Mesenchymal Stem Cells Treatment Research Articles

Urine-Derived Stem Cells Reverse Bleomycin‑Induced Experimental Pulmonary Fibrosis by Inhibition of the TGF-β1-Smad2/3 Pathway

BackgroundIdiopathic pulmonary fibrosis (IPF) is characterized by progressive lung interstitial lesions with the disease pathophysiology incompletely understood, which is a serious and fatal disorder with limited treatment options. Mesenchymal stem cells (MSCs) have exhibited promising therapeutic capability for IPF. While most types of MSCs are obtained invasively, urine-derived stem cells (USCs) can be gained in a safe, noninvasive, and inexpensive procedure, which are readily available and reported to exhibit no risk of teratoma formation or oncogenic potential in vivo, sounding alternative to other MSCs. This study aims to investigate the therapeutic effect and mechanism of USCs on IPF, using a bleomycin (BLM)-induced IPF model in mice. MethodsCell surface marker examination by flow cytometry analysis and cell differentiation culture were used to characterize USCs obtained from healthy individuals. BLM was instilled endotracheally in adult C57BL/6 mice, followed by USCs or human bone marrow-derived mesenchymal stem cells (BMSCs) treatment by tail vein injection on day 14. Mice were euthanized on day 14 before administration or day 21 for the evaluation of pulmonary histopathology and hydroxyproline (HYP) content. Inflammatory factors of the lung, including transforming growth factor (TGF)-β1, TNF-α, IL-6, MMP2 were analyzed by quantitative real-time PCR (qRT-PCR). Additionally, immunohistochemistry (IHC) and western blotting (WB) were applied to evaluate the expression of α-SMA and activation of TGF-β1-Smad2/3 in lung. ResultsUSCs highly expressed CD29 and CD90, showing negative expression of hematopoietic stem cell markers (CD45, CD34) and could differentiate into, at least, bone and fat in vitro. In mice challenged with BLM, septal thickening and prominent fibrosis were observed on day 14, with higher HYP content and mRNA levels of TGF-β1, TNF-α and IL-6 exhibited, compared to untreated mice. USCs could migrate to lung and accumulate there in mouse model after intravenous injection. Transplantation of USCs into BLM-induced mice improved their pulmonary histopathology, decreasing Ashcroft score, Szapiel score, HYP content and mRNA levels of TGF-β1 and MMP2 of lung, similar to the effects of BMSCs. IHC and WB further revealed that USCs could inhibit activation of the TGF‑β1-Smad2/3 pathway of lung in vivo. ConclusionsTransplantation of USCs effectively reverses pulmonary fibrotic phenotype in an experimental IPF model, inhibiting the TGF-β1-Smad2/3 pathway, a key driver of fibrosis. These results suggest the therapeutic application of USCs for IPF, instead of other types of MSCs obtained invasively.

Adipose-derived mesenchymal stem cells ameliorates experimental autoimmune encephalomyelitis via modulation of Th1/Th17 and expansion of Th2/Treg responses.

The most common central nervous system (CNS) inflammatory disease is multiple sclerosis (MS), modeled using experimental autoimmune encephalomyelitis (EAE). Mesenchymal stem cells (MSCs) exhibit potent immunomodulatory capabilities, including the suppression of immune cell functions and anti-inflammatory cytokine production. Female C57BL/6 mice (8-10 weeks old) were divided into three groups: 1. Control, 2. Allogeneic MSCs (ALO) treatment, and 3. Syngeneic MSCs (SYN) treatment. To induce EAE, myelin oligodendrocyte glycoprotein was injected subcutaneously with complete Freund's adjuvant, followed by intraperitoneal pertussis toxin. On Days 6 and 12 postimmunization, the treatment groups received intraperitoneal injections of 2 × 106 MSCs. Daily clinical and weight assessments were performed, and on Day 25, the mice were euthanized. At the end of the period, brain histological analysis was conducted to quantify lymphocyte infiltration. T-cell characteristics were determined usingenzyme-linked immunosorbent assay and Real-time polymerase chain reaction (RT-PCR). The assessment of transcription factor expression levels in the CNS was also performed using RT-PCR. Compared to the control group, both the allogeneic (ALO) and syngeneic (SYN) groups demonstrated significantly reduced disease progression. The maximum clinical scores for the control, ALO, and SYN groups were 4.4 ± 0.1, 2.4 ± 0.2, and 2.1 ± 0.2, respectively (ALO and SYN vs. Control: p < .001). In comparison to the control group, histological studies demonstrated that the allogeneic and syngeneic groups had less lymphocytic infiltration (ALO: 1.4 ± 0.1, SYN: 1.2 ± 0.2, and control: 2.8 ± 0.15; p < .001) and demyelination (ALO: 1.2 ± 0.15, SYN: 1.1 ± 0.1 and control: 2.9 ± 0.1, p < .001). ALO and SYN groups had lower expression of Th1 and Th17 cytokines and transcription factors (IFN-γ: 0.067, 0.051; STAT4: 0.189, 0.162; T-bet: 0.175, 0.163; IL-17: 0.074, 0.061; STAT3: 0.271, 0.253; ROR-γt: 0.163, 0.149, respectively) compared to the control group on Day 25 following EAE induction. Additionally, ALO and SYN groups compared to the control group, expressed more Th2 and Treg cytokines and transcription factors (IL-4: 4.25, 4.63; STAT6: 2.78, 2.96; GATA3: 2.91, 3.08; IL-27: 2.32, 2.46, IL-33: 2.71, 2.85; TGF-β: 4.8, 5.05; IL-10: 4.71, 4.93; CTLA-4: 7.72, 7.95; PD1: 4.12,4.35; Foxp3: 3.82,4.08, respectively). This research demonstrated that MSCs possess the potential to be a therapeutic option for MS and related CNS inflammatory disorders. Their immunomodulatory properties, coupled with the observed reductions in disease severity, lymphocytic infiltration, and demyelination, indicate that MSCs could play a crucial role in altering the course of MS by mitigating inflammatory immune responses and promoting regulatory immune processes. These findings open up new possibilities for the development of MSC-based therapies for MS, and further investigation and clinical trials may be warranted to explore their efficacy and safety in human patients.

Bone mesenchymal stem cells improve cholestatic liver fibrosis by targeting ULK1 to regulate autophagy through PI3K/AKT/mTOR pathway.

Cholestatic liver disease (CLD) is a severe disease, which can progress to liver cirrhosis, even liver cancer. Hepatic stellate cells (HSCs) activation plays a crucial role in CLD development. Bone mesenchymal stem cells (BMSCs) treatment was demonstrated to be beneficial in liver diseases. However, the therapeutic effect and mechanism of BMSCs on CLD are poorly known. In the present study, we investigated the therapeutic effects and underlying mechanisms of BMSCs transplantation in mouse models of bile duct ligation-induced cholestatic liver fibrosis (CLF). The results revealed that BMSCs significantly improved liver function and reduced the formation of fibrosis after portal vein transplantation. Mechanistically, after coculturing BMSCs and HSCs, we identified that BMSCs alleviated starvation-induced HSCs activation. Further, BMSCs inhibited HSCs activation by decreasing autophagy, and PI3K/AKT/mTOR pathway was involved in the regulation. More importantly, ULK1 is identified as the main autophagy-related gene regulated by BMSCs in HSCs autophagy. Overexpression of ULK1 reversed the suppression of HSCs autophagy by BMSCs. Collectively, our results provide a theoretical basis for BMSCs targeting ULK1 to attenuate HSCs autophagy and activation and suggest that BMSCs or ULK1 may be an alternative therapeutic approach/target for the treatment of CLF.

Meta-analysis shows that mesenchymal stem cell therapy can be a possible treatment for diabetes.

This meta-analysis includes the systematic literature review and meta-analysis involving clinical trials to assess the efficacy and safety of mesenchymal stem cell (MSC) transplantation for treating T1DM and T2DM. We searched PubMed, ScienceDirect, Web of Science, clinicaltrials.gov, and Cochrane Library for "published" research from their inception until November 2023. Two researchers independently reviewed the studies' inclusion and exclusion criteria. Our meta-analysis included 13 studies on MSC treatment for diabetes. The MSC-treated group had a significantly lower HbA1c at the last follow-up compared to the baseline (MD: 0.95, 95% CI: 0.33 to 1.57, P-value: 0.003< 0.05), their insulin requirement was significantly lower (MD: 0.19, 95% CI: 0.07 to 0.31, P-value: 0.002< 0.05), the level of FBG with MSC transplantation significantly dropped compared to baseline (MD: 1.78, 95% CI: -1.02 to 4.58, P-value: 0.212), the FPG level of the MSC-treated group was significantly lower (MD: -0.77, 95% CI: -2.36 to 0.81, P-value: 0.339 > 0.05), and the fasting C-peptide level of the MSC-treated group was slightly high (MD: -0.02, 95% CI: -0.07 to 0.02, P-value: 0.231 > 0.05). The transplantation of MSCs has been found to positively impact both types of diabetes mellitus without signs of apparent adverse effects.

A Mesenchymal stem cell Aging Framework, from Mechanisms to Strategies.

Mesenchymal stem cells (MSCs) are extensively researched for therapeutic applications in tissue engineering and show significant potential for clinical use. Intrinsic or extrinsic factors causing senescence may lead to reduced proliferation, aberrant differentiation, weakened immunoregulation, and increased inflammation, ultimately limiting the potential of MSCs. It is crucial to comprehend the molecular pathways and internal processes responsible for the decline in MSC function due to senescence in order to devise innovative approaches for rejuvenating senescent MSCs and enhancing MSC treatment. We investigate the main molecular processes involved in senescence, aiming to provide a thorough understanding of senescence-related issues in MSCs. Additionally, we analyze the most recent advancements in cutting-edge approaches to combat MSC senescence based on current research. We are curious whether the aging process of stem cells results in a permanent "memory" and if cellular reprogramming may potentially revert the aging epigenome to a more youthful state.

CXCL10 is a crucial chemoattractant for efficient intranasal delivery of mesenchymal stem cells to the neonatal hypoxic-ischemic brain

BackgroundHypoxic-Ischemic Encephalopathy (HIE) is a leading cause of mortality and morbidity in newborns. Recent research has shown promise in using intranasal mesenchymal stem cell (MSC) therapy if administered within 10 days after Hypoxia-Ischemia (HI) in neonatal mice. MSCs migrate from the nasal cavity to the cerebral lesion in response to chemotactic cues. Which exact chemokines are crucial for MSC guidance to the HI lesion is currently not fully understood. This study investigates the role of CXCL10 in MSC migration towards the HI-injured brain.MethodsHI was induced in male and female 9-day-old C57BL/6 mice followed by intranasal MSC treatment at day 10 or 17 post-HI. CXCL10 protein levels, PKH26-labeled MSCs and lesion size were assessed by ELISA, immunofluorescent imaging and MAP2 staining respectively. At day 17 post-HI, when CXCL10 levels were reduced, intracranial CXCL10 injection and intranasal PKH26-labeled MSC administration were combined to assess CXCL10-guided MSC migration. MSC treatment efficacy was evaluated after 18 days, measuring lesion size, motor outcome (cylinder rearing task), glial scarring (GFAP staining) and neuronal density (NeuN staining) around the lesion. Expression of the receptor for CXCL10, i.e. CXCR3, on MSCs was confirmed by qPCR and Western Blot. Moreover, CXCL10-guided MSC migration was assessed through an in vitro transwell migration assay.ResultsIntranasal MSC treatment at day 17 post-HI did not reduce lesion size in contrast to earlier treatment timepoints. Cerebral CXCL10 levels were significantly decreased at 17 days versus 10 days post-HI and correlated with reduced MSC migration towards the brain. In vitro experiments demonstrated that CXCR3 receptor inhibition prevented CXCL10-guided migration of MSCs. Intracranial CXCL10 injection at day 17 post-HI significantly increased the number of MSCs reaching the lesion which was accompanied by repair of the HI lesion as measured by reduced lesion size and glial scarring, and an increased number of neurons around the lesion.ConclusionsThis study underscores the crucial role of the chemoattractant CXCL10 in guiding MSCs to the HI lesion after intranasal administration. Strategies to enhance CXCR3-mediated migration of MSCs may improve the efficacy of MSC therapy or extend its regenerative therapeutic window.

Delivery of Mesenchymal Stem Cells during Hypothermic Machine Perfusion in a Translational Kidney Perfusion Study.

In transplantation, hypothermic machine perfusion (HMP) has been shown to be superior to static cold storage (SCS) in terms of functional outcomes. Ex vivo machine perfusion offers the possibility to deliver drugs or other active substances, such as Mesenchymal Stem Cells (MSCs), directly into an organ without affecting the recipient. MSCs are multipotent, self-renewing cells with tissue-repair capacities, and their application to ameliorate ischemia- reperfusion injury (IRI) is being investigated in several preclinical and clinical studies. The aim of this study was to introduce MSCs into a translational model of hypothermic machine perfusion and to test the efficiency and feasibility of this method. Methods: three rodent kidneys, six porcine kidneys and three human kidneys underwent HMP with 1-5 × 106 labelled MSCs within respective perfusates. Only porcine kidneys were compared to a control group of 6 kidneys undergoing HMP without MSCs, followed by mimicked reperfusion with whole blood at 37 °C for 2 h for all 12 kidneys. Reperfusion perfusate samples were analyzed for levels of NGAL and IL-β by ELISA. Functional parameters, including urinary output, oxygen consumption and creatinine clearance, were compared and found to be similar between the MSC treatment group and the control group in the porcine model. IL-1β levels were higher in perfusate and urine samples in the MSC group, with a median of 285.3 ng/mL (IQR 224.3-407.8 ng/mL) vs. 209.2 ng/mL (IQR 174.9-220.1), p = 0.51 and 105.3 ng/mL (IQR 71.03-164.7 ng/mL) vs. 307.7 ng/mL (IQR 190.9-349.6 ng/mL), p = 0.16, respectively. MSCs could be traced within the kidneys in all models using widefield microscopy after HMP. The application of Mesenchymal Stem Cells in an ex vivo hypothermic machine perfusion setting is feasible, and MSCs can be delivered into the kidney grafts during HMP. Functional parameters during mimicked reperfusion were not altered in treated kidney grafts. Changes in levels of IL-1β suggest that MSCs might have an effect on the kidney grafts, and whether this leads to a positive or a negative outcome on IRI in transplantation needs to be determined in further experiments.

Current Advances in Mesenchymal Stem Cell Therapies Applied to Wounds and Skin, Eye, and Neuromuscular Diseases in Companion Animals.

Mesenchymal stem cells (MSCs) are considered a very promising alternative tool in cell therapies and regenerative medicine due to their ease of obtaining from various tissues and their ability to differentiate into different cell types. This manuscript provides a review of current knowledge on the use of MSC-based therapies as an alternative for certain common pathologies in dogs and cats where conventional treatments are ineffective. The aim of this review is to assist clinical veterinarians in making decisions about the suitability of each protocol from a clinical perspective, rather than focusing solely on research. MSC-based therapies have shown promising results in certain pathologies, such as spinal cord injuries, wounds, and skin and eye diseases. However, the effectiveness of these cell therapies can be influenced by a wide array of factors, leading to varying outcomes. Future research will focus on designing protocols and methodologies that allow more precise and effective MSC treatments for each case.

Combined effect of pantoprazole and mesenchymal stem cells on experimentally induced gastric ulcer: implication of oxidative stress, inflammation and apoptosis pathways

Gastric ulcer (GU) is one of the most common diseases of the upper gastrointestinal tract that affects millions of people worldwide. This study aimed to investigate the possible alleviating effect of a combined treatment of pantoprazole (PANTO) and adipose tissue-derived mesenchymal stem cells (ADSCs) in comparison with each treatment alone on the healing process of the experimentally induced GU in rats, and to uncover the involved pathways. Rats were divided into five groups: (1) Control, (2) GU, (3) PANTO, (4) ADSCs and (5) ADSCs + PANTO. Markers of oxidative stress, inflammation and apoptosis were assessed. The current data indicated that PANTO-, ADSCs- and ADSCs + PANTO-treated groups showed significant drop (p < 0.05) in serum advanced oxidation protein products (AOPPs) and advanced glycation end products (AGEPs) along with significant elevation (p < 0.05) in serum TAC versus the untreated GU group. Moreover, the treated groups (PANTO, ADSCs and ADSCs + PANTO) displayed significant down-regulation (p < 0.05) in gastric nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor alpha (TNF-α), cyclooxygenase-2 (COX-2), intercellular adhesion molecule-1 (ICAM-1), matrix metallopeptidase 9 (MMP-9) and caspase-3 along with significant up-regulation (p < 0.05) in vascular endothelial growth factor (VEGF) and peroxisome proliferator-activated receptor gamma (PPARγ) genes expression compared to the untreated GU group. Immunohistochemical examination of gastric tissue for transforming growth factor β1 (TGF-β1), epidermal growth factor (EGF) and proliferating cell nuclear antigen (PCNA) showed moderate to mild and weak immune reactions, respectively in the PANTO-, ADSCs- and ADSCs + PANTO-treated rat. Histopathological investigation of gastric tissue revealed moderate to slight histopathological alterations and almost normal histological features of the epithelial cells, gastric mucosal layer, muscularis mucosa and submucosa in PANTO-, ADSCs- and ADSCs + PANTO-treated rats, respectively. Conclusively, the co-treatment with ADSCs and PANTO evidenced sententious physiological protection against GU by suppressing oxidative stress, inhibiting inflammation and reducing apoptosis with consequent acceleration of gastric tissue healing process.

The M2 Macrophages Derived Migrasomes From the Surface of Titania Nanotubes Array as a New Concept for Enhancing Osteogenesis.

As newly discovered substrate anchored extracellular vesicles, migrasomes (Migs) may bring a new opportunity for manipulating target cells bioactivities. In this study, the M2 macrophages derived Migs are obtained by titania nanotubes surface (NTs). Due to the benefits of nanostructuring, the NTs surface is not only able to induce RAW264.7 for M2 polarization but also to generate more Migs formation, which can be internalized by following seeded mesenchymal stem cells (MSCs). Then, the NTs surface induced Migs are collected by density-gradient centrifugation for MSCs treatment. As indicated by immunofluorescence staining, alkaline phosphatase activity, and alizarin red staining, the osteogenic differentiation capacity of MSCs is significantly enhanced by Migs treatment, in line with the dosage. By RNA-sequence analysis, the enhancement of osteogenic differentiation is correlated with PI3K-AKT pathway activation that may originate from the M2 polarization state of donor cells. Finally, the Migs are coated onto Ti surface for therapeutic application. Both the in vitro and in vivo analysis reveal that the Migs coated Ti implant shows significant enhancement of osteogenesis. In conclusion, this study suggests that the nanosurface may be a favorable platform for Migs production, which may bring a new concept for tissue regeneration.

Human Mesenchymal Stem Cells Improve Angiogenesis and Bone Formation in Severed Finger Rats through SIRT1/Nrf2 Signaling.

This study employed a severed finger rat model to analyze the effects of human mesenchymal stem cells (MSCs) on angiogenesis, inflammatory response, apoptosis, and oxidative stress, to evaluate the possible mechanism of the repair effect of MSCs on severed finger (SF) rats. Sixty Sprague-Dawley (SD) rats were categorized into five groups (n = 12). The pathological changes of severed finger tissues were investigated by Hematoxylin and eosin (H&E) staining on day 14 after the rats were sacrificed. The levels of inflammatory factors and oxidative stress factors were detected by ELISA. Terminal Deoxynucleotidyl Transferase (TdT) dUTP Nick End Labeling (TUNEL) was employed to assess the apoptosis of chondrocytes in severed finger tissues. The expression of osteocalcin (OCN), osteopontin (OPN), Collagen I (Col-1), and CD31 were detected by immunohistochemistry or immunofluorescence assay, respectively. The expression levels of related proteins were determined by western blot. Our study presented evidence that MSCs treatment improved pathological changes of skin and bone tissue, diminished the inflammatory response, prevented oxidative stress injury, suppressed chondrocyte apoptosis, and promoted angiogenesis, and bone formation compared to the model group. In addition, EX527 treatment attenuated the effect of MSCs, SRT1720 and ML385 co-treatment also attenuated the effect of MSCs. Importantly, the MSCs treatment increased the expression of Sirtuin 1(SIRT1)/Nuclear factor erythroid2-related factor 2(Nrf2) relate proteins. Our study indicated that the mechanism of the effect of MSCs on a severed finger was related to the SIRT1/ Nrf2 signaling pathway.

Mesenchymal stem cell-derived exosomes promote tissue repair injury in rats with liver trauma by regulating gut microbiota and metabolism

ObjectiveThe effects of mesenchymal stem cells (MSCs) and MSC-derived exosomes (MSC-exos) on serum metabolites and intestinal microbiota in rats after liver trauma were discussed. MethodsAdult Wistar Albino rats were assigned into control, model (liver trauma), MSCs, and MSC-exos groups (n = 6). The study examined changes in the inflammatory environment in liver tissues were analyzed by histological examination and analysis of macrophage phenotypes. Alterations in serum metabolites were determined by untargeted metabonomics, and gut microbiota composition was characterized by 16S rDNA sequencing. Correlations between specific gut microbiota, metabolites, and inflammatory response were calculated using Spearman correlation analysis. ResultsRats with liver trauma after MSCs and MSC-exos treatment exhibited attenuated inflammatory infiltration and necrosis in liver tissues. MSCs and MSC-exos treatment reduced the proportion of M1 macrophages, accompanied by a decrease in inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-α) levels. Furthermore, MSCs and MSC-exos treatment expanded the proportion of M2 macrophages, accompanied by an increase in arginase-1 (Arg-1) and interleukin-10 (IL-10) levels. The beneficial effects of MSC-exo treatment on rats with liver trauma were superior to those of MSC treatment. The composition and abundance of the gut microbiota and metabolites were altered in pathological rats, whereas MSC and MSC-exo intervention partially restored specific gut microbiota and metabolite alterations. At the phylum level, alterations in Bacteroidota, Proteobacteria, and Verrucomicrobiota were observed after MSC and MSC-exo intervention. At the genus level, Intestinimonas, Alistipes, Aerococcus, Faecalibaculum, and Lachnospiraceae_ND3007_group were the main differential microbiota. 6-Methylnicotinamide, N-Methylnicotinamide, Glutathione, oxidized, ISOBUTYRATE, ASCORBATE, EICOSAPENTAENOATE, GLYCEROL 3-PHOSPHATE, and Ascorbate radical were selected as important differential metabolites. There was a clear correlation between Ascorbate, Intestinimonas/Faecalibaculum and inflammatory cytokines. ConclusionMSC-exos promoted the repair of tissue damage in rats with liver trauma by regulating serum metabolites and intestinal microbiota, providing new insights into how MSC-exos reduced inflammation in rats with liver trauma.

Bone marrow-derived mesenchymal stem cells mitigate chronic colitis and enteric neuropathy via anti-inflammatory and anti-oxidative mechanisms

Current treatments for inflammatory bowel disease (IBD) are often inadequate due to limited efficacy and toxicity, leading to surgical resection in refractory cases. IBD’s broad and complex pathogenesis involving the immune system, enteric nervous system, microbiome, and oxidative stress requires more effective therapeutic strategies. In this study, we investigated the therapeutic potential of bone marrow-derived mesenchymal stem cell (BM-MSC) treatments in spontaneous chronic colitis using the Winnie mouse model which closely replicates the presentation and inflammatory profile of ulcerative colitis. The 14-day BM-MSC treatment regimen reduced the severity of colitis, leading to the attenuation of diarrheal symptoms and recovery in body mass. Morphological and histological abnormalities in the colon were also alleviated. Transcriptomic analysis demonstrated that BM-MSC treatment led to alterations in gene expression profiles primarily downregulating genes related to inflammation, including pro-inflammatory cytokines, chemokines and other biomarkers of inflammation. Further evaluation of immune cell populations using immunohistochemistry revealed a reduction in leukocyte infiltration upon BM-MSC treatment. Notably, enteric neuronal gene signatures were the most impacted by BM-MSC treatment, which correlated with the restoration of neuronal density in the myenteric ganglia. Moreover, BM-MSCs exhibited neuroprotective effects against oxidative stress-induced neuronal loss through antioxidant mechanisms, including the reduction of mitochondrial-derived superoxide and attenuation of oxidative stress-induced HMGB1 translocation, potentially relying on MSC-derived SOD1. These findings suggest that BM-MSCs hold promise as a therapeutic intervention to mitigate chronic colitis by exerting anti-inflammatory effects and protecting the enteric nervous system from oxidative stress-induced damage.

Human adipose tissue-derived stem cell extracellular vesicles attenuate ocular hypertension-induced retinal ganglion cell damage by inhibiting microglia- TLR4/MAPK/NF-κB proinflammatory cascade signaling

Microglia-mediated neuroinflammatory responses are recognized as a predominant factor during high intraocular pressure (IOP)-induced retinal and optic nerve injury along with potential therapeutic targets for the disease. Our previous research indicated that mesenchymal stem cell (MSC) treatment could reduce high IOP-induced neuroinflammatory responses through the TLR4 pathway in a rat model without apparent cell replacement and differentiation, suggesting that the anti-neuroinflammatory properties of MSCs are potentially mediated by paracrine signaling. This study aimed to evaluate the anti-neuroinflammatory effect of human adipose tissue-derived extracellular vesicles (ADSC-EVs) in microbead-induced ocular hypertension (OHT) animals and to explore the underlying mechanism since extracellular vesicles (EVs) are the primary transporters for cell secretory action. The anti-neuroinflammatory effect of ADSC-EVs on LPS-stimulated BV-2 cells in vitro and OHT-induced retinal and optic nerve injury in vivo was investigated. According to the in vitro research, ADSC-EV treatment reduced LPS-induced microglial activation and the TLR4/NF-κB proinflammatory cascade response axis in BV-2 cells, such as CD68, iNOS, TNF-α, IL-6, and IL-1β, TLR4, p-38 MAPK, NF-κB. According to the in vivo data, intravitreal injection of ADSC-EVs promoted RGC survival and function, reduced microglial activation, microglial-derived neuroinflammatory responses, and TLR4/MAPK/NF-κB proinflammatory cascade response axis in the OHT mice. Our findings provide preliminary evidence for the RGC protective and microglia-associated neuroinflammatory reduction effects of ADSC-EVs by inhibiting the TLR4/MAPK/NF-κB proinflammatory cascade response in OHT mice, indicating the therapeutic potential ADSC-EVs or adjunctive therapy for glaucoma.

Bone Marrow Nucleated Cells and Bone Marrow-Derived CD271+ Mesenchymal Stem Cell in Treatment of Encephalopathy and Drug-Resistant Epilepsy.

The broad spectrum of brain injuries in preterm newborns and the plasticity of the central nervous system prompts us to seek solutions for neurodegeneration to prevent the consequences of prematurity and perinatal problems. The study aimed to evaluate the safety and efficacy of the implantation of autologous bone marrow nucleated cells and bone marrow mesenchymal stem cells in different schemes in patients with hypoxic-ischemic encephalopathy and immunological encephalopathy. Fourteen patients received single implantation of bone marrow nucleated cells administered intrathecally and intravenously, followed by multiple rounds of bone marrow mesenchymal stem cells implanted intrathecally, and five patients were treated only with repeated rounds of bone marrow mesenchymal stem cells. Seizure outcomes improved in most cases, including fewer seizures and status epilepticus and reduced doses of antiepileptic drugs compared to the period before treatment. The neuropsychological improvement was more frequent in patients with hypoxic-ischemic encephalopathy than in the immunological encephalopathy group. Changes in emotional functioning occurred with similar frequency in both groups of patients. In the hypoxic-ischemic encephalopathy group, motor improvement was observed in all patients and the majority in the immunological encephalopathy group. The treatment had manageable toxicity, mainly mild to moderate early-onset adverse events. The treatment was generally safe in the 4-year follow-up period, and the effects of the therapy were maintained after its termination.

Recent progress in mesenchymal stem cell-based therapy for acute lung injury.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening diseases in critically ill patients. Although pathophysiology of ALI/ARDS has been investigated in many studies, effective therapeutic strategies are still limited. Mesenchymal stem cell (MSC)-based therapy is emerging as a promising therapeutic intervention for patients with ALI. During the last two decades, researchers have focused on the efficacy and mechanism of MSC application in ALI animal models. MSC derived from variant resources exhibited therapeutic effects in preclinical studies of ALI with different mechanisms. Based on this, clinical studies on MSC treatment in ALI/ARDS has been tried recently, especially in COVID-19 caused lung injury. Emerging clinical trials of MSCs in treating COVID-19-related conditions have been registered in past two years. The advantages and potential of MSCs in the defense against COVID-19-related ALI or ARDS have been confirmed. This review provides a brief overview of recent research progress in MSC-based therapies in preclinical study and clinical trials in ALI treatment, as well as the underlying mechanisms.

MSCs alleviate LPS-induced acute lung injury by inhibiting the proinflammatory function of macrophages in mouse lung organoid–macrophage model

Acute lung injury (ALI) is an inflammatory disease associated with alveolar injury, subsequent macrophage activation, inflammatory cell infiltration, and cytokine production. Mesenchymal stem cells (MSCs) are beneficial for application in the treatment of inflammatory diseases due to their immunomodulatory effects. However, the mechanisms of regulatory effects by MSCs on macrophages in ALI need more in-depth study. Lung tissues were collected from mice for mouse lung organoid construction. Alveolar macrophages (AMs) derived from bronchoalveolar lavage and interstitial macrophages (IMs) derived from lung tissue were co-cultured, with novel matrigel-spreading lung organoids to construct an in vitro model of lung organoids–immune cells. Mouse compact bone-derived MSCs were co-cultured with organoids–macrophages to confirm their therapeutic effect on acute lung injury. Changes in transcriptome expression profile were analyzed by RNA sequencing. Well-established lung organoids expressed various lung cell type-specific markers. Lung organoids grown on spreading matrigel had the property of functional cells growing outside the lumen. Lipopolysaccharide (LPS)-induced injury promoted macrophage chemotaxis toward lung organoids and enhanced the expression of inflammation-associated genes in inflammation-injured lung organoids–macrophages compared with controls. Treatment with MSCs inhibited the injury progress and reduced the levels of inflammatory components. Furthermore, through the nuclear factor-κB pathway, MSC treatment inhibited inflammatory and phenotypic transformation of AMs and modulated the antigen-presenting function of IMs, thereby affecting the inflammatory phenotype of lung organoids. Lung organoids grown by spreading matrigel facilitate the reception of external stimuli and the construction of in vitro models containing immune cells, which is a potential novel model for disease research. MSCs exert protective effects against lung injury by regulating different functions of AMs and IMs in the lung, indicating a potential mechanism for therapeutic intervention.

The therapeutic effect of mesenchymal stem cells in diabetic kidney disease

Diabetes mellitus (DM) often causes chronic kidney damage despite best medical practices. Diabetic kidney disease (DKD) arises from a complex interaction of factors within the kidney and the whole body. Targeting specific disease-causing agents using drugs has not been effective in treating DKD. However, stem cell therapies offer a promising alternative by addressing multiple disease pathways and promoting kidney regeneration. Mesenchymal stem cells (MSCs) offer great promise due to their superior accessibility ratio from adult tissues and remarkable modes of action, such as the production of paracrine anti-inflammatory and cytoprotective substances. This review critically evaluates the development of MSC treatment for DKD as it moves closer to clinical application. Results from animal models suggest that systemic MSC infusion may positively impact DKD progression. However, few registered and completed clinical trials exist, and whether the treatments are effective in humans is still being determined. Significant knowledge gaps and research opportunities exist, including establishing the ideal source, dose, and timing of MSC delivery, better understanding of in vivo mechanisms, and developing quantitative indicators to obtain a more significant therapeutic response. This paper reviews recent literature on using MSCs in preclinical and clinical trials in DKD. Potent biomarkers related to DKD are also highlighted, which may help better understand MSCs’ action in this disease progression.Key messagesMesenchymal stem cells have anti-inflammatory and paracrine effects in diabetic kidney disease.Mesenchymal stem cells alleviate in animal models having diabetic kidney disease.Mesenchymal stem cells possess promise for the treatment of diabetic kidney disease.

Priming and Combined Strategies for the Application of Mesenchymal Stem Cells in Ischemic Stroke: A Promising Approach.

Ischemic stroke (IS) is a leading cause of death and disability worldwide. Tissue plasminogen activator (tPA) administration and mechanical thrombectomy are the main treatments but have a narrow time window. Mesenchymal stem cells (MSCs), which are easily scalable in vitro and lack ethical concerns, possess the potential to differentiate into various types of cells and secrete a great number of growth factors for neuroprotection and regeneration. Moreover, MSCs have low immunogenicity and tumorigenic properties, showing safety and preliminary efficacy both in preclinical studies and clinical trials of IS. However, it is unlikely that MSC treatment alone will be sufficient to maximize recovery due to the low survival rate of transplanted cells and various mechanisms of ischemic brain damage in the different stages of IS. Preconditioning was used to facilitate the homing, survival, and secretion ability of the grafted MSCs in the ischemic region, while combination therapies are alternatives that can maximize the treatment effects, focusing on multiple therapeutic targets to promote stroke recovery. In this case, the combination therapy can yield a synergistic effect. In this review, we summarize the type of MSCs, preconditioning methods, and combined strategies as well as their therapeutic mechanism in the treatment of IS to accelerate the transformation from basic research to clinical application.

Evaluation of the healing and protective properties of adipose-derived mesenchymal stem cells from cisplatin-induced liver and kidney damage.

The occurrence of nephrotoxicity and hepatotoxicity as a result of cisplatin administration is a major concern in clinical practice. This study examined the potential protective effects of administering mesenchymal stem cells (MSCs) on the renal and hepatic damage caused by cisplatin. Moreover, the study investigated the potential protective effects of administering Adipose-Derived Mesenchymal Stem Cells (ADMSC) to counteract the harmful effects of cisplatin-induced kidney and liver damage. Male Sprague-Dawley rats were divided into three groups: normal control, cisplatin + saline, and cisplatin + ADMSC. Cisplatin was administered to induce toxicity, and ADMSC was administered intravenously as a potential therapeutic intervention. Biochemical parameters and histopathological changes were assessed in the kidney and liver tissues. Statistical analyses were performed using a one-way ANOVA. Cisplatin increased malondialdehyde (MDA), tumor necrosis factor alfa (TNF-alfa), IL-6, alanine transaminase (ALT), creatinine, Galectin-3, Tissue growth factor beta 1 (TGF-beta 1), compared to the normal control group. Cisplatin-MSC reduced these levels. Histopathology showed that cisplatin caused kidney tubular epithelial necrosis, luminal necrotic debris, tubular dilatation, interstitial inflammation, liver sinusoidal and central vein dilatation, congestion, necrosis, and cytoplasmic vacuolization. ADMSC administration significantly reduced histopathological changes. These findings highlight the potential therapeutic benefits of mesenchymal stem cell (MSC) administration in mitigating cisplatin-induced nephrotoxicity and hepatotoxicity. MSC treatment demonstrated protective effects by reducing oxidative stress, inflammatory markers, and histopathological alterations. Further investigations are warranted to elucidate the precise mechanisms underlying these protective effects and evaluate their clinical implications for managing cisplatin-induced organ damage.