Injection Of Adipose-derived Mesenchymal Stem Cells Research Articles

Abstract 1153: Adipose-derived Mesenchymal Stem-cell Therapy Improves Arteriogenesis, Hemodynamics, And Walking Performance In A Porcine Model Of Peripheral Artery Disease

Background: There are few effective alternatives to revascularization for peripheral artery disease (PAD). We used our porcine model of PAD to test the hypothesis that adipose derived mesenchymal stem cells (ADMSC) injected around the aortic trifurcation in the pelvis improve ischemic limb hemodynamics and walking performance (WP). Methods: In Ossabaw miniswine (N=13, Age=6 mo) with metabolic syndrome, right (R) hindlimb ischemia was induced with R External Iliac and Superficial Femoral artery coil occlusion (T0) via carotid artery access. All swine had weekly testing of WP on a treadmill. At weeks 0 (T0), 4 (T4), and 8 (T8), ankle brachial indices (ABI) and muscle tissue oximetry (STO 2 ) were measured. At T4 and T8 all swine underwent angiography. At T4, in treatment (Tx) swine (N=4) ADMSC were isolated using stromal vascular fractionation of autologous abdominal wall fat. Using jugular vein access, a catheter with a retractable side-deploying needle was inserted in the R iliac vein and stabilized by a juxtaposed angioplasty balloon. The needle was deployed to access the retroperitoneum and ADMSC were infused around the aortic trifurcation. Results: Ischemic controls (IC) had no differences between T4 and T8 in ABIs, and mean STO 2 differences between R and L in calves and thighs. Tx improved both ABI and mean STO 2 measurements (table 1). IC had no changes in WP between T4 and T8, while Tx showed improvements (table1). On angiography, IC had growth of R Internal iliac artery (RIIA, the main inflow to the ischemic R hindlimb) and shorter appearance time (AT) of RIIA compared to L with no difference between T4 and T8. Tx showed increased growth of RIIA and shorter AT at T8 compared to T4 (table 1). Conclusion: In a clinically-relevant (similar to humans in size, anatomy, physiology and comorbidities) porcine model of PAD we found that ADMSC injection around the aortic trifurcation in the pelvis induces arteriogenesis and improves ischemic limb hemodynamics and walking performance.

The therapeutic effects of ADSCs on photoaging of skin induced by UVB irradiation.

Skin photoaging affects appearance and is associated with a variety of skin diseases, even skin cancer. Therefore, the prevention and treatment of skin photoaging is very important. However, there is a lack of effective evaluation methods, so it is an urgent problem to explore a comprehensive, non-invasive and in vivo evaluation method. Adipose-derived mesenchymal stem cells (ADSCs) are widely used to improve skin conditions as easier to obtain and positive effects. Recently, as the development of ultrasound technology, skin ultrasound has been widely used. Changes in skin layer and structure can be observed by high-frequency ultrasound (HFUS). In addition, Shear wave elastography (SWE) technology can be used to monitor the change of skin hardness. However, it is necessary to further explore the ultrasound parameters in interpreting histological changes. We simulate the progression and treatment process of human skin photoaging by using UVB-induced nude mice skin photoaging model and ADSCs injection. The analysis of the degree and therapeutic effect of skin photoaging was conducted by HFUS, SWE and to verify with histopathology. Our study aims to clarify the value of HFUS combined SWE techniques in evaluating the degree and therapeutic efficacy of skin photoaging, which provides theoretical basis for diagnosis and treatment evaluation systems.

Synergistic Hepatoprotective Effects of Mesenchymal Stem Cells and Platelet-Rich Plasma in a Rat Model of Bile Duct Ligation-Induced Liver Cirrhosis.

Liver cirrhosis poses a global health challenge marked by significant prevalence and mortality. Current therapeutic options are limited by high costs and immune-mediated rejection, necessitating the exploration of innovative strategies to enhance hepatic self-rehabilitation, and counteract the underlying pathological mechanisms. We evaluated the hepatoprotective activity of rat adipose-derived mesenchymal stem cells (ADMSCs) in combination with platelet-rich plasma (PRP) and recombinant human hepatocyte growth factor (rh-HGF) on a rat model of liver fibrosis/cirrhosis induced by bile duct ligation (BDL). Treatment with PRP or rh-HGF alone did not yield significant hepatoprotection in the BDL-induced liver cirrhosis model. However, ADMSC transplantation alone exhibited the potential to alleviate impaired liver conditions. The combination of PRP and rh-HGF demonstrated superior ameliorative effects compared to either treatment alone. Notably, the combination of ADMSC + PRP or ADMSC + rh-HGF significantly enhanced hepatoprotective capacity compared to individual or combined PRP and rh-HGF therapies. Injection of ADMSC via the tail vein reduced inflammation, hepatocyte damage, and collagen deposition, improving overall liver function. This improvement was more pronounced when ADMSC was administered with PRP and rh-HGF versus monotherapy. Our study concludes that ADMSCs exert antifibrotic effects by inhibiting hepatic stellate cell proliferation, collagen synthesis, and inducing apoptosis. ADMSCs also demonstrate immune-modulatory effects and transdifferentiate into hepatic progenitor cells, secreting trophic factors, cytokines, and chemokines that promote impaired liver regeneration. The observed arrest in liver fibrosis progression highlights the potential therapeutic impact of these interventions.

Improvement of endometrial thickness and in vitro fertilization outcomes in patients with Asherman's refractory endometrium using autologous mesenchymal stem cells from the stromal vascular fraction.

Patients with Asherman's Syndrome (AS) and an endometrial thickness (EMT) less than 7 mm are infertile women with suboptimal endometrium due to uterine scarring or endometrial atrophy. This study aimed to examine the effect of intrauterine injections of adipose-derived mesenchymal stem cells (ADMSC) from the Stromal Vascular Fraction (SVF) of adipose tissue on EMT and in vitro fertilization (IVF) outcomes: which are improvements in EMT and pregnancy rates. This double-arm retrospective study included 41 AS patients with hysteroscopic adhesiolysis. Twenty-one patients with AS refractory endometrium (Group 2) were given ADMSC to improve EMT, and 20 non-treated, age-matched patients served as controls (Group 1). For Group 2, SVF was isolated from 15 ml of adipose tissue and transmyometrial injected into the patient's uterine cavity. For all patients, EMT was examined using ultrasound before embryo transfer. In Group 2, after ADMSC treatment, EMT significantly improved (3.2 ± 1.8 mm, P<0.001). Afterward, three patients spontaneously became pregnant, and eighteen underwent frozen embryo transfer. A significant increase in implantation (66.7% vs. 4.8%, P = 0.002) and live birth rates (0.0% vs. 47.6%, P = 0.001) were recorded. No significant difference was observed in EMT, cycle implantation, or clinical pregnancy between the two groups, but the live birth rate in Group 2 after ADMSC treatment was higher than in Group 1. The results demonstrate that autologous intrauterine ADMSC injection can improve EMT, implantation, and pregnancy rates in AS patients with refractory endometrium. This research underscores the life-changing potential of autologous ADMSC treatment for patients with refractory endometrium, providing a promising avenue for future treatments.

Prevention of methylmercury-triggered ROS-mediated impairment of embryo development by co-culture with adult adipose-derived mesenchymal stem cells.

Methylmercury (MeHg) is a potent toxin that exerts deleterious effects on human health via environmental contamination. Significant effects of MeHg on neuronal development in embryogenesis have been reported. Recently, our group demonstrated that MeHg exerts toxic effects on pre- and post-implantation embryonic development processes from zygote to blastocyst stage. Our results showed that MeHg impairs embryo development by induction of apoptosis through reactive oxygen species (ROS) generation that triggers caspase-3 cleavage and activation, which, in turn, stimulates p21-activated kinase 2 (PAK2) activity. Importantly, ROS were identified as a key upstream regulator of apoptotic events in MeHg-treated blastocysts. Data from the current study further confirmed that MeHg exerts hazardous effects on cell proliferation, apoptosis, implantation, and pre- and post-implantation embryo development. Notably, MeHg-induced injury was markedly prevented by co-culture with adipose-derived mesenchymal stem cells (ADMSCs) in vitro. Furthermore, ADMSC injection significantly reduced MeHg-mediated deleterious effects on embryo, placenta, and fetal development in vivo. Further investigation of the regulatory mechanisms by which co-cultured ADMSCs could prevent MeHg-induced impairment of embryo development revealed that ADMSCs effectively reduced ROS generation and its subsequent downstream apoptotic events, including loss of mitochondrial membrane potential and activation of caspase-3 and PAK2. The collective findings indicate that co-culture with mesenchymal stem cells (MSCs) or utilization of MSC-derived cell-conditioned medium offers an effective potential therapeutic strategy to prevent impairment of embryo development by MeHg.

Effect of collagen endometrial patch loaded with adipose-derived mesenchymal stem cells on endometrial regeneration in rats with a thin endometrium.

This study aimed to investigate the effects of a collagen endometrial patch (EM patch) loaded with adipose-derived mesenchymal stem cells (ADSCs) on endometrial regeneration in a rat model with thin endometrium. Thin endometrium was induced in female rats and divided into treatment groups as outlined: control, group 1(G1), local injection of ADSCs into the uterus, group 2 (G2), an EM patch without ADSCs, group 3 (G3), and an EM patch loaded with ADSCs, group 4 (G4). The rats were euthanized at either two weeks or four weeks after modeling and treatment followed by histological and biochemical analyses to examine the regenerative effects on the injured endometrium. Transplantation of the ADSC-loaded EM patch significantly promoted endometrial proliferation and increased the luminal epithelial area. Two weeks after treatment, the mean number of von Villebrand factor (vWF)+ or cluster of differentiation (CD) 31+-stained blood vessels was significantly higher in G4 than in G1 and G2. The mRNA and protein expression levels of TGF-β and FGF2 were significantly upregulated in G4 compared to those in the control. G4 exhibited significantly increased LIF mRNA levels and immunoreactivity compared with the other groups at both two weeks and four weeks after treatment. Cell tracking after ADSCs treatment revealed the presence of a substantial number of ADSCs grafted in the uterine tissues of G4, whereas a low number of ADSCs that were focally clustered were present in G2. Transplantation of EM patches loaded with ADSCs resulted in the histological and biochemical restoration of an injured endometrium. The strategic integration of EM patches and ADSCs holds significant promise as an innovative therapeutic approach for effectively treating impaired endometrial conditions.

Efficacy and Long-Term Outcomes of Intra-Articular Autologous Micro-Fragmented Adipose Tissue in Individuals with Glenohumeral Osteoarthritis: A 36-Month Follow-Up Study.

Glenohumeral osteoarthritis (GOA) is associated with disabling shoulder pain that affects everyday life. Its management comprises various treatment approaches, both conservative and surgical. Regenerative medicine has gained a major role in the conservative treatment of osteoarthritis. Intra-articular injection of adipose-derived mesenchymal stem cells (ADMSCs) is a widely used regenerative medicine approach. The aim of this retrospective study was to report the safety and clinical outcomes of intra-articular injection of ADMSCs in patients with GOA over 36-months. This retrospective observational study involved patients with chronic shoulder pain resistant to standard conservative treatment and a diagnosis of concentric GOA, who received an intra-articular injection of autologous micro-fragmented adipose tissue (μFAT). The values of the Constant-Murley score (CMS), the visual analog scale (VAS), and the simple shoulder test (SST), collected at baseline and at 12, 24, and 36 months, were analyzed to assess treatment efficacy. The single assessment numeric evaluation (SANE) was used to rate patient satisfaction. The Friedman test was used to compare observations of CMS, VAS, and SST values repeated on the same subjects. The significance threshold was set at 0.05. The participants were 65 patients with a mean age of 54.19 years and a nearly equal gender distribution. Most had mild concentric GOA classified as Samilson-Prieto grade 1. The mean follow-up duration was 44.25 months. The postoperative clinical scores showed significant improvement. At 36 months, the CMS was 84.60, the VAS score was 3.34, and the SST score was 10.15 (all p < 0.0001). The SANE score at 36 months indicated that 54 patients (83.08%) were completely satisfied with the treatment. ADMSC treatment exerted favorable effects on the clinical outcomes of patients with GOA, providing pain relief and improving shoulder function. Our data support its use as a conservative treatment option for osteoarthritis.

Mesenchymal stem cells alleviate dexamethasone-induced muscle atrophy in mice and the involvement of ERK1/2 signalling pathway

BackgroundHigh dosage of dexamethasone (Dex) is an effective treatment for multiple diseases; however, it is often associated with severe side effects including muscle atrophy, resulting in higher risk of falls and poorer life quality of patients. Cell therapy with mesenchymal stem cells (MSCs) holds promise for regenerative medicine. In this study, we aimed to investigate the therapeutic efficacy of systemic administration of adipose-derived mesenchymal stem cells (ADSCs) in mitigating the loss of muscle mass and strength in mouse model of DEX-induced muscle atrophy.Methods3-month-old female C57BL/6 mice were treated with Dex (20 mg/kg body weight, i.p.) for 10 days to induce muscle atrophy, then subjected to intravenous injection of a single dose of ADSCs (1times {10}^{6} cells/kg body weight) or vehicle control. The mice were killed 7 days after ADSCs treatment. Body compositions were measured by animal DXA, gastrocnemius muscle was isolated for ex vivo muscle functional test, histological assessment and Western blot, while tibialis anterior muscles were isolated for RNA-sequencing and qPCR. For in vitro study, C2C12 myoblast cells were cultured under myogenic differentiation medium for 5 days following 100 muM Dex treatment with or without ADSC-conditioned medium for another 4 days. Samples were collected for qPCR analysis and Western blot analysis. Myotube morphology was measured by myosin heavy chain immunofluorescence staining.ResultsADSC treatment significantly increased body lean mass (10–20%), muscle wet weight (15–30%) and cross-sectional area (CSA) (~ 33%) in DEX-induced muscle atrophy mice model and down-regulated muscle atrophy-associated genes expression (45–65%). Hindlimb grip strength (~ 37%) and forelimb ex vivo muscle contraction property were significantly improved (~ 57%) in the treatment group. Significant increase in type I fibres (~ 77%) was found after ADSC injection. RNA-sequencing results suggested that ERK1/2 signalling pathway might be playing important role underlying the beneficial effect of ADSC treatment, which was confirmed by ERK1/2 inhibitor both in vitro and in vivo.ConclusionsADSCs restore the pathogenesis of Dex-induced muscle atrophy with an increased number of type I fibres, stronger muscle strength, faster recovery rate and more anti-fatigue ability via ERK1/2 signalling pathway. The inhibition of muscle atrophy-associated genes by ADSCs offered this treatment as an intervention option for muscle-associated diseases. Taken together, our findings suggested that adipose-derived mesenchymal stem cell therapy could be a new treatment option for patient with Dex-induced muscle atrophy.

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).

Intravenous Transplantation of Adipose-Derived Mesenchymal Stem Cells Promoted The Production of Dopaminergic Neurons and Improved Spatial Memory in A Rat Model of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder described by the dynamic decline of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Stem cell transplantation is a new therapeutic strategy in the treatment of PD. The objective of the study was to assess the impact of intravenous infusion of adipose-derived mesenchymal stem cells (AD-MSCs) on memory disorder in Parkinsonian rats. In this experimental study, male Wistar rats were randomly divided to four groups containing sham, cell treatment, control, and lesion. The cell treatment group received intravenous injection of AD-MSCs 12 days after PD induction by bilateral injection of 6-hydroxydopamine. Four weeks after lesion formation, spatial memory was examined using the Morris water maze (MWM) assessment. The rats' brains were removed and assessed by bromodeoxyuridine (BrdU), tyrosine hydroxylase (TH), and glial fibrillary acidic protein (Gfap) immunostaining. Statistical analyses revealed a significant addition and reduction in time spent and escape latency in the target quadrant, respectively, in the cell group as compared to the lesion group. Also, BrdU-labeled cells were present in the substantia nigra (SN). The density of TH-positive cells was significantly increased in the AD-MSCs transplantation group as compared to the lesion group, and the density of astrocytes significantly diminished in the AD-MSCs transplantation group as compared to the lesion group. It appears that AD-MSCs treatment for Parkinson's could decrease the density of astrocytes and promote the density of TH-positive neurons. It appears that AD-MSCs could improve spatial memory impairment in PD.

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.

Adipose-Derived Mesenchymal Stem Cells Alleviate Hypertrophic Scar by Inhibiting Bioactivity and Inducing Apoptosis in Hypertrophic Scar Fibroblasts.

Background: As a fibrotic disease with a high incidence, the pathogenesis of hypertrophic scarring is still not fully understood, and the treatment of this disease is also challenging. In recent years, human adipose-derived mesenchymal stem cells (AD-MSCs) have been considered an effective treatment for hypertrophic scars. This study mainly explored whether the therapeutic effect of AD-MSCs on hypertrophic scars is associated with oxidative-stress-related proteins. Methods: AD-MSCs were isolated from adipose tissues and characterized through flow cytometry and a differentiation test. Afterwards, coculture, cell proliferation, apoptosis, and migration were detected. Western blotting and a quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect oxidative stress-related genes and protein expression in hypertrophic scar fibroblasts (HSFs). Flow cytometry was used to detect reactive oxygen species (ROS). A nude mouse animal model was established; the effect of AD-MSCs on hypertrophic scars was observed; and hematoxylin and eosin staining, Masson's staining, and immunofluorescence staining were performed. Furthermore, the content of oxidative-stress-related proteins, including nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), B-cell lymphoma 2(Bcl2), Bcl2-associated X(BAX) and caspase 3, was detected. Results: Our results showed that AD-MSCs inhibited HSFs' proliferation and migration and promoted apoptosis. Moreover, after coculture, the expression of antioxidant enzymes, including HO-1, in HSFs decreased; the content of reactive oxygen species increased; and the expression of Nrf2 decreased significantly. In animal experiments, we found that, at 14 days after injection of AD-MSCs into human hypertrophic scar tissue blocks that were transplanted onto the dorsum of nude mice, the weight of the tissue blocks decreased significantly. Hematoxylin and eosin staining and Masson's staining demonstrated a rearrangement of collagen fibers. We also found that Nrf2 and antioxidant enzymes decreased significantly, while apoptotic cells increased after AD-MSC treatment. Conclusions: Our results demonstrated that AD-MSCs efficiently cured hypertrophic scars by promoting the apoptosis of HSFs and by inhibiting their proliferation and migration, which may be related to the inhibition of Nrf2 expression in HSFs, suggesting that AD-MSCs may provide an alternative therapeutic approach for the treatment of hypertrophic scars.

Intra-Articular Injections of the Adipose-Derived Mesenchymal Stem Cells Suppress Progression of a Mouse Traumatic Knee Osteoarthritis Model.

This study aimed to determine whether the intra-articular injection of human adipose-derived mesenchymal stem cells (ADSCs) protects against the progression of murine post-traumatic osteoarthritis. ADSCs were isolated from human abdomen or buttock adipose tissues. In in vitro study, ADSCs conditioned medium was added to human chondrocytes pre-treated with interleukin-1β (IL-1β), and resultant gene expression of target inflammatory genes was measured by real-time quantitative polymerase chain reaction. A mouse model of knee osteoarthritis was generated by unilaterally transecting the medial meniscus in the right hind limb of 20 female C57BL/6 mice. Mice were randomly assigned to 2 treatment groups that received 6 µl intra-articular injections of either phosphate-buffered saline (control) or 2 × 104 cells/μl of ADSCs 14, 28, and 42 days post-surgery. Mice were euthanized 84 days post-surgery and histological and micro-computed tomography evaluation of knee joints were analyzed. Hind limb weight-bearing distribution was measured pre-surgery and 28 and 84 days post-surgery. Conditioned medium from cultured human adipose-derived mesenchymal stem cells suppressed the expression of target inflammatory genes in chondrocytes pre-treated with IL-1β, suggesting anti-inflammatory properties (P < 0.01). Histological analyses indicated that the progression of destabilization of medial meniscus-induced knee osteoarthritis was suppressed by the administration of ADSCs compared with control group at medial femorotibial joint in vivo. This protective effect was related to a reduction in articular cartilage loss. The intra-articular injection of ADSCs suppressed articular cartilage loss in a mouse model of knee osteoarthritis, possible through anti-inflammatory mechanisms.

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.

Metformin Ameliorates Senescence of Adipose-Derived Mesenchymal Stem Cells and Attenuates Osteoarthritis Progression via the AMPK-Dependent Autophagy Pathway.

Osteoarthritis (OA) is one of the most serious age-related diseases worldwide that drastically affects the quality of life of patients. Despite advancements in the treatment of arthritis, especially with adipose-derived mesenchymal stem cells (ADSCs), senescence-induced alterations in ADSCs negatively affect the treatment outcomes. This study was aimed at mechanistically exploring whether metformin could ameliorate the senescence of ADSCs and at exploring the effect of metformin-preconditioned ADSCs in an experimental OA mouse model. In this study, an H2O2-induced mouse ADSC senescent model was established. Cell proliferation, senescence, and autophagy were investigated in vitro. Moreover, the effects of intra-articular injection of metformin-preconditioned ADSCs were investigated in vivo. Metformin could promote autophagy and activate the AMPK/mTOR pathway in ADSCs. The metformin-enhanced autophagy could improve the survival and reduce the senescence of ADSCs. The protective effects of metformin against senescence were partially blocked by 3-methyladenine and compound C. Injection of metformin-preconditioned ADSCs slowed OA progression and reduced OA pain in mice. The results suggest that metformin activates the AMPK/mTOR-dependent autophagy pathway in ADSCs against H2O2-induced senescence, while metformin-preconditioned ADSCs can potentially inhibit OA progression.

Platelet-Rich Plasma and Adipose-Derived Mesenchymal Stem Cells in Association with Arthroscopic Microfracture of Knee Articular Cartilage Defects: A Pilot Randomized Controlled Trial.

Background This study aims to compare the effects of platelet-rich plasma (PRP) alone or in combination with adipose-derived mesenchymal stem cells (AD-MSCs) in patients affected by cartilage defects, undergoing knee arthroscopic microfracture. Methods Thirty-eight patients diagnosed with a knee monocompartmental cartilage defect (Outerbridge grade IV) on the MRI, underwent an arthroscopic procedure. After the confirmation of the lesion, they all received the same bone marrow stimulation technique (microfracture) and were randomized into two groups: the first one had additional PRP injection (group A), while the second received PRP and AD-MSC injection (group B). Knee assessment and pain score were documented with Knee Injury Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC) score, Short-Form (SF) 12, and Visual Analogue Scale (VAS) before the treatment and at 1, 3, 6, and 12 months of follow-up postoperatively. An additional arthroscopic procedure, performed in four patients for a subsequent meniscal lesion, let us evaluate cartilage evolution by performing a macro/microscopical assessment on cartilage biopsy specimens. Results At the 12-month follow-up, both groups showed a comparable functional improvement. The scores on the IKDC form, KOOS, pain VAS, and SF-12 significantly improved from baseline (p < 0.05) to 12 months postoperatively in both treatment groups. The four second-look arthroscopies showed a complete repair of the articular defects by smooth solid cartilage layer, with a good chondrocytic population, in both groups. A thick smooth hyaline-like cartilage with a predominantly viable cell population and normal mineralization (a form closely resembling native tissue) was observed in group B. Conclusions Modern regenerative medicine techniques, such as PRP and AD-MSC, associated with traditional arthroscopic bone marrow stimulating techniques, seem to enhance cartilage restoration ability. The preliminary results of this pilot study encourage the synergic use of these regenerative modulating systems to improve the quality of the regenerated cartilage.

Exploring the Role and Mechanism of Adipose Derived Mesenchymal Stem Cells on Reversal of Pigmentation Model Effects.

Interventions for extrinsic aging can be implemented, but these must address photoaging, which is the primary cause of extrinsic aging. Pigmentation due to photoaging depends on the duration and intensity of sun exposure. This study investigated the relationship between adipose-derived mesenchymal stem cells (ASCs) and photoaging pigmentation, and the underlying mechanism of action by establishing a photoaging pigmentation model using various treatments and exposure options in a guinea pigs. The energy dose of each UVB irradiation was 120 mJ/cm2 and the total dose of irradiation was 360 mJ/cm2. After successfully establishing the photoaging model, ASCs (1×106) in an balanced salt solution (0.9 ml), balanced salt solution (0.9 ml), and bFGF (9 μg) mixed with an balanced salt solution (0.9 ml) were injected intradermally in ten guinea pigs. ELISA, macroscopic skin and histological observations, and Masson-Fontana staining were done. At 2 and 4 weeks post-injection, noticeable changes were observed. Guinea pigs receiving ASCs injections displayed significantly lower visible skin scores while the melanin content continued to decrease. Somewhat improved histopathological morphology, including epidermal thinning, dermal thickening, and little inflammatory cell infiltration was observedimmediately after and up to 4 weeks of ASCs injection. Melanocortin 1 receptor (MC1R) and alpha-melanocyte test hormone (alpha-MSH) levels reduced significantly, and basic fibroblast growth factor (bFGF) levels increased significantly immediately after and up to 4 weeks of ASCs injection. The MC1R and alpha-MSH levels reduced significantly immediately after and up to 4 weeks of bFGF injection. Briefly, intradermal ASCs injection can notably eliminate pigmentation in a guinea pig photoaging pigmentation model. This may be related to the fact that bFGF secreted by ASCs lowers MC1R and alpha-MSH levels, blocks the cAMP signalling pathway, and inhibits melanin synthesis. This finding may present new options for treating photoaging pigmentation.Level of Evidence: N/A.

Human adipose and synovial mesenchymal stem cells improve osteoarthritis in rats by reducing chondrocyte reactive oxygen species and inhibiting inflammatory response.

BackgroundWe explored the therapeutic effects of Adipose‐derived mesenchymal stem cells (ADMSCs) and Synovial‐derived mesenchymal stem cells (SDMSCs) on osteoarthritis (OA).MethodsSDMSCs and ADMSCs were co‐cultured with chondrocytes and stimulated with interleukin (IL)‐1β. An OA model was established on rats by intra‐articular injection with ADMSCs and SDMSCs. After 8 weeks, the joint diameter difference was detected, and histological staining was used to observe the pathological changes in cartilage tissue. Enzyme‐linked immunosorbent assay (ELISA) was used to detect the expressions of IL‐6, tumor necrosis factor (TNF)‐α and IL‐1β in joint fluid. The expressions of COL2A1, Aggrecan, Matrix metalloproteinase (MMP)‐13, SOX9, IL‐6, TNF‐α and IL‐1β were detected by qRT‐PCR and Western blotting in cartilage tissue. Reactive oxygen species (ROS) content in cells and cartilage tissues was detected by ROS kit.ResultsSDMSCs and ADMSCs co‐cultured with chondrocytes could reduce MMP‐13 expression, increase the expressions of COL2A1, Aggrecan and SOX9, as well as reverse the effects of IL‐1β on promoting ROS content and inflammatory factors levels. After the OA model was established, the injection of ADMSCs and SDMSCs reduced the differences in joint diameter and tissue lesions in OA rats. The OA model led to increased levels of IL‐6, TNF‐α and IL‐1β in joint fluid and cartilage tissue, while the injection of ADMSCs and SDMSCs inhibited the inflammatory factor levels in OA rats, and increased the expressions of COL2A1, Aggrecan and SOX9 in OA rats.ConclusionADMSCs and SDMSCs improve osteoarthritis in rats by reducing chondrocyte ROS and inhibiting inflammatory response.

Intra-articular Injection of Autologous Adipose-Derived Stem Cells or Stromal Vascular Fractions: Are They Effective for Patients With Knee Osteoarthritis? A Systematic Review With Meta-analysis of Randomized Controlled Trials

Background: Intra-articular injection of adipose-derived stem cells, which are divided into adipose-derived mesenchymal stem cells (ASCs) and adipose-derived stromal vascular fractions (ADSVFs), has been reported to be a viable treatment modality for knee osteoarthritis (OA); however, its efficacy remains limited. Purpose: This study aimed to provide comprehensive information about the efficacy and safety of intra-articular injections of autologous ASCs and ADSVFs without adjuvant treatment in patients with knee OA. Study Design: Meta-analysis; Level of evidence, 1. Methods: A systematic search of the MEDLINE, Embase, Web of Science, and Cochrane Library databases was performed to identify randomized controlled trials (RCTs) that evaluated the efficacy and safety of intra-articular injections of autologous ASCs or ADSVFs without adjuvant treatments compared with placebo or hyaluronic acid in patients with knee OA. Clinically, the 100-mm visual analog scale for pain relief and the Western Ontario and McMaster Universities Osteoarthritis Index for functional improvement were implemented. Radiologically, cartilage status was assessed using magnetic resonance imaging (MRI). Procedure-related knee pain, swelling, and adverse events (AEs) were evaluated for safety. Additionally, we performed subgroup analyses comparing ASCs versus ADSVFs. Methodological quality was assessed using the modified Coleman Methodology Score (mCMS). Results: A total of 5 RCTs were included in this study. Based on the meta-analysis, ASCs or ADSVFs showed significantly better pain relief at 6 months (Z = 7.62; P < .0001) and 12 months (Z = 7.21; P < .0001) and functional improvement at 6 months (Z = 4.13; P < .0001) and 12 months (Z = 3.79; P = .0002), without a difference in procedure-related knee pain or swelling compared with controls. Although a meta-analysis with regard to cartilage improvements was not performed owing to heterogeneous MRI assessment, 3 studies reported significantly improved cartilage status after the injection. No serious AEs associated with ASCs or ADSVFs were reported. Subgroup analyses showed similar efficacy between ASC and ADSVF treatments. The median mCMS was 70 (range, 55-75). Conclusion: For patients with knee OA, intra-articular injection of autologous ASCs or ADSVFs without adjuvant treatment showed remarkable clinical efficacy and safety at short-term follow-up. Some degree of efficacy has been shown for cartilage regeneration in knee OA, although the evidence remains limited. Further RCTs that directly compare ASCs and ADSVFs are needed.

The role of adipose-derived mesenchymal stem cells in knee osteoarthritis: a meta-analysis of randomized controlled trials.

Adipose-derived mesenchymal stem cells (ADMSCs) have recently been studied for the treatment of knee osteoarthritis. The goal is pain reduction and improvement of joint function leading to superior health-related quality of life. The aim of this study was to provide a comprehensive meta-analysis assessing the evidence on the use of ADMSCs in knee osteoarthritis. This is a Meta-analysis of randomised controlled trials. PubMed/MEDLINE, Embase, and Cochrane Databases were searched for randomized controlled trials using ADMSCs to treat patients with knee osteoarthritis. Only trials comparing ADMSCs to placebo or conservative treatment were included. The outcomes studied were improvement in functional, pain, and quality of life scores along with radiographic findings. A total of four trials were included, representing 138 patients with knee osteoarthritis. WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) scores favored ADMSCs with a statistically and clinically significant difference over controls at 6- and 12-month follow-ups (p value < 0.0001). Pain, functional, and quality of life scores also favored ADMSCs at 12-month follow-up (p value < 0.0001). ADMSCs are effective in treating knee osteoarthritis symptoms as observed by functional and pain improvements. Furthermore, ADMSCs injection showed improvement of cartilage integrity, which indicates the potential for regenerating the knee cartilage. Future trials with larger number of patients and longer follow-up periods would help to elaborate further the therapeutic potential of ADMSCs. Adipose-derived mesenchymal stem cells use in knee osteoarthritis Knee osteoarthritis is an extremely common disease that causes damage of the lining of the knee joint.This will lead to pain and limited range of motion of the knee hence limited functionality.Multiple treatments are used currently for knee osteoarthritis which all aim at slowing down the progression and limiting the need for knee replacement surgery.Adipose-derived mesenchymal stem cells (ADMSCs) are stem cells harvested from the fat around the belly. These stem cells have the potential to be converted into cells of a certain origin (cartilage, muscle, fat).Many studies are being performed to see whether these cells can transform to cartilage and repair the damaged knee joint.In this study, we tried to find how the results of different studies comparing the usual treatments for knee osteoarthritis with that of ADMSCs compared.We were mostly interested in the pain, functional, stiffness, and quality of life scores.We also reviewed the MRI findings to find out whether the lining of the knee joint improved.Four studies were included with 138 patients having knee osteoarthritis.WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) score which is a self-administered questionnaire evaluating hip and knee osteoarthritis, showed better results in patients receiving ADMSC injections compared with other usual treatments at 12-month follow-up.Pain, functional, stiffness, and quality of life scores also showed better results in ADMSCs at 12-month follow-up.MRI images also showed better cartilage lining in the patients treated with ADMSCs.We concluded that ADMSCs are both effective and safe to be used in treating knee osteoarthritis symptoms. However, studies with longer follow-up periods are needed to better assess the regenerative potential of ADMSCs.