Transplantation Of Adipose-derived Mesenchymal Stem Cells Research Articles

The effect of adipose-derived mesenchymal stem cell transplantation on ovarian mitochondrial dysfunction in letrozole-induced polycystic ovary syndrome in rats: the role of PI3K-AKT signaling pathway

ObjectiveThe present study aimed to elucidate how mesenchymal stem cells (MSCs) application could efficiently attenuate pathological changes of letrozole-induced poly cystic ovary syndrome (PCOS) by modulating mitochondrial dynamic via PI3K-AKT pathway.MethodsThirty-two female rats were randomly divided into four experimental groups: Sham, PCOS, PCOS + MSCs, and PCOS + MSCs + LY294002. The Sham group received 0.5% w/v carboxymethyl cellulose (CMC); the PCOS group received letrozole (1 mg/kg, daily) in 0.5% CMC for 21 days. Animals in the PCOS + MSCs group received 1 × 106 MSCs/rat (i.p,) on the 22th day of the study. In the PCOS + MSCs + LY294002 group, rats received LY294002 (PI3K-AKT inhibitor) 40 min before MSC transplantation. Mitochondrial dynamic gene expression, mitochondrial membrane potential (MMP), citrate synthase (CS) activity, oxidative stress, inflammation, ovarian histological parameters, serum hormone levels, homeostatic model assessment for insulin resistance (HOMA-IR), insulin and glucose concentrations, p-PI3K and p-AKT protein levels were evaluated at the end of the experiment.ResultsPCOS rats showed a significant disruption of mitochondrial dynamics and histological changes, lower MMP, CS, ovary super oxide dismutase (SOD) and estrogen level. They also had a notable rise in insulin and glucose concentrations, HOMA-IR, testosterone level, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels, ovarian malondialdehyde (MDA) content as well as a notable decrease in p-PI3K and p-AKT protein levels compared to the Sham group. In the PCOS + MSCs group, the transplantation of MSCs could improve the above parameters. Administration of LY294002 (PI3K-AKT pathway inhibitor) deteriorated mitochondrial dynamic markers, oxidative stress status, inflammation markers, hormonal levels, glucose, and insulin levels and follicular development compared to the PCOS + MSCs group.ConclusionsThis study demonstrated that the protective effects of MSC transplantation in regulating mitochondrial dynamics, promoting mitochondrial biogenesis, competing with redox status and inflammation response were mainly mediated through the PI3K-AKT pathway in the PCOS model.

Augmented reparative potential of adipose-derived stem cells with silver nanoparticles against CCl4-induced liver injury in rats

Cymbopogon citratus (lemongrass) is a widely used medicinal plant. The previous literature studies demonstrated its diverse pharmacological activities such as anti-inflammatory, anti-diabetic, antibacterial and antifungal properties. The present study involves the green synthesis of silver nanoparticles from lemongrass and their characterization by X-ray diffraction (XRD), scanning electron microscope (SEM) and Fourier transmission infrared (FTIR). The purpose of this study is to evaluate the hepatoprotective potential of silver nanoparticles derived from the aqueous extract of lemongrass (LG-NPs) in comparison with the rat adipose-derived mesenchymal stem cells (ASCs) treated with lemongrass-derived silver nanoparticles (LG-NPs + ASCs). To assess the hepatoprotective effect of LG-NPs + ASCs, CCl4-induced fibrosis model rats were employed and it was revealed that transplanting LG-NPs + ASCs decreased fibrosis development compared to transplanting naive ASCs and LG-NPs, as demonstrated by improved hepatic architecture and functions. Additionally, the liver parenchyma's expression of fibrosis-associated gene markers Interleukin 1 beta (IL-1β), Cytochrome P450 2E1 (CYP2E1), Transforming Growth Factor Beta 1 (TGF-β1), collagen type I alpha 1(Col1α1), α-smooth muscle actin (α-SMA) reduced after LG-NPs + ASCs transplantation. These results suggest that pretreating ASCs with LG-NPs increase their effectiveness.

Evaluation of canine adipose-derived mesenchymal stem cells for neurological functional recovery in a rat model of traumatic brain injury

BackgroundTraumatic brain injury (TBI) is a common condition in veterinary medicine that is difficult to manage.Veterinary regenerative therapy based on adipose mesenchymal stem cells seem to be an effective strategy for the treatment of traumatic brain injury. In this study, we evaluated therapeutic efficacy of canine Adipose-derived mesenchymal stem cells (AD-MSCs)in a rat TBI model, in terms of improved nerve function and anti-neuroinflammation.ResultsCanine AD-MSCs promoted neural functional recovery, reduced neuronal apoptosis, and inhibited the activation of microglia and astrocytes in TBI rats. According to the results in vivo, we further investigated the regulatory mechanism of AD-MSCs on activated microglia by co-culture in vitro. Finally, we found that canine AD-MSCs promoted their polarization to the M2 phenotype, and inhibited their polarization to the M1 phenotype. What’s more, AD-MSCs could reduce the migration, proliferation and Inflammatory cytokines of activated microglia, which is able to inhibit inflammation in the central system.ConclusionsCollectively, the present study demonstrates that transplantation of canine AD-MSCs can promote functional recovery in TBI rats via inhibition of neuronal apoptosis, glial cell activation and central system inflammation, thus providing a theoretical basis for canine AD-MSCs therapy for TBI in veterinary clinic.

АНТИНОЦИЦЕПТИВНОЕ И РЕПАРАТИВНОЕ ДЕЙСТВИЕ МЕЗЕНХИМАЛЬНЫХ СТВОЛОВЫХ КЛЕТОК ЖИРОВОЙ ТКАНИ ПРИ ЭКСПЕРИМЕНТАЛЬНОЙ ИШЕМИИ КОНЕЧНОСТИ

Background. Transplantation of adipose-derived mesenchymal stem cells (ADMSCs) appears to be a promising method for relieving pain in peripheral arterial diseases and revascularization of an ischemic limb. Objective. To study the effect of various modes of local administration of ADMSCs on nociceptive reactions, gait parameters, and soft tissue histostructure of the ischemic limb in rats. Material and methods. Experimental limb ischemia was induced in Wistar rats by transection of the common femoral artery with preliminary bilateral ligation. On the 7th day of the experiment, allogeneic ADMSCs were transplanted to the corresponding groups of animals in the amount of 1×106 cells/kg (single and double administration). An assessment of nociceptive reactions to a mechanical stimulus, gait parameters, as well as the histostructure of the soft tissues in the rat hind limb with ischemia was carried out. Results. Transplantation of ADMSCs at a dose of 1×106 cells/kg into the area of the hind limb ischemia, regardless of the multiplicity, weakened mechanical hyperalgesia, produced a protective effect on the myelin sheaths of nerve fibers, and contributed to the restoration of gait parameters. A single transplantation of ADMSCs proved to be more effective in terms of anti-inflammatory and anti-ischemic effects on the tissues of the ipsilateral limb. Conclusions. Local allogeneic transplantation of ADMSCs effectively attenuated mechanical hyperalgesia and gait disturbances caused by arterial transection, and prevented thinning of the myelin sheath of nerves in the area of vessel damage.

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.

Pharmacological blockade of cannabinoid type II receptors and mesenchymal stem cell transplantation in a model of peripheral neuropathic pain

Objective. To evaluate the anti-nociceptive and reparative effects of adipose-derived mesenchymal stem cells (ADMSCs) under the pharmacological blockade of cannabinoid CB2 receptors in a model of peripheral neuropathic pain.Material and methods. In 40 male Wistar rats, modeling of peripheral neuropathy (NP) was performed by excising a sciatic nerve. On day 7 of the study, ADMSCs (1 × 106 cells/kg) were transplanted into the area of sciatic nerve injury without additional influences or after administration of the CB2 receptor antagonist AM630, as well as after incubation with AM630. Within 90  days, nociceptive sensitivity was studied, as well as a detailed analysis of gait using CatWalk XT (Noldus, Netherlands). On day 21 and day 90, histostructure of the distal segment of the sciatic nerve was assessed.Results. Pharmacological blockade of CB2 receptors both on the ADMSCs and in the soft tissues surrounding the site of sciatic nerve injury led to a decrease in withdrawal threshold and withdrawal latency from day 28 of the study compared with the group of rats with NP and transplantation of ADMSCs only. Local injection of AM630 before transplantation of ADMSCs contributed to the development of  NP-induced gait disturbances and increase of the number of damaged nerve fibers in the distal segment of sciatic nerve. Transplantation of ADMSCs pretreated with  AM630 did not significantly affect the rate of recovery of gait parameters, and decreased the number of damaged nerve fibers by day 90 of study.Conclusion. Blockade of CB2 receptors, both on the membranes of MSCs and in the area of damage to the peripheral nerve, has a negative effect on the development of the anti-nociceptive and reparative effects of MSCs.

Improvement of Inflammation and Abnormal Vascularization by TSP1 Treatment Combined with ADSCs Transplantation in Mice with Induced Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disease with a certain degree of chronic inflammation and abnormal ovarian angiogenesis in reproductive women. Mesenchymal stem cells (MSCs) have potent immunomodulatory properties to regulate ovarian function, while thrombospondin 1 (TSP1) improves the abnormal formation of ovarian vessels. The present study investigated the efficacy of the combined use of adipose-derived mesenchymal stem cells (ADSCs) and TSP1 in PCOS mice. The PCOS model is established using dehydroepiandrosterone (DHEA) by subcutaneous injection. Ovarian apoptosis is assessed using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Real-time quantitative PCR (RT-PCR) and western blotting are used to detect the expression of inflammatory factors and the levels of angiogenesis-related factors in ovarian tissues. Inflammatory cells count and ovarian angiogenesis are evaluated by immunofluorescence staining. This research shows that TSP1 and ADSCs treatment can significantly reduce the inflammatory state of PCOS mice, relieve the degree of ovarian cell apoptosis, optimize the ovarian histological manifestations, and restore the levels of related hormones. The proportion of CD31-positive cells in PCOS mice returned to near-normal levels. The synergistic use of ADSCs and TSP1 therapy can exert a more impressive effect by inhibiting the ovarian inflammatory response and regulating the balance of angiogenesis than the single application in PCOS mice.

Integrated Transcriptome and Metabolomics to Reveal the Mechanism of Adipose Mesenchymal Stem Cells in Treating Liver Fibrosis.

Liver fibrosis (LF) is a late-stage process observed in various chronic liver diseases with bile and retinol metabolism closely associated with it. Adipose-derived mesenchymal stem cells (ADMSCs) have shown significant therapeutic potential in treating LF. In this study, the transplantation of ADMSCs was applied to a CCl4-induced LF model to investigate its molecular mechanism through a multi-omics joint analysis. The findings reveal that ADMSCs effectively reduced levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), gamma-glutamyltransferase (GGT), Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and α-Smooth muscle actin (α-SMA), thereby mitigating liver lesions, preventing liver parenchymal necrosis, and improving liver collagen deposition. Furthermore, 4751 differentially expressed genes (DEGs) and 270 differentially expressed metabolites (DMs) were detected via transcriptome and metabolomics analysis. Conjoint analysis showed that ADMSCs up-regulated the expression of Cyp7a1, Baat, Cyp27a1, Adh7, Slco1a4, Aldh1a1, and Adh7 genes to promote primary bile acids (TCDCA: Taurochenodeoxycholic acid; GCDCA: Glycochenodeoxycholic acid; GCA: glycocholic acid, TCA: Taurocholic acid) synthesis, secretion and retinol metabolism. This suggests that ADMSCs play a therapeutic role in maintaining bile acid (BA) homeostasis and correcting disturbances in retinol metabolism.

Promotion of adipose stem cell transplantation using GelMA hydrogel reinforced by PLCL/ADM short nanofibers

Adipose-derived mesenchymal stem cells (ADSCs) show poor survival after transplantation, limiting their clinical application. In this study, a series of poly(l-lactide-co-ϵ-caprolactone) (PLCL)/acellular dermal matrix (ADM) nanofiber scaffolds with different proportions were prepared by electrospinning. By studying their morphology, hydrophilicity, tensile mechanics, and biocompatibility, PLCL/ADM nanofiber scaffolds with the best composition ratio (PLCL:ADM = 7:3) were selected to prepare short nanofibers. And based on this, injectable gelatin methacryloyl (GelMA) hydrogel loaded with PLCL/ADM short nanofibers (GelMA-Fibers) was constructed as a transplantation vector of ADSCs. ADSCs and GelMA-Fibers were co-cultured, and the optimal loading concentration of PLCL/ADM nanofibers was investigated by cell proliferation assay, live/dead cell staining, and cytoskeleton staining in vitro. In vivo investigations were also performed by H&E staining, Oil red O staining, and TUNEL staining, and the survival and apoptosis rates of ADSCs transplanted in vivo were analyzed. It was demonstrated that GelMA-Fibers could effectively promote the proliferation of ADSCs in vitro. Most importantly, GelMA-Fibers increased the survival rate of ADSCs transplantation and decreased their apoptosis rate within 14 d. In conclusion, the constructed GelMA-Fibers would provide new ideas and options for stem cell tissue engineering and stem cell-based clinical therapies.

ПАРАМЕТРЫ ПОХОДКИ КРЫС С ПЕРИФЕРИЧЕСКОЙ НЕЙРОПАТИЕЙ ПРИ ТРАНСПЛАНТАЦИИ МЕЗЕНХИМАЛЬНЫХ СТВОЛОВЫХ КЛЕТОК И ФАРМАКОЛОГИЧЕСКОЙ СТИМУЛЯЦИИ КАННАБИНОИДНЫХ РЕЦЕПТОРОВ II ТИПА

Background. The study of the role of cannabinoid CB2 receptors in the effectiveness of adipose-derived (AD) mesenchymal stem cells (MSCs) in preventing motor activity disorders in the affected limb will deepen understanding of the mechanisms of MSCs effects when administered locally. Aim. To evaluate the effect of pharmacological stimulation of cannabinoid CB2 receptors during transplantation of AD MSCs on changes in gait parameters in rats in a model of peripheral neuropathy. Material and methods. In 40 male Wistar rats peripheral neuropathic pain was modeled by sciatic nerve transection. On the 7th day after NP modeling, AD MSCs transplantation was performed without additional interventions upon the pharmacological stimulation of CB2 receptors in the area of sciatic nerve transection, as well as after stimulation of CB2 receptors on the AD MSCs membranes during pretreatment. Within 90 days a detailed analysis of the gait was carried out using the CatWalk XT 10.6. Results. Transplantation of AD MSCs accelerated the recovery of dynamic gait parameters, as well as sciatic functional index, and abolished the development of static gait disturbances in rats after sciatic nerve transection. Significant differences in the analyzed gait parameters in the study groups with AD MSCs transplantation were not found. Conclusion. Pharmacological stimulation of CB2 receptors did not enhance or suppress the effect of AD MSCs on the rate of recovery of gait parameters in experimental animals.

Activation of type II cannabinoid receptors as variant for mesenchymal stem cell potentiation in a model of peripheral neuropathic pain

Transplantation  of  adipose-derived  mesenchymal  stem  cells  (ADMSCs)  is  currently considered as one of the treatment methods of peripheral neuropathic pain. The analgesic effect of ADMSCs has been proven, and one of the potential options for its enhancement and prolongation could be the activation of type 2 cannabinoid receptors (CB2 receptors). The antinociceptive and reparative effects of ADMSCs were analyzed after type 2 cannabinoid receptors (CB2) pharmacological stimulation by the selective agonist AM1241 on the ADMSC’s membranes and in the tissues of the area of sciatic nerve traumatic injury in rats. It was found that  pharmacological  stimulation  of  CB2  receptors  on  ADMSC’s  membranes  accelerated the  recovery  of  nociceptive  sensitivity  to  mechanical  and  thermal  stimuli  compared  with transplantation of ADMSCs alone. Early (before transplantation of ADMSCs) activation of CB2 receptors in tissues surrounding the sciatic nerve more effectively attenuated nociceptive responses to thermal stimuli in the long-term period of the experiment. Stimulation of CB2 receptors did not significantly affect the rate of recovery of gait parameters in rats after ADMSCs transplantation, but led to the structure recovery of the sciatic nerve distal segment of rats. The latter was expressed in increased proliferation of Schwann cells and a decrease in the number of damaged nerve fibers.

The role of cannabinoid CB1 receptors in the antinociceptive and reparative actions of mesenchymal stem cells in rats with peripheral neuropathic pain.

Mesenchymal stem cells (MSCs) can produce antinociceptive and reparative effects. Presumably, the MSCs-induced antinociception may be partly due to the involvement of the endocannabinoid system. The study aimed to evaluate the antinociceptive and reparative effects of adipose-derived MSCs (ADMSCs) upon pharmacological modulation of cannabinoid CB1 receptor in peripheral tissues or on ADMSCs' membranes in a rat model of peripheral neuropathy. ADMSCs were injected into the area of rat sciatic nerve injury (i) with no additional treatments, (ii) at the tissue CB1 receptor activation by endogenous agonist anandamide (AEA) or blockade with a selective AM251 antagonist; and (iii) preincubated with AEA or AM251. The evaluation of CB1 receptor activity involved analyzing nociceptive responses, gait parameters, and histology. Transplantation of ADMSCs upon activation of CB1 receptors, both on AMSCs' membranes or in the area of nerve injury, accelerated the analgesia and recovery of dynamic gait parameters, abolished static gait disturbances, and promoted the fastest nerve regeneration. Only blockade of CB1 receptors on ADMSCs shortened ADMSCs-induced analgesia and decreased the number of preserved nerve fibers. CB1 receptors on ADMSCs significantly contribute to their pain-relieving and tissue-repairing capabilities by stimulating the growth factors secretion and suppressing the release of pro-inflammatory cytokines. Peripheral CB1 receptors do not significantly influence ADMSC-induced antinociception.

Allogeneic Adipose-Derived Mesenchymal Stem Cell Transplantation Alleviates Atherosclerotic Plaque by Inhibiting Ox-LDL Uptake, Inflammatory Reaction and Endothelial Damage in Rabbits.

Atherosclerosis (AS) is a chronic inflammatory disease of arteries fueled by lipids. It is a major cause of cardiovascular morbidity and mortality. Mesenchymal stem cells have been used for the treatment of atherosclerotic lesions. Adipose-derived stem cells (ADSCs) have been shown to regulate the activation state of macrophages and exhibit anti-inflammatory capabilities. However, the effect of allogeneic ADSCs in the treatment of AS have not been investigated. In this study, the early treatment effect and preliminary mechanism analysis of allogeneic rabbit ADSCs intravenous transplantation were investigated in a high-fat diet rabbit model. The polarization mechanism of rabbit ADSCs on the macrophage was further analyzed in vitro. Compared with the model group, blood lipid levels declined, the plaque area, oxidized low-density lipoprotein (ox-LDL) uptake, scavenger receptor A1 and cluster of differentiation (CD) 36 levels were all significantly reduced, and the accumulation of inflammatory M1 macrophages, apoptosis, interleukin (IL)-6 and tumor necrosis factor (TNF)-α expression were decreased. The endothelial cells (CD31), M2 macrophages, IL-10 and the transforming growth factor (TGF)-β levels increased. In vitro, ADSCs can promote the M1 macrophage phenotypic switch toward the M2 macrophage through their secreted exosomes, and the main mechanism includes increasing arginase 1 expression and IL-10 secretion, declining inducible nitric oxide synthase (iNOS) expression and TNF-α secretion, and activating the STAT6 pathway. Therefore, allogeneic rabbit ADSC transplantation can transmigrate to the aortic atherosclerotic plaques and show a good effect in lowering blood lipids and alleviating atherosclerotic plaque in the early stage of AS by inhibiting ox-LDL uptake, inflammatory response, and endothelial damage.

Comparative evaluation of the effectiveness of systemic and local administration of mesenchymal stem cells in experimental neuropathy

Objective. Compare the effectiveness of systemic and local administration of adipose-derived mesenchymal stem cells (ADMSC) at a dose of 1х106 cells/kg on nociceptive sensitivity to mechanical and thermal stimuli in rats and changes in histostructure of sciatic nerve and surrounded tissues of affected hind paw in experimental model of peripheral neuropathy of sciatic nerve.Materials and methods. 26 male Wistar rats were used to perform a model of peripheral neuropathy by axotomy of the sciatic nerve. On the 7th day, the experimental animals underwent systemic or local transplantation of ADMSC at a dose of 1x106 cells/kg. Nociceptive responses to mechanical and thermal stimuli were assessed for 90 days, and the histostructure of the sciatic nerve and surrounding tissues was analyzed after systemic and local transplantation of ADMSC.Results. Systemic administration of ADMSC at a dose of 1x106 cells/kg to rats with sciatic nerve axotomy increased the mechanical withdrawal threshold (MWT) by 17.1% and had no effect on the thermal withdrawal latency (TWL). Local administration of ADMSCs in an equivalent dose contributed to the full recovery of the MWT and TWL by the 21st day of the experiment, as well as suppressed the inflammatory reaction in the soft tissues of the operated hind paw of experimental animals.Conclusion. Intramuscular administration of ADMSC into the area of sciatic nerve axotomy of rats was significantly more effective than systemic administration of an equivalent dose of a cell transplant. This method of administration is more appropriate for further studies of the mechanisms of antinociceptive and reparative effects of ADMSCs.

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.

Mitochondrial Transfer Induced by Adipose-Derived Mesenchymal Stem Cell Transplantation Improves Cardiac Function in Rat Models of Ischemic Cardiomyopathy.

Although mesenchymal stem cell transplantation has been successful in the treatment of ischemic cardiomyopathy, the underlying mechanisms remain unclear. Herein, we investigated whether mitochondrial transfer could explain the success of cell therapy in ischemic cardiomyopathy. Mitochondrial transfer in co-cultures of human adipose-derived mesenchymal stem cells and rat cardiomyocytes maintained under hypoxic conditions was examined. Functional recovery was monitored in a rat model of myocardial infarction following human adipose-derived mesenchymal stem cell transplantation. We observed mitochondrial transfer in vitro, which required the formation of cell-to-cell contacts and synergistically enhanced energy metabolism. Rat cardiomyocytes exhibited mitochondrial transfer 3 days following human adipose-derived mesenchymal stem cell transplantation to the ischemic heart surface post-myocardial infarction. We detected donor mitochondrial DNA in the recipient myocardium concomitant with a significant improvement in cardiac function. Mitochondrial transfer is vital for successful cell transplantation therapies and improves treatment outcomes in ischemic cardiomyopathy.

Regenerative Effect of Adipose Derived Mesenchymal Stem Cells on Ganglion Cells in the Hypoxic Organotypic Retina Culture.

To examine whether ischemic retinal ganglion cells (RGCs) will be salvaged from cell death by human adipose-derived mesenchymal stem cells (ADSCs) in an organotypic retina model. Deprived of arterial oxygen supply, whole mice retinas were cultured as an ex vivo organotypic cultures on an insert membrane in a 24-well plate. The therapeutic potential of ADSCs was examined by co-culture with organotypic retinas. ADSCs were seeded on top of the RGCs allowing direct contact, or at the bottom of the well, sharing the same culture media and allowing a paracrine activity. The number of surviving RGCs was assessed using Brn3a staining and confocal microscopy. Cytokine secretion of ADSCs to medium was analyzed by cytokine array. When co-cultured with ADSCs, the number of surviving RGCs was similarly significantly higher in both treatment groups compared to controls. Analysis of ADSCs cytokines secretion profile, showed secretion of anti-apoptotic and pro-proliferative cytokines (threshold＞1.4). Transplantation of ADSCs in a co-culture system with organotypic ischemic retinas resulted in RGCs recovery. Since there was no advantage to direct contact of ADSCs with RGCs, the beneficial effect seen may be related to paracrine activity of ADSCs. These data correlated with secretion profile of ADSCs' anti-apoptotic and pro-proliferative cytokines.

Autologous Adipose-Derived Mesenchymal Stem Cell Transplantation for Management of Chronic Kidney Disease Patients: A Clinical Trial in Human

The current clinical trial presents a review of CKD-patients enrolled for Autologous Adipose-Derived Mesenchymal Stem Cells (adMSCs) transplantation at Bangladesh Laser & Cell Surgery (BLCS) Institute & Hospital. Between April 2019 to June 2021, 52 CKD-patients were enrolled in this phase 1 & 2 trial receiving intravenous autologous adMSCs transplantation. Twenty-three CKD-patients who had received MSCs transplantation and had also followed-up with di-ethylene tri-amine Penta-acetic acid (DTPA) -based glomerular filtration rate (GFR) assessment, were considered for analysis. The mean (SD) DTPA-based GFR was significantly improved after adMSCs transplantation among study participants than the baseline mean (SD) DTPA-based GFR (19.79 [12.4] vs 15.07 [11.4], p=0.003). The DTPA-based GFR improved in stage-5 CKD patients with and without dialysis after MSCs transplantation, but a significant mean difference was observed only in CKD patients on dialysis (7.1 [6.9] vs 14.2 [12.6], p=0.011). Hence, pre-dialysis patients DTPA-GFR both at baseline and endline was higher than patients those on dialysis. The obtained results revealed that renal function improves in CKD patients through MSCs transplantation. No significant side effects or complication pertaining specifically to stem cell transplantation was observed during the study period.

Adipose‑derived mesenchymal stem cell‑derived HCAR1 regulates immune response in the attenuation of sepsis.

Sepsis serves as a leading cause of admission to and death of patients in the intensive care unit (ICU) and is described as a systemic inflammatory response syndrome caused by abnormal host response to infection. Adipose-derived mesenchymal stem cells (ADSCs) have exhibited reliable and promising clinical application potential in multiple disorders. However, the function and the mechanism of ADSCs in sepsis remain elusive. In the present study, the crucial inhibitory effect of ADSC-derived hydroxy-carboxylic acid receptor 1 (HCAR1) on sepsis was identified. Reverse transcription quantitative-PCR determined that the mRNA expression of HCAR1 was reduced while the mRNA expression of Toll-like receptor 4 (TLR4), major histocompatibility complex class II (MHC II), NOD-like receptor family pyrin domain containing 3 (NLRP3), and the levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), and interleukin-18 (IL-18) were enhanced in the peripheral blood of patients with sepsis. The expression of HCAR1 was negatively correlated with TLR4 (r=−0.666), MHC II (r=−0.587), and NLRP3 (r=−0.621) expression and the expression of TLR4 was positively correlated with NLRP3 (r=0.641), IL-1β (r=0.666), TNF-α (r=0.606), and IL-18 (r=0.624) levels in the samples. Receiver operating characteristic (ROC) curve analysis revealed that the area under the ROC curve (AUC) of HCAR1, TLR4, MHC II and NLRP3 mRNA expression was 0.830, 0.853, 0.735 and 0.945, respectively, in which NLRP3 exhibited the highest diagnostic value, and the AUC values of IL-1β, IL-18, TNF-α, and IL-10 were 0.751, 0.841, 0.924 and 0.729, respectively, in which TNF-α exhibited the highest diagnostic value. A sepsis rat model was established by injecting lipopolysaccharide (LPS) and the rats were randomly divided into 5 groups, including a normal control group (NC group; n=6), a sepsis model group (LPS group; n=6), an ADSC transplantation group (L + M group; n=6), a combined HCAR1 receptor agonist group [L + HCAR1 inducer (Gi) + M group; n=6], and a combined HCAR1 receptor inhibitor group [L + HCAR1 blocker (Gk) + M group; n=6]. Hematoxylin and eosin staining determined that ADSCs attenuated the lung injury of septic rats and ADSC-derived HCAR1 enhanced the effect of ADSCs. The expression of HCAR1, TLR4, MHC II, NLRP3, IL-1β, IL-18 and TNF-α levels were suppressed by ADSCs and the effect was further induced by ADSC-derived HCAR1. However, ADSC-derived HCAR1 induced the levels of anti-inflammatory factor IL-10. The negative correlation of HCAR1 expression with TLR4, MHC II, and NLRP3 expression in the peripheral blood and lung tissues of the rats was then identified. It is thus concluded that ADSC-derived HCAR1 regulates immune response in the attenuation of sepsis. ADSC-derived HCAR1 may be a promising therapeutic strategy for sepsis.

Rapamycin Improves Adipose-Derived Mesenchymal Stem Cells (ADMSCs) Renoprotective Effect against Cisplatin-Induced Acute Nephrotoxicity in Rats by Inhibiting the mTOR/AKT Signaling Pathway.

Objective: Because the poor survival of transplanted cells in a hostile microenvironment limits stem cell therapy, in the current study, we investigated the effect of rapamycin (Rapa)-preactivated autophagy on the survival and homing of transplanted adipose mesenchymal stem cells (ADMSCs) in a rat model of cisplatin (Cis)-induced nephrotoxicity, as well as the possible role of the mTOR/AKT signaling pathway. Materials and methods: In vitro, ADMSCs isolated from rats were treated with 50 nmol/L rapamycin for 2 h, after which the cytoprotective and autophagy-inducing effects of Rapa were investigated. The cis-induced acute nephrotoxicity rat model was constructed in vivo. ADMSCs and Rapa-ADMSCs were administered into the tail vein before Cis therapy. At 3, 7, and 10 days after Cis injection, all animals were euthanized. The renal functions and morphology as well as autophagy response were assessed. Results: The pretreatment of cultured ADMSCs with Rapa caused a significant increase in autophagic activities and lysosome production of the cells, with a significant increase in the secretion of SDF-1, IL-10 and autophagy promoter LC3 and Beclin from these cells, while mTOR/AKT pathways were inhibited. In addition, the transplantation of Rapa-pretreated ADMSCs restored the kidney functions and morphology dramatically. Renal expression of SDF-1 and HIF1 was upregulated, while expression of IL-6, NF-kB and TGF-β1 was downregulated. Conclusions: We concluded that the preactivation of autophagy with Rapa improves the survival and differentiation of the transplanted ADMSCs by inhibiting the mTOR/AKT signaling pathway, which in turn could significantly attenuate the Cis-induced acute renal injury.