and opens a new avenue for exploring apoEV-based therapy for skin and hair disorders.

Exocrine pancreas regeneration modifies original pancreas to alleviate diabetes in mouse models.

Diabetes is a major public health issue because of its widely epidemic nature and lack of cure. Here, we show that pancreas-derived mesenchymal stem cells (PMSCs) are capable of regenerating exocrine pancreas when implanted into the kidney capsule of mice with streptozotocin (STZ)-induced diabetes. Mechanistically, we found that the regenerated exocrine pancreas elevated interleukin-6 (IL-6) in PMSC implants, which transiently activated tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) to inhibit IL-17, thereby rescuing damaged exocrine pancreas and islet ß cells. In addition, we used knockout mouse models to show that global lack of IL-6, TNF-α, or IFN-γ resulted in increased severity of STZ-induced diabetes and resistance to PMSC implantation therapy, confirming the roles of these factors in safeguarding pancreatic ß cells. Furthermore, removal of the kidney capsule PMSC implants at 28 days after implantation did not affect the PMSC-initiated therapeutic effect on diabetic mice. This study reveals a previously unknown role of exocrine pancreas regeneration in safeguarding ß cells and demonstrates a "soil-rescues-seed" strategy for type 1 diabetes therapy.

Apoptotic vesicles inherit SOX2 from pluripotent stem cells to accelerate wound healing by energizing mesenchymal stem cells.

Billions of cells undergo apoptosis every day in the human body, resulting in the generation of a large number of apoptotic vesicles (apoVs) to maintain organ and tissue homeostasis. However, the characteristics and function of pluripotent stem cell (PSC)-derived apoVs (PSC-apoVs) are largely unknown. In this study, we showed that human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) produced larger numbers of apoVs than human umbilical cord mesenchymal stem cells (UMSCs) do when induced by staurosporine. In addition to expressing the general apoV markers cleaved caspase 3, Annexin V, calreticulin, ALIX, CD63 and TSG101, ESC-apoVs inherited pluripotent-specific molecules SOX2 from ESCs in a caspase 3-dependent manner. Moreover, ESC-apoVs could promote mouse skin wound healing via transferring SOX2 into skin MSCs via activating Hippo signaling pathway. Collectively, these findings reveal that apoVs are capable of inheriting pluripotent molecules from ESCs to energize adult stem cells, suggesting the potential to use PSC-apoVs for clinical applications. STATEMENT OF SIGNIFICANCE: Apoptotic vesicles (apoVs) are essential to maintain organ and tissue homeostasis. However, the characteristics and function of pluripotent stem cell (PSC)-derived apoVs (PSC-apoVs) are largely unknown. This study showed that PSC-apoVs produced 100 times more apoVs than human umbilical cord mesenchymal stem cells (UMSCs). Despite expressing the general apoV makers, PSC-apoVs inherited pluripotent-specific molecule SOX2 from PSCs in a caspase 3-dependent manner. Moreover, PSC-apoVs promote mouse skin wound healing via transferring SOX2 into skin MSCs, thus activating Hippo signaling pathway. These findings reveal that apoVs are capable of inheriting pluripotent molecules from PSCs to energize adult stem cells, thus providing a cell-free strategy for clinical applications of PSCs.

An Appearance Data-Driven Model Visualizes Cell State and Predicts Mesenchymal Stem Cell Regenerative Capacity.

Mesenchymal stem cells (MSCs) are widely used in treating various diseases. However, lack of a reliable evaluation approach to characterize the potency of MSCs has dampened their clinical applications. Here, a function-oriented mathematical model is established to evaluate and predict the regenerative capacity (RC) of MSCs. Processed by exhaustive testing, the model excavates four optimal fitted indices, including nucleus roundness, nucleus/cytoplasm ratio, side-scatter height, and ERK1/2 from the given index combinations. Notably, three of them except ERK1/2 are cell appearance-associated features. The predictive power of the model is validated via screening experiments of these indices by predicting the RC of newly enrolled and chemical inhibitor-treated MSCs. Further RNA-sequencing analysis reveals that cell appearance-based indices may serve as major indicators to visualize the results of integration-weighted signals in and out of cells and reflect MSC stemness. In general, this study proposes an appearance data-driven predictive model for the RC and stemness of MSCs.

Stem Cells from Human Exfoliated Deciduous Teeth Ameliorate Autistic-Like Behaviors of SHANK3 Mutant Beagle Dogs.

Mesenchymal stem cell-based therapy has emerged as a great potential approach to treat individuals with autism spectrum disorders (ASD), a group of developmental disabilities characterized by impairments in social interaction and communication. Stem cells from human exfoliated deciduous teeth (SHED), holding earlier developing characteristics, have immune-modulatory and anti-inflammatory properties. To investigate whether SHED transplantation can rescue autistic-like symptoms in SHANK3 mutant beagle dogs, 12 SHANK3 mutant beagle dogs were randomly assigned into 2 groups according to their behavior evaluated by social interaction tests. Six mutant dogs received 6 intravenous infusions of SHED and were followed up for 3 months by testing social interaction and inflammatory cytokine levels. We found that infusion of SHED significantly improved impaired social novel preference of SHANK3 mutant beagle dogs at 1- and 3-month follow-ups. Social intimacies (following, sniffing, and licking) between mutant beagle dogs and human experimenters were partly improved. Stressed tail posture, indicating social stress, was also significantly alleviated. In addition, we showed that the levels of serum interferon-γ and interleukin-10 were notably increased and decreased, respectively, in SHANK3 mutant beagle dogs. Infusion of SHED was able to rescue altered interferon-γ and interleukin-10 levels. We failed to observe any serious adverse events after infusion of SHED. In summary, SHED transplantation may be a safe and effective therapy for ASD. The correction in the levels of serum interferon-γ and interleukin-10 may serve as an index to predict autistic severity and therapeutic outcomes.

Electrostatic Charge-Mediated Apoptotic Vesicle Biodistribution Attenuates Sepsis by Switching Neutrophil NETosis to Apoptosis.

Mesenchymal stem cell (MSC) therapy can attenuate organ damage and reduce mortality in sepsis; however, the detailed mechanism is not fully elucidated. In this study, it is shown that MSC-derived apoptotic vesicles (apoVs) can ameliorate multiple organ dysfunction and improve survival in septic mice. Mechanistically, it is found that tail vein-infused apoVs mainly accumulate in the bone marrow of septic mice via electrostatic charge interactions with positively charged neutrophil extracellular traps (NETs). Moreover, apoVs switch neutrophils NETosis to apoptosis via the apoV-Fas ligand (FasL)-activated Fas pathway. In summary, these findings uncover a previously unknown role of apoVs in sepsis treatment and an electrostatic charge-directed target therapeutic mechanism, suggesting that cell death is associated with disease development and therapy.

Mesenchymal stem cells empower T cells in the lymph nodes via MCP-1/PD-L1 axis.

Mesenchymal stem cells (MSCs) are a type of immunosuppressive stromal cell found in multiple tissues and organs. However, whether MSCs possess immunosupportive characteristics remains unclear. In this study, we showed that the lymph nodes contain immunosupportive MSCs. They produce and secrete a high level of MCP-1 to promote T-cell proliferation and differentiation, in contrast to bone marrow MSCs (BMMSCs), which repress T-cell activation. Unlike BMMSCs, lymph node MSCs (LNMSCs) fail to respond to activated T-cell-induced production of PD-L1 to induce T-cell apoptosis. Mechanistically, MCP-1 activates phospho-Erk to sustain T-cell proliferation and activation while it represses NF-κB/PD-L1 pathway to avoid induction of T-cell apoptosis. Interestingly, inflammatory lymph node-derived LNMSCs abolish their immunosupportive function due to reduction of MCP-1 expression. Finally, we show that systemic infusion of LNMSCs rescues immunosuppression in cytoxan (CTX)-treated mice. This study reveals a previously unrecognized mechanism underlying MSC-based immunoregulation using the MCP-1/PD-L1 axis to energize T cells and suggests a potential to use MSCs to treat immunosuppressive disorders.