Adipose-derived Mesenchymal Stem Cells Group Research Articles

Adipose-derived mesenchymal stem cells mitigate doxorubicin-induced cardiomyopathy in rats

Purpose: To investigate the effect of adipose-derived mesenchymal stem cells (ADMSCs) on doxorubicin (DOX)-induced cardiomyopathy in rats. Methods: A total of 30 male Sprague-Dawley rats were randomized into control (n = 10) and study groups (n = 20). Control group received no intervention while the study group received DOX administered intraperitoneally (i.p.) six times daily at a dose of 2.5 mg/kg/ day. The study group was divided into 2 groups. One group received DOX + normal saline (0.9 %w/v) sodium chloride (NaCl) solution ntraperitoneally at a dose of 1 mL/kg/day. Another group received DOX + ADMSC at a dose of 2.0 x 106 cells/kg intraperitoneally twice a week. Biochemical parameters and histopathological changes in blood and heart tissue samples were compared among groups. Results: Caspase-3 immuno-expression, plasma malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), growth differentiation factor-15 (GDF-15), pro-brain natriuretic peptide (Pro-BNP), troponin, heart transforming growth factor–β (TGF-β) were significantly lower in DOX+ ADMSC compared to DOX + saline group (p < 0.05). However, caspase-3 immune expression and the number of regularly arranged cardiomyocytes significantly decreased in DOX + ADMSC group compared to DOX + saline group (p < 0.05). Conclusion: Adipose-derived mesenchymal stem cells (ADMSCs) reduce caspase-3 immunoexpression, restore cardiac histology, and ameliorate DOX- induced cardiac injury. Further investigation and clinical trials are recommended, especially to determine the continued safety and efficacy of AD-MSC-based therapy in cardiac injury.

Adipose-derived mesenchymal stem cells mitigate methotrexate-induced liver cirrhosis (fibrosis) model.

Hepatic fibrosis is a severe liver condition characterized by abnormal fibroblast activity, excessive extracellular matrix deposition, inflammation, and structural alterations. Methotrexate (MTX), a pharmaceutical agent widely used for its therapeutic properties, is known to induce hepatotoxicity. However, the precise mechanisms underlying MTX-induced liver injury remain elusive. This study investigates the therapeutic potential of Adipose-Derived Mesenchymal Stem Cells (ADMSCs) in alleviating MTX-induced liver injury in a rat model. Thirty male Wistar albino rats were employed in this study. Liver injury was induced in twenty rats by a single MTX dose, while ten rats constituted the control group. The MTX group was further subdivided into two cohorts, one receiving ADMSC treatment and the other saline solution. The treatment duration was 14 days. ADMSCs, isolated from adipose tissue, were characterized by CD13, CD29, and CD105 markers. Biomarker analysis, histopathological evaluations, and various measurements were conducted to assess ADMSCs' therapeutic efficacy. MTX administration significantly increased Transforming Growth Factor-β (TGF-β), Platelet-Derived Growth Factor (PDGF), Plasma Cytokeratin 18, Plasma Malondialdehyde (MDA), and Liver MDA levels, with histopathological liver damage. ADMSC treatment notably lowered TGF-β, PDGF, Plasma Cytokeratin 18, Plasma MDA, and Liver MDA levels, accompanied by reduced liver damage observed histologically. Liver Enzyme ALT levels were also reduced in the MTX and ADMSC groups compared to the MTX and Saline groups. ADMSCs exhibit significant potential in ameliorating MTX-induced liver injury, with notable anti-oxidative and anti-apoptotic properties. These findings suggest that ADMSCs may effectively mitigate oxidative stress and inflammation associated with MTX-induced liver damage. Further research is essential to investigate the clinical application of ADMSCs in liver disease management and uncover the underlying therapeutic mechanisms.

Effects of nebulized adipose-derived mesenchymal stem cells on acute lung injury following smoke inhalation in sheep

IntroductionTreatment of ARDS caused by smoke inhalation is challenging with no specific therapies available. The aim of this study was to test the efficacy of nebulized adipose-derived mesenchymal stem cells (ASCs) in a well-characterized, clinically relevant ovine model of smoke inhalation injury. Material and MethodsFourteen female Merino sheep were surgically instrumented 5–7 days prior to study. After induction of acute lung injury (ALI) by cooled cotton smoke insufflation into the lungs (under anesthesia and analgesia), sheep were placed on a mechanical ventilator for 48 hrs and monitored for cardiopulmonary hemodynamics in a conscious state. ASCs were isolated from ovine adipose tissue. Sheep were randomly allocated to two groups after smoke injury: 1) ASCs group (n = 6): 10 million ASCs were nebulized into the airway at 1 hr post-injury; and 2) Control group (n = 8): Nebulized with saline into the airways at 1 hr post-injury. ASCs were labeled with green fluorescent protein (GFP) to trace cells within the lung. ASCs viability was determined in bronchoalveolar lavage fluid (BALF). ResultsPaO2/FiO2 in the ASCs group was significantly higher than in the control group (p = 0.001) at 24 hrs. Oxygenation index: (mean airway pressure × FiO2/PaO2) was significantly lower in the ASCs group at 36 hr (p = 0.003). Pulmonary shunt fraction tended to be lower in the ASCs group as compared to the control group. GFP-labelled ASCs were found on the surface of trachea epithelium 48 hrs after injury. The viability of ASCs in BALF was significantly lower than those exposed to the control vehicle solution. ConclusionNebulized ASCs moderately improved pulmonary function and delayed the onset of ARDS.

Effects of hepatocyte growth factor-transfected mesenchymal stem cell transplantation in canine injured vocal folds

This study aimed to assess the efficacy of hepatocyte growth factor (HGF)-transfected adipose-derived mesenchymal stem cell (ADSC) transplantation in the injured vocal folds (VFs) of canines. A lentiviral vector encoding HGF was successfully produced via Gateway cloning, which was used to infect ADSCs. Four weeks after transoral laser microsurgery (type II) with CO2 laser, the beagles of each group were injected with HGF-transfected ADSCs or uninfected ADSCs into VFs. The results showed that the retention of HGF-transfected ADSCs in the VFs persisted about three months post-injection. The VFs in the HGF-transfected ADSCs group exhibited a closer-to-normal structure with less collagen deposition and higher amounts of hyaluronic acid (HA) in the third month. The short microvilli in the HGF-transfected ADSCs group showed a dense and uniform distribution. These results revealed that HGF-transfected ADSC is a potential treatment option for injured VFs.

Clinical Efficacy and Safety of the Intra-articular Injection of Autologous Adipose-Derived Mesenchymal Stem Cells for Knee Osteoarthritis: A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial

Background: Intra-articular injection of autologous culture-expanded adipose-derived mesenchymal stem cells (ADMSCs) has introduced a promising treatment option for knee osteoarthritis. Although the clinical efficacy and safety of ADMSCs have been reported, the treatment remains controversial owing to the small sample sizes and heterogeneous osteoarthritis grades in previous studies. Purpose: To assess the efficacy and safety of intra-articular injection of ADMSCs as compared with placebo in alleviating pain and improving functional capacity in a large sample of patients with knee osteoarthritis of Kellgren-Lawrence (K-L) grade 3. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: This phase III multicenter clinical trial was a double-blind randomized controlled study that included 261 patients with K-L grade 3 symptomatic knee osteoarthritis who were administered a single injection of autologous culture-expanded ADMSCs or placebo. Clinical data were assessed at baseline and at 3 and 6 months after the injection. The primary endpoints were improvements in 100-mm visual analog scale (VAS) for pain and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) for function at 6 months after the injection. The secondary endpoints included clinical and radiologic examinations and safety after injection. The changes in cartilage defects after injection were assessed by magnetic resonance imaging at 6 months. Results: The ADMSC and control groups included 125 and 127 patients available for follow-up, respectively. At 6 months, the ADMSC group showed significantly better improvements in 100-mm VAS (ADMSC vs control, 25.2 vs 15.5; P = .004) and total WOMAC score (21.7 vs 14.3; P = .002) as compared with the control group. The linear mixed model analysis indicated significantly better improvements in all clinical outcomes in the ADMSC group after 6 months. At 6 months, the ADMSC group achieved significantly higher proportions of patients above the minimal clinically important difference in 100-mm VAS and WOMAC score. Radiologic outcomes and adverse events did not demonstrate significant differences between the groups. No serious treatment-related adverse events were observed. Magnetic resonance imaging revealed no significant difference in change of cartilage defects between the groups at 6 months. Conclusion: Intra-articular injection of autologous culture-expanded ADMSCs provided significant pain relief and functional improvements in patients with K-L grade 3 osteoarthritis. Long-term results are needed to determine the disease-modifying effects of ADMSCs, such as structural changes, and the duration of effect of intra-articular injection of ADMSCs in knee osteoarthritis. Registration: NCT03990805 (ClinicalTrials.gov identifier).

Melatonin pretreatment can improve the therapeutic effect of adipose-derived stem cells on CCl4-induced liver fibrosis

In this study, the therapeutic effect of Mel-incubated Adipose-derived mesenchymal stem cells (ADSCs) on CCl4-induced hepatic fibrosis was investigated. Mice with hepatic fibrosis were intraperitoneally injected with 8% CCl4 twice a week for 4 weeks. Starting from week 5, mice in the ADSC group and ADSC + Mel group were injected with 1 mL PBS cell suspension containing 1 × 106 ADSCs or ADSCs pretreated with 50 nM Mel twice a week for 2 consecutive weeks. Results: In the model group, severe histopathological changes were observed in the liver, including severe vacuolation, nuclear fragmentation, and liver fibrosis, and these changes were ameliorated by Mel-pretreated ADSCs. RT-qPCR results showed that Mel-induced ADSCs significantly inhibited the expression of proapoptotic genes (Caspase-8, Bax, and Caspase-3) and promoted the expression of an anti-apoptotic gene (Bcl-2). Immunohistochemical results showed that a large number of MMP-9-, TGF-β-, and MMP-2-positive cells were present in the liver tissues of the model group, while the number of positive cells was reduced by Mel-induced ADSCs. ELISA results showed that the ADSC pretreated with Mel also significantly reduced the expression levels of TNF-α and IL-6. Conclusion: ADSCs pretreated with Mel significantly improved CCl4-induced liver fibrosis.

Cisplatin-induced azoospermia and testicular damage ameliorated by adipose-derived mesenchymal stem cells

BackgroundThe testes are highly susceptible to the adverse effects of chemotherapy and radiation at all stages of life. Exposure to these threats mainly occurs during cancer treatment and as an occupational hazard in radiation centers. The present study investigated the regenerative ability of adipose-derived mesenchymal stem cells (ADMSCs) against the adverse effects of cisplatin on the structure and function of the testes.MethodsNew Zealand white rabbits (N = 15) were divided into three groups of five: a negative control group (no treatment), a cisplatin group (single dose of cisplatin into each testis followed three days later by a PBS injection), and a cisplatin + ADMSCs group (cisplatin injection followed three days later by an ADMSC injection). On day 45 post-treatment, serum testosterone levels were evaluated, and the testes and epididymis were collected for histology, oxidative stress examination, and epididymal sperm analysis.ResultsCisplatin caused damage to the testicular tissue and decreased serum testosterone levels, epididymal sperm counts, and oxidants. An antioxidant imbalance was detected due to increasing malondialdehyde (MDA) and reduced glutathione (GSH) levels in testicular tissue. The ADMSC-treated group displayed a moderate epididymal sperm count, adequate antioxidant protection, suitable hormone levels, and enhanced testicular tissue morphology.ConclusionsADMSCs treatment repaired damaged testicular tissue, enhanced biochemical parameters, and modified pathological changes caused by cisplatin.

Auricular cartilage regeneration using different types of mesenchymal stem cells in rabbits

BackgroundCartilaginous disorders comprise a wide range of diseases that affect normal joint movement, ear and nose shape; and they have great social and economic impact. Mesenchymal stem cells (MSCs) provide a promising regeneration alternative for treatment of degenerative cartilaginous disorders. This study aimed to compare therapeutic potential of different types of laser activated MSCs to promote auricular cartilage regeneration. Twelve adult rabbit allocated equally in four groups, all animals received a surgical mid auricular cartilage defect in one ear; Group I (Positive control) injected sub-perichondrially with phosphate-buffered saline (PBS), Group II (ADMSC-transplanted group) injected adipose-derived MSCs (ADMSCs), Group III (BMMSCs-transplanted group) received bone marrow-derived MSCs (BMMSCs), and Group IV (EMSC-transplanted group) received ear MSCs (EMSCs) in the defected ear. The auricular defect was analyzed morphologically, histopathologically and immunohistochemically after 4 weeks. In addition, a quantitative real-time polymerase chain reaction was used to examine expression of the collagen type II (Col II) and aggrecan as cartilage growth factors.ResultsThe auricles of all treatments appeared completely healed with smooth surfaces and similar tissue color. Histopathologically, defective areas of control positive group, ADMSCs and EMSCs treated groups experienced a small area of immature cartilage. While BMMSCs treated group exhibited typical features of new cartilage formation with mature chondrocytes inside their lacunae and dense extracellular matrix (ECM). In addition, BMMSC treated group showed a positive reaction to Masson’s trichrome and orcein stains. In contrary, control positive, ADMSC and EMSC groups revealed faint staining with Masson’s trichrome and Orcein. Immunohistochemically, there was an intense positive S100 expression in BMMSCs (with a significant increase of area percentage + 21.89 (P < 0.05), a moderate reaction in EMSCs (with an area percentage + 17.97, and a mild reaction in the control group and ADMSCs (area percentages + 8.02 and + 11.37, respectively). The expression of relative col II and aggrecan was substantially highest in BMMSCs (± 0.91 and ± 0.89, respectively). While, Control positive, ADMSCs and EMSCs groups recorded (± 0.41: ± 0.21, ± 0.6: ± 0.44, ± 0.61: ± 0.63) respectively.ConclusionBMMSCs showed the highest chondrogenic potential compared to ADMSCs and EMSCs and should be considered the first choice in treatment of cartilaginous degenerative disorders.

Effect of three clinical therapies on cytokines modulation in the hip articular cartilage and bone improvement in rat early osteonecrosis of the femoral head

BackgroundExtracorporeal shockwave therapy (ESWT) and adipose-derived mesenchymal stem cells (ADSCs) have been used clinically for the treatment of osteonecrosis of the femoral head (ONFH). The study elucidated that ESWT, ADSCs, and combination therapy modulated pro-inflammatory cytokines in the articular cartilage and subchondral bone of early rat ONFH. MethodsESWT and ADSCs were prepared and isolated for treatment. Micro-CT, pathological analysis, and immunohistochemistry were performed and analysed. ResultsAfter treatments, subchondral bone of ONFH was improved in trabecular bone volume (BV/TV) (p < 0.001), thickness (Tb.Th) (p < 0.01 and 0.001), and separation (Tb.Sp) (p < 0.001) and bone mineral density (BMD) (p < 0.001) using micro-CT analysis. The articular cartilage was protected and decreased apoptosis markers after all the treatments. The expression of IL33 (p < 0.001), IL5 (p < 0.001), IL6 (p < 0.001), and IL17A (p < 0.01) was significantly decreased in the ESWT, ADSCs, and Combination groups as compared with ONFH group. The IL33 receptor ST2 was significantly increased after treatment (p < 0.001) as compared with ONFH group. The Combination group (p < 0.01) decreased the expression of IL6 better than the ESWT and ADSCs groups. ConclusionESWT, ADSCs and combination therapy significantly protected articular cartilage and subchondral bone of early rat ONFH by modulating the expression of pro-inflammatory cytokines including, IL33 and its receptor ST2, IL5, IL6, and IL17A.

Effect of Adipose-Derived Mesenchymal Stem Cells (ADMSCs) Application in Achilles-Tendon Injury in an Animal Model.

Achilles-tendon rupture prevails as a common tendon pathology. Adipose-derived mesenchymal stem cells (ADMSCs) are multipotent stem cells derived from adipose tissue with attractive regeneration properties; thus, their application in tendinopathies could be beneficial. Male rabbit ADMSCs were obtained from the falciform ligament according to previously established methods. After tenotomy and suture of the Achilles tendon, 1 × 106 flow-cytometry-characterized male ADMSCs were injected in four female New Zealand white rabbits in the experimental group (ADMSC group), whereas four rabbits were left untreated (lesion group). Confirmation of ADMSC presence in the injured site after 12 weeks was performed with quantitative sex-determining region Y (SRY)-gene RT-PCR. At Week 12, histochemical analysis was performed to evaluate tissue regeneration along with quantitative RT-PCR of collagen I and collagen III mRNA. Presence of male ADMSCs was confirmed at Week 12. No statistically significant differences were found in the histochemical analysis; however, statistically significant differences between ADMSC and lesion group expression of collagen I and collagen III were evidenced, with 36.6% and 24.1% GAPDH-normalized mean expression, respectively, for collagen I (p &lt; 0.05) and 26.3% and 11.9% GAPDH-normalized mean expression, respectively, for collagen III (p &lt; 0.05). The expression ratio between the ADMSC and lesion group was 1.5 and 2.2 for collagen I and collagen III, respectively. Our results make an important contribution to the understanding and effect of ADMSCs in Achilles-tendon rupture.

Safety and efficacy of adipose-derived mesenchymal stem cells for knee osteoarthritis: A systematic review and m-analysis.

This research aimed to study the safety and efficacy of adipose-derived mesenchymal stem cells (ADMSCs) for knee osteoarthritis (OA). We used six databases to search for records and then screened them for eligibility. In both randomized and non-randomized studies, the risk of bias was assessed. The data were then retrieved and used in single-arm and double-arm analyses using Comprehensive Meta-Analysis (CMA) Version 3.0 and RevMan Version 5.3, respectively. Based on the study's inclusion criteria, we included 15 studies with a total of 463 patients. According to our single-arm analyses, there was a significant improvement in quality of life (QOL) among the three dose subgroups (high, medium, and low doses), as measured by SF-36 scores after a year of follow-up [low dose: mean (M)=-23.99; 95% confidence interval (CI) [-31.49 to -16.49]; P&lt;0.001; medium dose: M=-15.96; 95% CI [-23.5 to-8.42]; P&lt;0.001; high dose: M=-19.31; 95% CI [-28.02 to -10.59], P&lt;0.001] and the knee injury and osteoarthritis outcome score (KOOS) QOL sub-score after six months following ADMSCs injection in the low-dose group (M=24.9; 95% CI [4.3 to 45.6]; P&lt;0.05). Moreover, after three months of follow-up, we detected significant pain reduction as measured by the numeric pain rating scale (NPRS), with no significant difference between the low and medium doses (low dose: M=-3.12; 95% CI [-5.09 to -1.14]; P&lt;0.01; medium dose; M=-2.17; 95% CI [-3.13 to -1.21]; P&lt;0.001). However, after a year, the results were no longer significant. Despite finding no significant difference between them after 6 and 12 months post-treatment in the Visual Analogue scale (VAS) scale and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score, double-arm analyses revealed significant pain reduction in the ADMSCs group over the control after 12 months as estimated by the WOMAC pain sub-score (mean difference (MD)=-1.85, 95% CI [-3.55, -0.15], P&lt;0.05). After six months, the low dosage group's knee functions and activity levels improved significantly, as determined by the WOMAC physical function and stiffness subscales (M=-23.79; 95% CI [-38.43 to -9.16]; P=0.001; M=-10.25; 95% CI [-17.31 to -2.59]; P&lt;0.01, respectively), as well as the KOOS scores after a year (P&lt;0.01 for all KOOS subscales). In the ADMSCs injections group, there were no serious adverse effects [event rate (ER)=0.11; 95% CI [0.03-0.3]; P=0.001]. In the present single-arm meta-analysis, ADMSCs were associated with significant reduction in pain and improvement in QOL and knee functions in patients with knee OA. However, double arm analyses did not confirm these positive findings, which may be returned to the small sample size of included patients. Therefore, to introduce ADMSCs into clinical practice and establish guidelines for their use, more randomized controlled clinical trials with large sample sizes and long-term follow-ups are needed.

Can mobilization of bone marrow stem cells be an alternative regenerative therapy to stem cell injection in a rat model of chronic kidney disease?

Chronic kidney disease (CKD) is a priority health problem affecting 36% of Egyptians. Adipose‐derived mesenchymal stem cells (ADMSCs) have multidifferentiation capacity and the ability to restore several types of cells including damaged renal cells. Granulocyte colony‐stimulating factor (G‐CSF) is known to mobilize hematopoietic stem cells from bone marrow to the peripheral circulation. The aim of this study was to compare the effect of endogenous CD34+ cells mobilization and exogenous ADMSCs administration in the treatment of a rat model of adriamycin (ADR)‐induced CKD. A total of 48 male albino rats of the local strain (200 ± 50 g) were equally divided into four groups: control negative, ADR (control positive), ADMSCs group, and G‐CSF group. Six rats from each group were sacrificed after 4 weeks and the other 6 after 12 weeks. Renal function was assessed frequently by measuring serum creatinine, albumin, urea, 24‐h urinary protein level, and hemoglobin level throughout the study. Oxidative stress markers malondialdehyde (MDA) and total antioxidant (TAO) were measured on day 28. CD‐34+ cell percentage was measured on day 9. After the sacrification of the rats, kidneys were removed for histopathological assessment. Results revealed that both ADMSCs and G‐CSF significantly improved serum creatinine, albumin, urea, 24‐h urinary protein level, and histopathological damage score, with the G‐CSF‐treated group showing better improvement in 24‐h urinary protein level, serum albumin, and histopathological damage score compared with ADMSCs‐treated group. The G‐CSF group also had significantly higher levels of CD34+ cells. Oxidative stress markers (MDA and TAO) levels were significantly improved with both therapies. We conclude that mobilization of endogenous hematopoietic stem cells by G‐CSF is more effective than exogenously injected ADMSCs in protecting the kidneys against AD‐induced toxicity.

Intra-articular Injection of Mesenchymal Stem Cells After High Tibial Osteotomy in Osteoarthritic Knee: Two-Year Follow-up of Randomized Control Trial.

Intra-articular injection of adipose-derived mesenchymal stem cell (ADMSC) after medial open-wedge high tibial osteotomy (MOWHTO) would be a promising disease-modifying treatment by correcting biomechanical and biochemical environment for arthritic knee with varus malalignment. However, there is a paucity of clinical evidence of the treatment. This randomized controlled trial (RCT) was aimed to assess regeneration of cartilage defect, functional improvement, and safety of intra-articular injection of ADMSCs after MOWHTO compared with MOWHTO alone for osteoarthritic knee with varus malalignment. This RCT allocated 26 patients into the MOWHTO with ADMSC-injection group (n = 13) and control (MOWHTO-alone) group (n = 13). The primary outcome was the serial changes of cartilage defect on periodic magnetic resonance imaging (MRI) evaluation using valid measurements until postoperative 24 months. Secondary outcomes were the 2-stage arthroscopic evaluation for macroscopic cartilage status and the postoperative functional improvements of patient-reported outcome measures until the latest follow-up. Furthermore, safety profiles after the treatment were evaluated. Cartilage regeneration on serial MRIs showed significantly better in the ADMSC group than in the control group. The arthroscopic assessment revealed that total cartilage regeneration was significantly better in the ADMSC group. Although it was not significant, functional improvements after the treatment showed a tendency to be greater in the ADMSC group than in the control group from 18 months after the treatment. No treatment-related adverse events, serious adverse events, and postoperative complications occurred in all cases. Concomitant intra-articular injection of ADMSCs with MOWHTO had advantages over MOWHTO alone in terms of cartilage regeneration with safety at 2-year follow-up, suggesting potential disease-modifying treatment for knee OA with varus malalignment.

Adipose-derived mesenchymal stem cells combined with platinum nanoparticles accelerate fracture healing in a rat tibial fracture model.

BackgroundAt present, bone union delay or failure remains challenging for clinicians. It has been reported that adipose-derived mesenchymal stem cells (ADMSCs) offer a promising way to promote bone fracture healing. In recent years, nanomaterials have been applied in regenerative medicine. This study aimed to investigate whether ADMSCs combined with platinum nanoparticles (PtNPs) could further improve fracture healing on the basis of ADMSCs.MethodsADMSCs were co-cultured with PtNPs in vitro to investigate the effect of PtNPs on the differentiation of ADMSCs. Twenty Sprague-Dawley (SD) rats were randomly divided into four groups (with five rats in each group). The left tibias of all rats were fractured. Phosphate-buffered saline (PBS), PtNPs, ADMSC, and ADMSC mixed with PtNPs were then injected into the fracture sites based on the group classifications. The fracture was monitored by X-ray immediately after the fracture and on days 14 and 28 post-fracture. The tibias of the rats were subsequently harvested after the last X-ray and evaluated by micro computed tomography (micro-CT), histological analysis, and immunohistochemical detection.ResultsPtNPs significantly enhanced the osteogenic differentiation of ADMSCs in vitro. On days 14 and 28 post-fracture, the radiographic score of the ADMSC + PtNPs group was higher than that of the ADMSC group, the score of the ADMSC group was higher than that of the PtNPs and control groups, and there was no significant difference between the PtNPs and control groups. Micro-CT confirmed that combined ADMSCs with PtNPs were more effective than using ADMSCs alone in promoting fracture healing. The histological and immunohistochemical results further supported this conclusion.ConclusionsOur findings demonstrated that PtNPs could promote osteogenic differentiation of ADMSC in vitro. ADMSCs combined with PtNPs could accelerate fracture healing further in vivo and are a promising a potential method for the treatment of fracture healing.

Comparison of the Regenerative Effect of Adipose Tissue Mesenchymal Stem Cell Encapsulated into Two Hydrogel Scaffolds on Spinal Cord Injury

Background: Spinal cord injury (SCI) is a severe neurological disease leading to poor quality of life. Objectives: The regenerative effect of adipose-derived mesenchymal stem cells (AD-MSCs) encapsulated into fibrin, and collagen hydrogel scaffolds on a rat model of SCI was investigated using clinical and histopathological examinations. Methods: A total of 18 adult male Wistar rats (250 - 300 g) were prepared and randomly divided into three equal groups, each with six rats, including the control or SCI group (SCI contusion model without treatment), SCI contusion model treated with AD-MSCs encapsulated in fibrin hydrogel, and SCI contusion model treated with AD-MSCs encapsulated in collagen hydrogel groups. Clinically, functional recovery or hindlimb locomotor activity was assessed using Basso, Beattie, and Bresnahan's (BBB) scoring system four weeks post-treatment. The rats were sacrificed at week four post-treatment, and their spinal cords were examined histopathologically. Results: Faster functional recovery indicated with hindlimb locomotor activity was seen in both treatment groups compared to the control group. Severe polio and leuko-myelomalacia associated with disruption of spinal cord structure were identified in the control group. Mild polio and leuko-myelomalacia associated with mild to moderate disruption of spinal cord structure were seen in the collagen hydrogel + AD-MSCs and fibrin hydrogel + AD-MSCs groups. Conclusions: AD-MSCs encapsulated into fibrin and collagen hydrogels, as two of the most promising ECM-based or natural scaffolds have the potential to be developed in neural tissue engineering (NTE), such as for the treatment of SCI.

Promotion of Burn Wound Healing by Local Application of Adipose-Derived Mesenchymal Stem Cells: An Experimental Study

Background:The burn wound is one of the health problems in the world that affects physical and mental health. Today, adipose-derived mesenchymal stem cells (ADSCs) have received medical attention for their accessibility and the ability to reproduce and repair. The present study was designed to investigate the effect of ADSCs on burn wound healing. Methods : The present experimental study was performed on 36 male Wistar rats divided into 1 control group and 3 experimental groups. The second-degree burns with a radius of 10 mm were induced after anesthesia. ADSCs and Dulbecco's Modified Eagle Medium (DMEM) were injected into the dermis around the burn area in the ADSCs and DMEM groups, respectively. Silver sulfadiazine (SSD) ointment was applied topically once daily as the SSD group. The control group did not receive any treatment. The rats were evaluated for 21 days. Wound healing rate, histopathological parameters, and the number of fibroblasts were evaluated by the immunofluorescence technique and vascular endothelial growth factor and transforming growth factor β (TGF-β) gene expression by reverse transcription-polymerase chain reaction. The results were entered into SPSS software (SPSS Inc) and analyzed with 1-way analysis of variance and repeated measures analysis. Results: The number of fibroblasts, the number of vessels, TGF-β, and VEGF gene expression in the burn area were significantly higher in the ADSCs group than in the SSD, DMEM, and control groups. The results also showed that the amount of inflammation was significantly lower in the ADSCs group compared with the control group (p<0.001). Moreover, the percentage of wound recovery was significantly higher in the ADSCs group compared with other groups (p<0.001). Conclusion: ADSCs accelerate and improve burn wound healing by affecting fibroblasts, keratinocytes, and inflammatory cells as well as increasing the expression of the TGF-β and VEGF genes, and thus increase in angiogenesis.

Exosomes from adipose-derived mesenchymal stem cells alleviate liver ischaemia reperfusion injury subsequent to hepatectomy in rats by regulating mitochondrial dynamics and biogenesis.

Hepatic ischaemia reperfusion injury (HIRI) is a major factor leading to liver dysfunction after liver resection and liver transplantation. Adipose‐derived mesenchymal stem cells (ADSCs) have potential therapeutic effects on HIRI. Exosomes derived from ADSCs (ADSCs‐exo) have been widely studied as an alternative of ADSCs therapy. Thus, the aim of this study was to evaluate the potential protective effect and related mechanism of ADSCs‐exo on HIRI subsequent to hepatectomy. Rats were randomly divided into four groups: Sham, I30R+PH, ADSCs and ADSCs‐exo group. After 24 h of reperfusion, liver and serum of the rats were immediately collected. ADSCs‐exo improved liver function, inhibited oxidative stress and reduced apoptosis of hepatocytes in HIRI subsequent to hepatectomy in rats. ADSCs‐exo significantly promoted the recovery of mitochondrial function, markedly increased the content of ATP in the liver tissue, and improved the ultrastructure of mitochondria in hepatocytes. Moreover, ADSCs‐exo significantly increased the expression of OPA‐1, MFN‐1 and MFN‐2 proteins related to mitochondrial fusion, while DRP‐1 and Fis‐1 mRNA and protein expression associated with mitochondrial fission were significantly decreased after the treatment with ADSCs‐exo. In addition, ADSCs‐exo significantly increased the expression of PGC‐1α, NRF‐1 and TFAM genes and proteins related to mitochondrial biogenesis. ADSCs‐exo improves liver function induced by HIRI subsequent to hepatectomy in rats and maintains mitochondrial homeostasis by inhibiting mitochondrial fission, promoting mitochondrial fusion and promoting mitochondrial biogenesis. Therefore, ADSCs‐exo may be considered as a potential promising alternative to ADSCs in the treatment of HIRI subsequent to hepatectomy.

Adipose-Derived Mesenchymal Stem Cell Transplantation in Chemotherapy-Induced Premature Ovarian Insufficiency: the Role of Connexin and Pannexin

In women undergoing chemotherapy, it is inevitable that infertility risk will increase because of impaired reproductive functions. Premature ovarian insufficiency (POI), which occurs as a devastating result of chemotherapy, is the complete depletion or dysfunction of ovarian follicles. Adipose-derived mesenchymal stem cells (ADMSCs) transplantation is among the alternative treatment methods for POI, which currently do not have an effective treatment method. Apoptosis of granulosa cells in POI is seen as the main mechanism of the disease. It is also reported that in addition to molecules directly associated with apoptosis, connexins, and pannexins are also potential effector molecules in apoptosis. The roles of these molecules in POI, which are known to play a role in many important mechanisms in the ovary, are unknown. In this study, it was aimed to analyze the expressions of Connexin43 and Pannexin1, which are thought to be effective in the formation of POI, and to show the relationship between the antiapoptotic effects of ADMSCs transplantation and these molecules in POI. For this purpose, Caspase3, Connexin43, Pannexin1 proteins, and mRNA expressions were analyzed by immunohistochemistry and RT-qPCR, and AMH levels were measured by ELISA. It was determined that Pannexin1, Caspase3 proteins, and mRNA levels increased in the POI, while Pannexin1 and Caspase3 expressions decreased in the ADMSCs treated group. While Connexin43 level decreased in POI, Connexin43 protein and mRNA levels increased in ADMSCs group. Consequently, this study demonstrated for the first time that Connexin43 and Pannexin1 were associated with apoptosis in POI. In addition, it was revealed that ADMSCs transplantation could produce antiapoptotic effects by modulating these molecules.

The neuro-restorative effect of adipose-derived mesenchymal stem cell transplantation on a mouse model of diabetic neuropathy

ABSTRACT Diabetic neuropathy (DN) is the most common degenerative complication associated with Diabetes Mellitus. Despite widespread awareness about DN, the only effective treatments are blood glucose control and pain management. The aim of the current study was to determine the effect of intramuscular adipose-derived mesenchymal stem cell (AMSC) transplantation on sciatic nerves in DN using EMG and histological analyses. A total of 27 mice were randomly divided into three groups: control group, DN group and AMSC group. In EMG, CMAP amplitude in the sciatic nerves was lower, but distal latency was higher in the DN group compared with the control group. CMAP amplitude in the sciatic nerves was higher in the AMSC group compared with the DN group. Distal latency in the sciatic nerve was lower in the AMSC group compared with the DN group. Histologic examination of the tissues in the animals treated with AMSC showed a remarkable improvement in microscopic morphology. Fluorescence microscopy analyses demonstrated that intramuscularly transplanted AMSC was selectively localized in the sciatic nerves. Transplantation of AMSC increased protein expression of S100, cdk2, NGF and DHH, all of which, interfered with DN onset in sciatic nerves. The findings of the present study suggest that AMSC transplantation improved DN through a signal-regulatory effect on Schwann cells, neurotrophic actions and restoration of myelination.

The effect of photobiomodulation therapy on antioxidants and oxidative stress profiles of adipose derived mesenchymal stem cells in diabetic rats

We studied the effects of photobiomodulation therapy (PBMT) on adipose-derived mesenchymal stem cells (ADSCs) which were extracted from streptozotocin (STZ) induced diabetic rats. Adipose tissue was extracted from the hypodermis of diabetic rats, and diabetic ADSCs were extracted, characterized, and cultured. There were two in vitro groups: control-diabetic ADSCs, and PBMT-diabeticADSCs. We used 630 nm and 810 nm laser at 1.2 J/cm2 with 3 applications 48 h apart. We measured cell viability, apoptosis, population doubling time (PDT), and reactive oxygen species (ROS) by flow cytometry. Gene expression of antioxidants, including cytosolic copper-zinc superoxide dismutase (SOD1), catalase (CAT), total antioxidant capacity (TAC), and oxidative stress biomarkers (NADPH oxidase 1 and 4) by quantitative real time (qRT) - PCR. In this study, data were analyzed using t-test. Viability of PBMT-diabetic- ADSC group was higher than control- diabetic-ADSC (p = 0.000). PDT and apoptosis of PBMT- diabetic-ADSC group were lower than control-diabetic -ADSC (p = 0.001, p = 0.02). SOD1 expression and TAC of PBMT- diabetic-ADSC group were higher than control –diabetic -ADSC (p = 0.018, p = 0.005). CAT of PBMT –diabetic-ADSC group was higher than control-diabetic -ADSC. ROS, NOX1, and NOX4 of PBMT- diabetic -ADSC group were lower than control-diabetic-ADSC (p = 0.002, p = 0.021, p = 0.017). PBMT may improve diabetic- ADSC function in vitro by increasing levels of cell viability, and gene expression of antioxidant agents (SOD1, CAT, and TAC), and significantly decreasing of levels of PDT, apoptosis, ROS, and gene expression of oxidative stress biomarkers (NOX1 and NOX4).