Mesenteric lymph nodes: a critical site for the up-regulatory effect of hUC-MSCs on Treg cells by producing TGF-ß1 in colitis treatment.

BACKGROUND: Mesenchymal stem cells (MSCs) demonstrate a wide range of therapeutic capabilities in the treatment of inflammatory bowel disease (IBD). The intraperitoneal injection of MSCs has exhibited superior therapeutic efficacy on IBD than intravenous injection. Nevertheless, the precise in vivo distribution of MSCs and their biological consequences following intraperitoneal injection remain inadequately understood. Additional studies are required to explore the correlation between MSCs distribution and their biological effects. METHODS: First, the distribution of human umbilical cord MSCs (hUC-MSCs) and the numbers of Treg and Th17 cells in mesenteric lymph nodes (MLNs) were analyzed after intraperitoneal injection of hUC-MSCs. Subsequently, the investigation focused on the levels of transforming growth factor beta1 (TGF-ß1), a key cytokine to the biology of both Treg and Th17 cells, in tissues of mice with colitis, particularly in MLNs. The study also delved into the impact of hUC-MSCs therapy on Treg cell counts in MLNs, as well as the consequence of TGFB1 knockdown hUC-MSCs on the differentiation of Treg cells and the treatment of IBD. RESULTS: The therapeutic effectiveness of intraperitoneally administered hUC-MSCs in the treatment of colitis was found to be significant, which was closely related to their quick migration to MLNs and secretion of TGF-ß1. The abundance of hUC-MSCs in MLNs of colitis mice is much higher than that in other organs even the inflamed sites of colon. Intraperitoneal injection of hUC-MSCs led to a significant increase in the number of Treg cells and a decrease in Th17 cells especially in MLNs. Furthermore, the concentration of TGF-ß1, the key cytokine for Treg differentiation, were also found to be significantly elevated in MLNs after hUC-MSCs treatment. Knockdown of TGFB1 in hUC-MSCs resulted in a noticeable reduction of Treg cells in MLNs and the eventually failure of hUC-MSCs therapy in colitis. CONCLUSIONS: MLNs may be a critical site for the regulatory effect of hUC-MSCs on Treg/Th17 cells and the therapeutic effect on colitis. TGF-ß1 derived from hUC-MSCs promotes local Treg differentiation in MLNs. This study will provide new ideas for the development of MSC-based therapeutic strategies in IBD patients.

Autophagy modulation effect on homotypic transfer of intracellular components via tunneling nanotubes in mesenchymal stem cells.

BACKGROUND: Recent studies have proved the role of autophagy in mesenchymal stem cell (MSCs) function and regenerative properties. How and by which mechanism autophagy modulation can affect the juxtacrine interaction of MSCs should be addressed. Here, the role of autophagy was investigated in the formation of tunneling nanotubes (TNTs) and homotypic mitochondrial donation. METHODS: MSCs were incubated with 15 µM Metformin (Met) and/or 3 µM 3-methyladenine (3-MA) for 48 h. The formation of TNTs was assessed using bright-field and SEM images. The mitochondria density and ΔΨ values were monitored using flow cytometry analysis. Using RT-PCR and protein array, the close interaction and shared mediators between autophagy, apoptosis, and Wnt signaling pathways were also monitored. The total fatty acid profile was assessed using gas chromatography. RESULT: Data indicated the increase of TNT length and number, along with other cell projections after the induction of autophagy while these features were blunted in 3-MA-treated MSCs (p < 0.05). Western blotting revealed the significant reduction of Rab8 and p-FAK in 3-MA-treated MSCs (p < 0.05), indicating the inhibition of TNT assembly and vesicle transport. Likewise, the stimulation of autophagy increased autophagic flux and mitochondrial membrane integrity compared to 3-MA-treated MSCs. Despite these findings, protein levels of mitochondrial membrane Miro1 and 2 were unchanged after autophagy inhibition/stimulation (p > 0.05). We found that the inhibition/stimulation of autophagy can affect the protein, and transcription levels of several mediators related to Wnt and apoptosis signaling pathways involved in different cell bioactivities. Data confirmed the profound increase of mono and polyunsaturated/saturated fatty acid ratio in MSCs exposed to autophagy stimulator. CONCLUSIONS: In summary, autophagy modulation could affect TNT formation which is required for homotypic mitochondrial donation. Thus, the modulation of autophagy creates a promising perspective to increase the efficiency of cell-based therapies.

Research progress and prospects of benefit-risk assessment methods for umbilical cord mesenchymal stem cell transplantation in the clinical treatment of spinal cord injury.

Over the past decade, we have witnessed the development of cell transplantation as a new strategy for repairing spinal cord injury (SCI). However, due to the complexity of the central nervous system (CNS), achieving successful clinical translation remains a significant challenge. Human umbilical cord mesenchymal stem cells (hUMSCs) possess distinct advantages, such as easy collection, lack of ethical concerns, high self-renewal ability, multilineage differentiation potential, and immunomodulatory properties. hUMSCs are promising for regenerating the injured spinal cord to a significant extent. At the same time, for advancing SCI treatment, the appropriate benefit and risk evaluation methods play a pivotal role in determining the clinical applicability of treatment plans. Hence, this study discusses the advantages and risks of hUMSCs in SCI treatment across four dimensions-comprehensive evaluation of motor and sensory function, imaging, electrophysiology, and autonomic nervous system (ANS) function-aiming to improve the rationality of relevant clinical research and the feasibility of clinical translation.

SPARC overexpression in allogeneic adipose-derived mesenchymal stem cells in dog dry eye model induced by benzalkonium chloride.

BACKGROUND: Nowadays, companion and working dogs hold significant social and economic importance. Dry eye, also known as dry keratoconjunctivitis (KCS), a common disease in ophthalmology, can readily impact a dog's working capacity and lead to economic losses. Although there are several medications available for this disease, all of them only improve the symptoms on the surface of the eye, and they are irritating and not easy to use for long periods of time. Adipose-derived mesenchymal stem cells (ADMSC) are promising candidates for tissue regeneration and disease treatment. However, long-term in vitro passaging leads to stemness loss of ADMSC. Here, we aimed to use ADMSC overexpressing Secreted Protein Acidic and Rich in Cysteine (SPARC) to treat 0.25% benzalkonium chloride-treated dogs with dry eye to verify its efficacy. For in vitro validation, we induced corneal epithelial cell (HCECs) damage using 1 µg/mL benzalkonium chloride. METHODS: Fifteen male crossbred dogs were randomly divided into five groups: normal, dry eye self-healing control, cyclosporine-treated, ADMSC-CMV-treated and ADMSC-OESPARC-treated. HCECs were divided into four groups: normal control group, untreated model group, ADMSC-CMV supernatant culture group and ADMSC-OESRARC supernatant culture group. RESULTS: SPARC-modified ADMSC had the most significant effect on canine ocular surface inflammation, corneal injury, and tear recovery, and the addition of ADMSC-OESPARC cell supernatant also had a salvage effect on HCECs cellular damage, such as cell viability and cell proliferation ability. Moreover, analysis of the co-transcriptome sequencing data showed that SPARC could promote corneal epithelial cell repair by enhancing the in vitro viability, migration and proliferation and immunosuppression of ADMSC. CONCLUSION: The in vitro cell test and in vivo model totally suggest that the combination of SPARC and ADMSC has a promising future in novel dry eye therapy.

Understanding molecular characteristics of extracellular vesicles derived from different types of mesenchymal stem cells for therapeutic translation.

Mesenchymal stem cells (MSCs) have been studied for decades as candidates for cellular therapy, and their secretome, including secreted extracellular vesicles (EVs), has been identified to contribute significantly to regenerative and reparative functions. Emerging evidence has suggested that MSC-EVs alone, could be used as therapeutics that emulate the biological function of MSCs. However, just as with MSCs, MSC-EVs have been shown to vary in composition, depending on the tissue source of the MSCs as well as the protocols employed in culturing the MSCs and obtaining the EVs. Therefore, the importance of careful choice of cell sources and culture environments is receiving increasing attention. Many factors contribute to the therapeutic potential of MSC-EVs, including the source tissue, isolation technique, and culturing conditions. This review illustrates the molecular landscape of EVs derived from different types of MSC cells along with culture strategies. A thorough analysis of publicly available omic datasets was performed to advance the precision understanding of MSC-EVs with unique tissue source-dependent molecular characteristics. The tissue-specific protein and miRNA-driven Reactome ontology analysis was used to reveal distinct patterns of top Reactome ontology pathways across adipose, bone marrow, and umbilical MSC-EVs. Moreover, a meta-analysis assisted by an AI technique was used to analyze the published literature, providing insights into the therapeutic translation of MSC-EVs based on their source tissues.

Improved Preservation of Rat Small Intestine Transplantation Graft by Introduction of Mesenchymal Stem Cell-Secreted Fractions.

Segmental grafts from living donors have advantages over grafts from deceased donors when used for small intestine transplantation. However, storage time for small intestine grafts can be extremely short and optimal graft preservation conditions for short-term storage remain undetermined. Secreted factors from mesenchymal stem cells (MSCs) that allow direct activation of preserved small intestine grafts. Freshly excised Luc-Tg LEW rat tissues were incubated in preservation solutions containing MSC-conditioned medium (MSC-CM). Preserved Luc-Tg rat-derived grafts were then transplanted to wild-type recipients, after which survival, injury score, and tight junction protein expression were examined. Luminance for each graft was determined using in vivo imaging. The findings indicated that 30-100 and 3-10 kDa fractions of MSC-CM have superior activating effects for small intestine preservation. Expression of the tight-junction proteins claudin-3, and zonula occludens-1 preserved for 24 h in University of Wisconsin (UW) solution containing MSC-CM with 50-100 kDa, as shown by immunostaining, also indicated effectiveness. Reflecting the improved graft preservation, MSC-CM preloading of grafts increased survival rate from 0% to 87%. This is the first report of successful transplantation of small intestine grafts preserved for more than 24 h using a rodent model to evaluate graft preservation conditions that mimic clinical conditions.

Biomimetic Metal-Organic Framework Gated Nanoplatform for Sonodynamic Therapy against Extensively Drug Resistant Bacterial Lung Infection.

Novel antimicrobial strategies are urgently needed to treat extensively drug-resistant (XDR) bacterial infections due to the high mortality rate and lack of effective therapeutic agents. Herein, nanoengineered human umbilical cord mesenchymal stem cells (hUC-MSCs), named PMZMU, are designed as a sonosensitizer for synergistic sonodynamic-nano-antimicrobial therapy against gram-negative XDR bacteria. PMZMU is composed of a bacterial targeting peptide (UBI29-41) modified hUC-MSCs membrane (MSCm), a sonosensitizer meso-tetra(4-car-boxyphenyl) porphine doped mesoporous organo-silica nanoparticle and an acidity-responsive metal-organic framework ZIF-8. This innovative formulation enables efficient loading of polymyxin B, reduces off-target drug release, increases circulation and targeting efficacy, and generates reactive oxygen species upon ultrasound irradiation. PMZMU exhibits remarkable in vitro inhibitory activity against four XDR bacteria: Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa (PA), and Escherichia coli. Taking advantage of the bacterial targeting ability of UBI29-41 and the inflammatory chemotaxis of hUC-MSC, PMZMU can be precisely delivered to lung infection sites thereby augmenting polymyxin B concentration. PMZMU-mediated sonodynamic therapy significantly reduces bacterial burden, relieves inflammatory damage by promoting the polarization of macrophages toward M2 phenotype, and improves survival rates without introducing adverse events. Overall, this study offers promising strategies for treating deep-tissue XDR bacterial infections, and guides the design and optimization of biomimetic nanomedicine.

Lovastatin Combination Therapy Increases the Survival and Proliferation of Rat Bone Marrow-Derived Mesenchymal Stem Cells Against the Inflammatory Activity of Lipopolysaccharide.

Oxidative stress hurts the survival of transplanted mesenchymal stem cells (MSCs). Lipopolysaccharide (LPS) preconditioning inhibits apoptotic death in MSCs. Also, Lovastatin's protective effect was reported on MSCs. Here, we investigated the potential of LPS and Lovastatin combination therapy on the survival and proliferation of MSCs. MSCs harvested from adult rats (240-260 g) femur and tibia bone marrow. Third passage MSCs were divided into 6 groups control group, LPS, LPS + Lovastatin (10 and 15 µM), and Lovastatin (10 and 15 µM). Cell survival and proliferation were assessed using an MTT assay 24 h after LPS, Lovastatin, or LPS + Lovastatin treatment. Also, Malondialdehyde (MDA) as a lipid peroxidation marker and antioxidant enzymes such as Glutathione peroxidase (GPX) and Superoxide dismutase (SOD) activity levels evaluated. Finally, the expression level of tumor protein P53 (P53) and octamer-binding transcription factor 4 (OCT4) genes were measured by qRT-PCR test. Lovastatin 10 µM potentiated proliferation and survival of MSCs. It can increase the activity of GPX and SOD. 10 µM Lovastatin could not affect MDA amounts but decreased the expression levels of P53 and Oct4 significantly. Nevertheless, treatment with LPS reduced the survival and proliferation of MSCs, along with a significant reduction in GPX activity. LPS + Lovastatin could increase SOD activity, however, GPX enzyme activity and MSCs proliferation did not change so, and it was not effective. We propose Lovastatin at the dose of 10 µM as a suitable combination agent to increase the survival and proliferation of MSCs in oxidative stress conditions.

Combined effect of naringin and adipose tissue-derived mesenchymal stem cell on cisplatin nephrotoxicity through Sirtuin1/Nrf-2/HO-1 signaling pathway: a promising nephroprotective candidate.

Cisplatin nephrotoxicity is a well-known emergency clinical condition caused by oxidative stress and inflammation. Naringin (NAR) is considered an antioxidant agent with renoprotective effects capable of removing reactive oxygen species. Adipose tissue-derived mesenchymal stem cells (AD-MSCs) are reported to have anti-inflammatory and antioxidant properties. The present research examined the renoprotective effect of the combination of NAR and AD-MSCs as opposed to each one alone on cisplatin-induced nephrotoxicity through SIRT-1/Nrf-2/HO-1 pathway. This study included five groups (n = 8 each) of male Sprague-Dawley rats (200 - 220 g): sham, cisplatin: rats receiving cisplatin (6.5 mg/kg, i.p.) on the 4th day; NAR+cisplatin: rats pretreated with NAR (1 week, i.p.) + cisplatin on the 4th day; AD-MSCs: rats receiving AD-MSCs (1 × 106) by injection through the tail vein on the 5th day + cisplatin on the 4th day; and NAR+AD-MSCs+cisplatin. On the 8th day, the animals were anesthetized to obtain tissue and blood samples. Biochemical factors, inflammation, oxidative stress, and gene expression were explored. Cisplatin increased blood urea nitrogen, creatinine, inflammation, and oxidative stress. Moreover, mRNA expression of Sirtuin1, nuclear factor erythroid 2-related factor 2 (Nrf-2), and heme oxygenase-1 (HO-1) remarkably reduced. Furthermore, cisplatin led to a disturbance in kidney structure (glomerular atrophy, cell infiltrations, and tubular dysfunction) as confirmed by histology findings. However, NAR pretreatment, AD-MSC administration, or a combination of both significantly reversed these changes. Overall, when used together, NAR and AD-MSCs had stronger cisplatin-induced effects on kidney dysfunction by inhibiting inflammation, reducing oxidative stress, and increasing the Sirtuin1/Nrf-2/HO-1 pathway.

The Effect of Exercise on Mesenchymal Stem Cells and their Application in Obesity Treatment.

Mesenchymal stem cells (MSCs) have demonstrated considerable potential in tissue repair and the treatment of immune-related diseases, but there are problems with homing efficiency during MSCs transplantation. Exercise, as an intervention, has been shown to have an important impact on the properties of MSCs. This review summarizes the effects of exercise on the properties (including proliferation, apoptosis, differentiation, and homing) of bone marrow-derived MSCs and adipose-derived MSCs. Studies indicated that exercise enhances bone marrow-derived MSCs proliferation, osteogenic differentiation, and homing while reducing adipogenic differentiation. For adipose-derived MSCs, exercise enhances proliferation and reduces adipogenic differentiation. In addition, studies have investigated the therapeutic effects of combined therapy of MSCs transplantation with exercise on diseases of the bone, cardiac, and nervous systems. The combined therapy improves tissue repair by increasing the homing of transplanted MSCs and cytokine secretion (such as neurotrophin 4). Furthermore, MSCs transplantation also has potential for the treatment of obesity. Although the effect is not significant in weight loss, MSCs transplantation shows effects in controlling blood glucose, improving dyslipidemia, reducing inflammation, and improving liver disease. Finally, the potential role of combined MSCs transplantation and exercise therapy in addressing obesity is discussed.

Compact bone mesenchymal stem cells-derived paracrine mediators for cell-free therapy in sepsis.

Sepsis, a life-threatening condition resulting in multiple organ dysfunction, is characterized by a dysregulated immune response to infection. Current treatment options are limited, leading to unsatisfactory outcomes for septic patients. Here, we present a series of studies utilizing compact bone mesenchymal stem cells (CB-MSCs) and their derived paracrine mediators, especially exosome (CB-MSCs-Exo), to treat mice with cecal ligation and puncture-induced sepsis. Our results demonstrate that CB-MSCs treatment significantly improves the survival rate of septic mice by mitigating excessive inflammatory response and attenuating sepsis-induced organ injuries. Furthermore, CB-MSCs-conditioned medium, CB-MSCs secretome (CB-MSCs-Sec), and CB-MSCs-Exo exhibit potent anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated murine macrophage (RAW264.7). Intriguingly, intravenous administration of CB-MSCs-Exo confers superior protection against inflammation and organ damage in septic mice compared to CB-MSCs in certain aspects. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS) shotgun proteomic analysis, we identify a range of characterized proteins derived from the paracrine activity of CB-MSCs, involved in critical biological processes such as immunomodulation and apoptosis. Our findings highlight that the paracrine products of CB-MSCs could serve as a promising cell-free therapeutic agent for sepsis.

Mesenchymal Stem Cells Alleviate Acute Liver Failure through Regulating Hepatocyte Apoptosis and Macrophage Polarization.

Background and Aims: Acute liver failure (ALF) is a life-threatening clinical problem with limited treatment options. Administration of human umbilical cord mesenchymal stem cells (hUC-MSCs) may be a promising approach for ALF. This study aimed to explore the role of hUC-MSCs in the treatment of ALF and the underlying mechanisms. Methods: A mouse model of ALF was induced by lipopolysaccharide and d-galactosamine administration. The therapeutic effects of hUC-MSCs were evaluated by assessing serum enzyme activity, histological appearance, and cell apoptosis in liver tissues. The apoptosis rate was analyzed in AML12 cells. The levels of inflammatory cytokines and the phenotype of RAW264.7 cells co-cultured with hUC-MSCs were detected. The C-Jun N-terminal kinase/nuclear factor-kappa B signaling pathway was studied. Results: The hUC-MSCs treatment decreased the levels of serum alanine aminotransferase and aspartate aminotransferase, reduced pathological damage, alleviated hepatocyte apoptosis, and reduced mortality in vivo. The hUC-MSCs co-culture reduced the apoptosis rate of AML12 cells in vitro. Moreover, lipopolysaccharide-stimulated RAW264.7 cells had higher levels of tumor necrosis factor-α, interleukin-6, and interleukin-1ß and showed more CD86-positive cells, whereas the hUC-MSCs co-culture reduced the levels of the three inflammatory cytokines and increased the ratio of CD206-positive cells. The hUC-MSCs treatment inhibited the activation of phosphorylated (p)-C-Jun N-terminal kinase and p-nuclear factor-kappa B not only in liver tissues but also in AML12 and RAW264.7 cells co-cultured with hUC-MSCs. Conclusions: hUC-MSCs could alleviate ALF by regulating hepatocyte apoptosis and macrophage polarization, thus hUC-MSC-based cell therapy may be an alternative option for patients with ALF.

Black phosphorus quantum dot-modified ADSCs as a novel therapeutic for periodontitis bone loss coupling of osteogenesis and osteoimmunomodulation.

Alveolar bone defect repair remains a persistent clinical challenge for periodontitis treatment. The use of peripheral functional seed cells is a hot topic in periodontitis. Herein, we explored the cellular behaviors and osteogenic ability of adipose-derived mesenchymal stem cells (ADSCs) treated with black phosphorus quantum dots (BPQDs). Additionally, macrophage polarization, osteogenic effects and angiogenesis were investigated through the paracrine pathway regulated by BPQD-modified ADSCs. Our results demonstrated that BPQDs showed good biocompatibility with ADSCs and BPQD-modified ADSCs could improve the bone repair in vivo inflammatory microenvironment by regulating osteogenesis and osteoimmunomodulation. The BPQDs increased the osteogenic differentiation of ADSCs via the Wnt/ß-catenin and BMP2/SMAD5/Runx2 signaling pathway. In addition, BPQD-modified ADSCs promoted the osteogenic effect of BMSCs and facilitated the polarization of macrophages from M1 towards M2 phenotype transformation through the paracrine pathway in the periodontitis microenvironment. This strategy provides a novel idea for treatment of alveolar bone defects for periodontitis in the foreseeable future.

Mesenchymal stem cells and their derived exosomes in multiple sclerosis disease: from paper to practice.

Multiple sclerosis (MS) is a chronic neurodegenerative, inflammatory, and demyelinating disease of the central nervous system (CNS). Current medicines are not sufficient to control the inflammation and progressive damage to the CNS that is known in MS. These drawbacks highlight the need for novel treatment options. Cell therapy can now be used to treat complex diseases when conventional therapies are ineffective. Mesenchymal stem cells (MSCs) are a diverse group of multipotential non-hematopoietic stromal cells which have immunomodulatory, neurogenesis, and remyelinating capacity. Their advantageous effects mainly rely on paracrine, cell-cell communication and differentiation properties which introduced them as excellent candidates for MS therapy. Exosomes, as one of the MSCs secretomes, have unique properties that make them highly promising candidates for innovative approach in regenerative medicine. This review discusses the therapeutic potential of MSCs and their derived exosomes as a novel treatment for MS, highlighting the differences between these two approaches.

Preclinical Therapeutic Efficacy of Extracellular Vesicles Derived from Adipose-Derived Mesenchymal Stromal/Stem Cells in Diabetic Wounds: a Systematic Review and Meta-Analysis.

Extracellular vesicles isolated from adipose tissue-derived mesenchymal stromal/stem cells (ADSC-EVs) have demonstrated promising potential in wound healing treatment. To determine the therapeutic efficacy of ADSC-EVs for diabetic wounds in preclinical models, we performed a meta-analysis of available studies. PubMed and Embase were searched (to April 23, 2023). All full-text articles describing the therapeutic application of ADSC-EVs in diabetic wounds were included. Study outcomes were pooled using a random effects meta-analysis, including wound closure, angiogenesis, and collagen deposition. Other outcomes were only discussed descriptively. Seventy unique records were identified from our search; 20 full-text articles were included for qualitative analysis. Twelve studies were eligible for quantitative meta-analysis. The results showed that ADSC-EVs accelerated diabetic wound healing compared to controls with a large effect (standardized mean difference (SMD) 4.22, 95% confidence interval (CI) 3.07 to 5.36). The administration of ADSC-EVs also improved neovascularization (SMD 9.27, 95% CI 4.70 to 13.83) and collagen deposition (SMD 2.19, 95% CI 0.94 to 3.44), with a large effect. The risk of bias was unclear in all included studies. Conclusively, ADSC-EV is an effective treatment for diabetic wounds in preclinical trials, and it appears justified for transfer into the clinical field.

Efficacy and safety of culture-expanded mesenchymal stromal cell therapy in the treatment of 4 types of inflammatory arthritis: A systematic review and meta-analysis of 36 randomized controlled trials.

OBJECTIVE: This study aims to assess the effectiveness and safety of mesenchymal stem cell (MSC) transplantation in the treatment of inflammatory arthritis. METHODS: Two researchers conducted a comprehensive search of Chinese and English databases from their inception until July 2023. The literature screening and data extraction were then performed. Statistical analysis was carried out using RevMan 5.4 software. RESULTS: A total of 36 relevant RCTs, involving 2,076 participants, were ultimately included in this study. These RCTs encompassed four types of inflammatory arthritis, namely rheumatoid arthritis (RA), osteoarthritis (OA), ankylosing spondylitis (AS), and systemic sclerosis (SSc). The results demonstrated that MSC therapy exhibited improvements in the Visual Analog Scale (VAS) for pain in OA patients (bone marrow: SMD=-0.95, 95 % CI: -1.55 to -0.36, P = 0.002; umbilical cord: SMD=-2.03, 95 % CI: -2.99 to -1.07, P < 0.0001; adipose tissue: SMD=-1.26, 95 % CI: -1.99 to -0.52, P = 0.0009). Specifically, MSCs sourced from adipose tissue showed enhancements in Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain (P = 0.0001), WOMAC physical function (P = 0.001), and total WOMAC scores (P = 0.0003). As for MSC therapy in RA, AS, and SSc, the current systematic review suggests a potential therapeutic effect of MSCs on these inflammatory arthritic conditions. Safety assessments indicated that MSC therapy did not increase the incidence of adverse events. CONCLUSION: MSCs have the potential to alleviate joint pain and improve joint function in patients with inflammatory arthritis. Moreover, MSC therapy appears to be relatively safe and could be considered as a viable alternative treatment option for inflammatory arthritis.

New advances of NG2-expressing cell subset in marrow mesenchymal stem cells as novel therapeutic tools for liver fibrosis/cirrhosis.

BACKGROUND: Bone marrow-derived mesenchymal stem cell (BMMSC)-based therapy has become a major focus for treating liver fibrosis/cirrhosis. However, although these cell therapies promote the treatment of this disease, the heterogeneity of BMMSCs, which causes insufficient efficacy during clinical trials, has not been addressed. In this study, we describe a novel Percoll-Plate-Wait procedure (PPWP) for the isolation of an active cell subset from BMMSC cultures that was characterized by the expression of neuroglial antigen 2 (NG2/BMMSCs). METHODS: By using the key method of PPWP and other classical biological techniques we compared NG2/BMMSCs with parental BMMSCs in biological and functional characteristics within a well-defined diethylnitrosamine (DEN)-induced liver fibrosis/cirrhosis injury male C57BL/6 mouse model also in a culture system. Of note, the pathological alterations in the model is quite similar to humans'. RESULTS: The NG2/BMMSCs revealed more advantages compared to parentalBMMSCs. They exhibited greater proliferation potential than parental BMMSCs, as indicated by Ki-67 immunofluorescence (IF) staining. Moreover, higher expression of SSEA-3 (a marker specific for embryonic stem cells) was detected in NG2/BMMSCs than in parental BMMSCs, which suggested that the "stemness" of NG2/BMMSCs was greater than that of parental BMMSCs. In vivo studies revealed that an injection of NG2/BMMSCs into mice with ongoing DEN-induced liver fibrotic/cirrhotic injury enhanced repair and functional recovery to a greater extent than in mice treated with parental BMMSCs. These effects were associated with the ability of NG2/BMMSCs to differentiate into bile duct cells (BDCs). In particular, we discovered for the first time that NG2/BMMSCs exhibit unique characteristics that differ from those of parental BMMSCs in terms of producing liver sinusoidal endothelial cells (LSECs) to reconstruct injured blood vessels and sinusoidal structures in the diseased livers, which are important for initiating hepatocyte regeneration. This unique potential may also suggest that NG2/BMMSCs could be an novel off-liver progenitor of LSECs. Ex vivo studies revealed that the NG2/BMMSCs exhibited a similar trend to that of their in vivo in terms of functional differentiation responding to the DEN-diseased injured liver cues. Additionally, the obvious core role of NG2/BMMSCs in supporting the functions of BMMSCs in bile duct repair and BDC-mediated hepatocyte regeneration might also be a novel finding. CONCLUSIONS: Overall, the PPWP-isolated NG2/BMMSCs could be a novel effective cell subset with increased purity to serve as a new therapeutic tool for enhancing treatment efficacy of BMMSCs and special seed cell source (BDCs, LSECs) also for bioliver engineering.

Comparative effectiveness of mesenchymal stem cell versus bone-marrow mononuclear cell transplantation in heart failure: a meta-analysis of randomized controlled trials.

BACKGROUND: There is no clear evidence on the comparative effectiveness of bone-marrow mononuclear cell (BMMNC) vs. mesenchymal stromal cell (MSC) stem cell therapy in patients with chronic heart failure (HF). METHODS: Using a systematic approach, eligible randomized controlled trials (RCTs) of stem cell therapy (BMMNCs or MSCs) in patients with HF were retrieved to perform a meta-analysis on clinical outcomes (major adverse cardiovascular events (MACE), hospitalization for HF, and mortality) and echocardiographic indices (including left ventricular ejection fraction (LVEF)) were performed using the random-effects model. A risk ratio (RR) or mean difference (MD) with corresponding 95% confidence interval (CI) were pooled based on the type of the outcome and subgroup analysis was performed to evaluate the potential differences between the types of cells. RESULTS: The analysis included a total of 36 RCTs (1549 HF patients receiving stem cells and 1252 patients in the control group). Transplantation of both types of cells in patients with HF resulted in a significant improvement in LVEF (BMMNCs: MD (95% CI) = 3.05 (1.11; 4.99) and MSCs: MD (95% CI) = 2.82 (1.19; 4.45), between-subgroup p = 0.86). Stem cell therapy did not lead to a significant change in the risk of MACE (MD (95% CI) = 0.83 (0.67; 1.06), BMMNCs: RR (95% CI) = 0.59 (0.31; 1.13) and MSCs: RR (95% CI) = 0.91 (0.70; 1.19), between-subgroup p = 0.12). There was a marginally decreased risk of all-cause death (MD (95% CI) = 0.82 (0.68; 0.99)) and rehospitalization (MD (95% CI) = 0.77 (0.61; 0.98)) with no difference among the cell types (p > 0.05). CONCLUSION: Both types of stem cells are effective in improving LVEF in patients with heart failure without any noticeable difference between the cells. Transplantation of the stem cells could not decrease the risk of major adverse cardiovascular events compared with controls. Future trials should primarily focus on the impact of stem cell transplantation on clinical outcomes of HF patients to verify or refute the findings of this study.

Investigation on the molecular mechanism of SPA interference with osteogenic differentiation of bone marrow mesenchymal stem cells.

Binding of Staphylococcus aureus protein A (SPA) to osteoblasts induces apoptosis and inhibits bone formation. Bone marrow-derived mesenchymal stem cells (BMSCs) have the ability to differentiate into bone, fat and cartilage. Therefore, it was important to analyze the molecular mechanism of SPA on osteogenic differentiation. We introduced transcript sequence data to screen out differentially expressed genes (DEGs) related to SPA-interfered BMSC. Protein-protein interaction (PPI) network of DEGs was established to screen biomarkers associated with SPA-interfered BMSC. Receiver operating characteristic (ROC) curve was plotted to evaluate the ability of biomarkers to discriminate between two groups of samples. Finally, we performed GSEA and regulatory analysis based on biomarkers. We identified 321 DEGs. Subsequently, 6 biomarkers (Cenpf, Kntc1, Nek2, Asf1b, Troap and Kif14) were identified by hubba algorithm in PPI. ROC analysis showed that six biomarkers could clearly discriminate between normal differentiated and SPA-interfered BMSC. Moreover, we found that these biomarkers were mainly enriched in the pyrimidine metabolism pathway. We also constructed '71 circRNAs-14 miRNAs-5 mRNAs' and '10 lncRNAs-5 miRNAs-2 mRNAs' networks. Kntc1 and Asf1b genes were associated with rno-miR-3571. Nek2 and Asf1b genes were associated with rno-miR-497-5p. Finally, we found significantly lower expression of six biomarkers in the SPA-interfered group compared to the normal group by RT-qPCR. Overall, we obtained 6 biomarkers (Cenpf, Kntc1, Nek2, Asf1b, Troap, and Kif14) related to SPA-interfered BMSC, which provided a theoretical basis to explore the key factors of SPA affecting osteogenic differentiation.