Bone Marrow-derived Mesenchymal Stem Cells Therapy Research Articles

BM-MSCs alleviate diabetic nephropathy in male rats by regulating ER stress, oxidative stress, inflammation, and apoptotic pathways.

Introduction: Diabetic nephropathy (DN), a chronic kidney disease, is a major cause of end-stage kidney disease worldwide. Mesenchymal stem cells (MSCs) have become a promising option to mitigate several diabetic complications. Methods: In this study, we evaluated the therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) in a rat model of STZ-induced DN. After the confirmation of diabetes, rats were treated with BM-MSCs and sacrificed at week 12 after treatment. Results: Our results showed that STZ-induced DN rats had extensive histopathological changes, significant upregulation in mRNA expression of renal apoptotic markers, ER stress markers, inflammatory markers, fibronectin, and intermediate filament proteins, and reduction of positive immunostaining of PCNA and elevated P53 in kidney tissue compared to the control group. BM-MSC therapy significantly improved renal histopathological changes, reduced renal apoptosis, ER stress, inflammation, and intermediate filament proteins, as well as increased positive immunostaining of PCNA and reduced P53 in renal tissue compared to the STZ-induced DN group. Conclusion: In conclusion, our study indicates that BM-MSCs may have therapeutic potential for the treatment of DN and provide important insights into their potential use as a novel therapeutic approach for DN.

Cell transplantation therapies for spinal cord injury focusing on bone marrow mesenchymal stem cells: Advances and challenges

Spinal cord injury (SCI) is a devastating condition with complex pathological mechanisms that lead to sensory, motor, and autonomic dysfunction below the site of injury. To date, no effective therapy is available for the treatment of SCI. Recently, bone marrow-derived mesenchymal stem cells (BMMSCs) have been considered to be the most promising source for cellular therapies following SCI. The objective of the present review is to summarize the most recent insights into the cellular and molecular mechanism using BMMSC therapy to treat SCI. In this work, we review the specific mechanism of BMMSCs in SCI repair mainly from the following aspects: Neuroprotection, axon sprouting and/or regeneration, myelin regeneration, inhibitory microenvironments, glial scar formation, immunomodulation, and angiogenesis. Additionally, we summarize the latest evidence on the application of BMMSCs in clinical trials and further discuss the challenges and future directions for stem cell therapy in SCI models.

Bone marrow-derived mesenchymal stem cells attenuate complete Freund's adjuvant-induced inflammatory pain by inhibiting the expression of P2X3.

Bone marrow-derived mesenchymal stem cells (BMSCs) show a good property for pain treatment by modulating inflammatory response. However, the underlying therapeutic effect and related mechanism of BMSCs on inflammatory pain remain unclear. Therefore, we explored the function and potential mechanism of BMSCs performing in a complete Freund's adjuvant (CFA)-induced inflammatory pain model in this study. Here, BMSCs were injected into the CFA-treated rats, and we used behavioural tests to evaluate the changes in hypersensitivity. High-throughput sequencing was used to screen out the hub genes. Molecular biology experiments were performed to detect the level of P2X3 or inflammatory mediators in rats and observed the distribution of P2X3 in neural cells. Furthermore, the function of the P2X3 was explored via inhibitor and activator experiments. Finally, we found that BMSCs alleviated hyperalgesia and spinal levels of pro-inflammatory factors in CFA-treated rats. High-throughput sequencing showed that P2X3 and P2X7 were identified as hub genes, and only the expression level of P2X3 was significantly down-regulated after BMSCs treatment. Immunohistochemistry showed that P2X3 mainly colocalized with microglia and astrocytes. The levels of P2X3 and pro-inflammatory factors were all significantly reduced after BMSC injection. Moreover, similar attenuation was found in the CFA-treated rats after injecting the P2X3 inhibitor, and a P2X3 antagonist reversed the attenuation induced by the BMSCs. These findings suggest that BMSCs exerted a therapeutic effect on inflammatory pain by inhibiting the expression of P2X3 and the excessive production of inflammatory mediators was associated with an increased P2X3 level and BMSC therapy reverse these effects.

Bone Marrow-Derived Mesenchymal Stem Cells Transplantation Attenuates Renal Fibrosis Following Acute Kidney Injury in Rats by Diminishing Pericyte-Myofibroblast Transition and Extracellular Matrix Augment

Renal fibrosis is a common chronic outcome of acute kidney injury (AKI). Pericyte-myofibroblasts transition and production of abundant extracellular matrix are the important pathologic basis. This study investigated the effect of bone marrow-derived mesenchymal stem cells (BMSCs) transplantation on the AKI kidney fibrosis and the possible mechanisms. By constructing the animal and cell model of AKI pericyte injury, the therapeutic effect of BMSCs on pericyte-myofibroblasts transition was detected. The production and accumulation of extracellular matrix, including collagen I, collagen III, and fibronectin were also tested. The mechanism was revealed by means of analysis of signal pathway. After AKI insult, many myofibroblasts emerged in the renal interstitium together with a large amount of extracellular matrix components. The BMSCs transplantation significantly decreased the number of myofibroblasts trans-differentiated from pericytes in the AKI model. The changes of vascular endothelial growth factor subtypes and Ang-I/AngII secreted by pericytes were also significantly reduced after BMSCs co-culture. At the same time, extracellular matrix components, including collagen I, collagen III, and fibronectin, decreased significantly. Transplantation treatment alleviated the fibrosis score. The transforming growth factor β (TGF-β) concentration decreased as well as the levels of Smad2/3 and p-Smad2/3 with the presence of BMSCs therapy. Bone marrow-derived mesenchymal stem cells transplantation diminished pericyte-myofibroblast transition and extracellular matrix augment after AKI by regulating the TGF-β/Smad2/3 signaling pathway. It may be used as a novel therapeutic method for retarding renal fibrosis, which is worthy of further study.

Mechanistic approach of the therapeutic potential of mesenchymal stem cells on brain damage in irradiated mice: Emphasis on anti-inflammatory and anti-apoptotic effects

Background and Objectives: Brain damage which has been induced by radiation generally occurs in radiotherapeutics patient. Stem cells transplantation represents a vital applicant for alleviating neurodegenerative disorders. This work aims at exploring the potential of bone marrow derived mesenchymal stem cells (BM-MSCs) on brain injury induced by γ radiation in mice and the possible underlying mechanisms were elucidated. Materials & Methods: Mice were allocated into three groups; Group I (Control), Group II (Irradiated control) where mice submitted to 5 Gy of whole body γ radiation, Group III (Irradiated + BM-MSCs) where mice were intravenouslyinjected of BM-MSCs at a dose of 106 cells/mice 24 hours following irradiation. Animals were sacrificed 28 days following exposure to γ radiation. Results: It was observed that BM-MSCs therapy provided a valuable tissue repair as evidenced by reduction in inflammatory mediators including tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), nuclear factor kappa (NF-κβ), interferon gamma (IFN γ) and monocyte chemoattractant protein-1 (MCP-1) associated with decreased levels of transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) in brain tissues of irradiated mice. Furthermore, neuronal apoptosis was declined in brain tissues of BM-MSCs group as remarkable inhibition of caspase-3 and Bax accompanied by elevation of Bcl-2 proteins expression. These results were supported by histopathological investigation. Conclusions: In conclusion, BM-MSCs could display a vital rule in alleviating brain injury in radio-therapeutic patients.

Phase I Trial of Intra-arterial Administration of Autologous Bone Marrow-Derived Mesenchymal Stem Cells in Patients with Multiple System Atrophy.

Background This study is aimed at investigating the safety and tolerability of the intra-arterial administration of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in patients with multiple system atrophy- (MSA-) cerebellar type (MSA-C). Methods This was a single-center, open-label phase I clinical trial in patients with MSA-C. A three-stage dose escalation scheme (low-dose, 3.0 × 105 cells/kg; medium-dose, 6.0 × 105 cells/kg; high-dose, 9.0 × 105 cells/kg) was applied to determine the maximum tolerated dose of intra-arterial administration of BM-MSCs based on the no-observed-adverse-effect level derived from the toxicity study. The occurrence of adverse events was evaluated 1 day before and 1, 14, and 28 days after BM-MSC therapy. Additionally, we assessed changes in the Unified MSA Rating Scale (UMSARS) score 3 months after BM-MSC treatment. Results One serious adverse drug reaction (ADR) of leptomeningeal enhancement following the intra-arterial BM-MSC administration occurred in one patient in the low-dose group. The safety review of the Internal Monitoring Committee interpreted this as radiological evidence of the blood-brain barrier permeability for MSCs. No other ADRs were observed in the medium- or high-dose groups. In particular, no ischemic lesions on diffusion-weighted images were observed in any of the study participants. Additionally, the medium- and high-dose groups tended to show a slower increase in UMSARS scores than the low-dose group during the 3-month follow-up. Conclusion The present study confirmed that a single intra-arterial administration of autologous BM-MSCs is a safe and promising neuroprotective strategy in patients with MSA-C.

Safety of autologous bone marrow-derived mesenchymal stem cells in erectile dysfunction: an open-label phase 1 clinical trial

Background aimsThe efficacy of phosphodiesterase type 5 inhibitors (PDE5Is), which are commonly used to treat erectile dysfunction (ED), is not satisfactory in patients with denervation of the cavernous nerve due to pelvic surgeries and diabetes mellitus (DM). Pre-clinical studies using bone marrow-derived mesenchymal stem cells (BMSCs) to treat ED have shown promising results. The authors conducted a phase 1 clinical trial with autologous BMSCs in patients with ED due to radical prostatectomy or DM. MethodsTen patients (five with post-prostatectomy ED and five with DM-associated ED) who could not perform sexual activity despite taking the maximum dose of a PDE5I were enrolled. The brief clinical trial protocol was registered with the US National Institutes of Health on ClinicalTrials.gov (NCT02344849). The primary outcome was the safety of stem cell therapy, and the secondary outcome was the improvement of erectile function. ResultsOf the 13 patients screened, 10 were registered in the clinical trial and received autologous BMSCs and nine completed the clinical trial. One patient with post-prostatectomy ED experienced two treatment-emergent adverse events (TEAEs) (pyrexia and back pain), and two patients with DM-associated ED experienced a total of five TEAEs (one case each of viral upper respiratory tract infection, prostatitis and pruritus and two cases of hyperglycemia). Of these patients, one with DM-associated ED experienced two serious TEAEs (two instances of hyperglycemia). All TEAEs were considered not to be related to autologous BMSC therapy. In addition, no clinical significance was identified related to other safety measures, such as laboratory tests and vital signs. The mean International Index of Erectile Function score increased significantly at 1 month versus baseline (24.9 versus 18.1, P = 0.0222). ConclusionsThis phase 1 clinical trial confirmed the safety and potential efficacy of autologous BMSC therapy in patients with ED. The authors’ results need to be confirmed by a phase 2 clinical trial.

Cordycepin promotes osteogenesis of bone marrow-derived mesenchymal stem cells and accelerates fracture healing via hypoxia in a rat model of closed femur fracture

Fracture is the most frequently encountered traumatic large-organ injury observed in human patients. Cordycepin possesses beneficial effects in osteogenesis of mesenchymal stem cells (MSCs), but its effect on fracture healing is largely unknown. A rat model of closed femur fracture was established, and treated with therapy using bone marrow-derived MSCs (BMMSCs). The effect of cordycepin on the osteogenic process of BMMSCs in vitro was evaluated by Alizarin Red S (ARS) staining and expressions of osteogenic marker genes. Radiographic evaluations and four-point bending mechanical testing were performed on model rats after BMMSC treatment, to assess the effect of cordycepin on fracture healing. Cordycepin promoted osteogenesis of BMMSCs in vitro, and enhanced radiographic parameters and mechanical properties in rat closed femur fracture model using BMMSC therapy in vivo. A hypoxia inhibitor echinomycin could negate the above-mentioned therapeutic effects of cordycepin, indicating that the beneficial effects of cordycepin were mediated via hypoxic response pathway. This study demonstrates that cordycepin promotes osteogenesis of BMMSCs and accelerates fracture healing via hypoxia in a rat model of closed femur fracture, and proposes the clinical potential of cordycepin in bone fracture treatments.

Bone Marrow-Derived and Adipose-Derived Mesenchymal Stem Cell Therapy in Primary Knee Osteoarthritis: A Narrative Review.

Regenerative medicine in the context of musculoskeletal injury is a broad term that offers potential therapeutic solutions to restore or repair damaged tissue. The current focus in recent literature and clinical practice has been on cell based therapy. In particular, much attention has been centered on autologous bone marrow concentrate and adipose-derived mesenchymal stem cells (MSCs) for cartilage and tendon disorders. This article provides an overview of MSC-derived therapy and offers a comprehensive review of adipose- and bone marrow-derived MSC therapy in primary knee osteoarthritis. LEVEL OF EVIDENCE: IV.

Superoxide dismutase 3 facilitates the chondrogenesis of bone marrow-derived mesenchymal stem cells

Articular cartilage defects are considered a major clinical problem because they cannot heal by themselves. To date, bone marrow-derived mesenchymal stem cells (BMSCs)-based therapy has been widely applied for cartilage repair. However, fibrocartilage was often generated after BMSC therapy; therefore, there is an urgent need to stimulate and maintain BMSCs chondrogenic differentiation. The specific role of superoxide dismutase 3 (SOD3) in chondrogenesis is unknown; therefore, the present study aimed to clarify whether SOD3 could facilitate the chondrogenic differentiation of BMSCs. We first evaluated SOD3 protein levels during chondrogenesis of BMSCs using plate cultures. We then tested whether SOD3 could facilitate chondrogenesis of BMSCs using knockdown or overexpression experiments. Increased SOD3 protein levels were observed during BMSCs chondrogenesis. SOD3 knockdown inhibited collagen type II alpha 1 chain (COL2A1), aggrecan (ACAN), and SRY-box 9 (SOX9) expression. Overexpression of SOD3 increased the levels of chondrogenesis markers (COL2A1, ACAN, and SOX9). Elevated superoxide anions were observed when SOD3 was knocked down. We concluded that SOD3 could facilitate chondrogenesis of BMSCs to improve cartilage regeneration.

N-Acetylcysteine enhances the therapeutic efficacy of bone marrow-derived mesenchymal stem cell transplantation in rats with severe acute pancreatitis

BackgroundSevere acute pancreatitis (SAP) is a high mortality disease, for which there is a lack of effective therapies. Previous research has demonstrated that bone marrow-derived mesenchymal stem cells (BMSCs), which have immunomodulatory and antioxidant properties, have potential for the treatment of SAP. It remains unclear, however, whether the free radical scavenger N-acetylcysteine (NAC) can enhance the therapeutic efficacy of BMSC transplantation in SAP. In this study, we investigated the effect of combining treatment with NAC and BMSCs in a rat model of SAP. MethodsSAP was induced by injection of sodium taurocholate into the pancreatic duct and, after successful induction of SAP, the rats were treated with BMSCs and NAC, either singly or in combination. ResultsAfter 3 days, serum levels of amylase, proinflammatory factors, malondialdehyde, and reactive oxygen species were significantly decreased in animals treated with BMSCs or NAC, compared with vehicle-treated animals. In contrast, total glutathione, superoxide dismutase and catalase were markedly increased after treatment with BMSCs or NAC. However, oxidative stress markers and inflammatory factors were significantly improved in the SAP + BMSCs + NAC group compared with those in the SAP + NAC group and the SAP + BMSCs group. ConclusionsCombined NAC and BMSC therapy was found to alleviate oxidative stress damage to the pancreas and to inhibit the inflammatory response to a significantly greater extent than single therapy with either BMSCs or NAC. Because NAC enhances the therapeutic efficacy of BMSC transplantation in a rat model of SAP, combined therapy may provide a promising new approach for the treatment of SAP.

Mesenchymal stem cells therapy enhances the efficacy of pregabalin and prevents its motor impairment in paclitaxel-induced neuropathy in rats: Role of Notch1 receptor and JAK/STAT signaling pathway

Peripheral neuropathy is a common adverse effect observed during the use of paclitaxel (PTX) as chemotherapy. The present investigation was directed to estimate the modulatory effect of bone marrow derived mesenchymal stem cells (BM-MSCs) on pregabalin (PGB) treatment in PTX-induced peripheral neuropathy. Neuropathic pain was induced in rats by injecting PTX (2 mg/kg, i.p) 4 times every other day. Rats were then treated with PGB (30 mg/kg/day, p.o.) for 21 days with or without a single intravenous administration of BM-MSCs. At the end of experiment, behavioral and motor abnormalities were assessed. Animals were then sacrificed for measurement of total antioxidant capacity (TAC), nerve growth factor (NGF), nuclear factor kappa B p65 (NF-κB p65), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and active caspase-3 in the sciatic nerve. Moreover, protein expressions of Notch1 receptor, phosphorylated Janus kinase 2 (p-JAK2), phosphorylated signal transducer and activator of transcription 3 (p-STAT3), and phosphorylated p38 mitogen-activated protein kinase (p-p38-MAPK) were estimated. Finally, histological examinations were performed to assess severity of sciatic nerve damage and for estimation of BM-MSCs homing. Combined PGB/BM-MSCs therapy provided an additional improvement toward reducing PTX-induced oxidative stress, neuro-inflammation, and apoptotic markers. Interestingly, BM-MSCs therapy effectively prevented motor impairment observed by PGB treatment. Combined therapy also induced a significant increase in cell homing and prevented PTX-induced sciatic nerve damage in histological examination. The present study highlights a significant role for BM-MSCs in enhancing treatment potential of PGB and reducing its motor side effects when used as therapy in the management of peripheral neuropathy.

Simvastatin and bone marrow-derived mesenchymal stem cells (BMSCs) affects serum IgE and lung cytokines levels in sensitized mice

IntroductionThe effects of bone marrow-derived mesenchymal stem cells (BMSCs) and simvastatin combination therapy on serum total and specific IgE levels and lung IL-13 and TGF-β levels in sensitized mouse were examined. Material and methodsControl (n = 5), Sensitized (S), (n = 5), S + BMSC (n = 6), S + simvastatin (n = 6) and S + BMSC + simvastatin (n = 4) groups of BALB/c mice were studied. Mice were sensitized by ovalbumin. Sensitized mice were treated with a single intravenous injection of BMSCs (1 × 106) or daily intraperitoneal injection of simvastatin (40 mg/kg) or both BMSCs and simvastatin on the last week of challenge. Serum total and ovalbumin specific IgE levels as well as IL-13 and TGF-β levels in broncho-alveolar lavage (BAL) fluid were evaluated. ResultsSerum total and specific IgE levels as well as lung IL-13 and TGF-β levels were significantly increased in S group compared to control group (P < 0.001 for all cases). Treatment with BMSCs, simvastatin and their combination significantly decreased serum total and specific IgE levels (P < 0.05 to P < 0.01). However, IL-13 and TGF-β levels were significantly decreased by BMSCs and BMSC + simvastatin combination therapy (P < 0.05 for all cases). The effect of simvastatin and BMSCs combination therapy on serum specific IgE levels as well as lung IL-13 and TGF-β levels were significantly higher than the effect of BMSCs and simvastatin alone (P < 0.001 for IL-13 and P < 0.01 for other cases). ConclusionsSimvastatin and BMSCs combination therapy affects serum IgE as well as lung IL-13 and TGFβ levels more than BMSC therapy and simvastatin therapy alone which may be due to increased BMSCs migration into the lung tissue.

Overexpression of c-Met in bone marrow mesenchymal stem cells improves their effectiveness in homing and repair of acute liver failure

BackgroundTransplantation of bone marrow-derived mesenchymal stem cells (BMSCs) has emerged as a novel therapy for acute liver failure (ALF). However, the homing efficiency of BMSCs to the injured liver sites appears to be poor. In this study, we aimed to determine if overexpression of c-Met in BMSCs could promote the homing ability of BMSCs to rat livers affected by ALF.MethodsOverexpression of c-Met in BMSCs (c-Met-BMSCs) was attained by transfection of naive BMSCs with the lenti-c-Met-GFP. The impact of transplanted c-Met-BMSCs on both homing and repair of ALF was evaluated and compared with lenti-GFP empty vector transfected BMSCs (control BMSCs).ResultsAfter cells were transfected with the lenti-c-Met-GFP vector, the BMSCs displayed very high expression of c-Met protein as demonstrated by Western blot. In addition, in vitro transwell migration assays showed that the migration ability of c-Met-BMSCs was significantly increased in comparison with that of control BMSCs (P < 0.05), and was dependent on hepatocyte growth factor (HGF). Furthermore, rats with ALF that received transplanted c-Met-BMSCs showed significantly improved homing ability to the injured liver; this was accompanied by elevated survival rates and liver function in the ALF rats. Parallel pathological examination further confirmed that transplantation of c-Met-BMSCs ameliorated liver injury with reduced hepatic activity index (HAI) scores, and that the effects of c-Met-BMSCs were more profound than those of control BMSCs.ConclusionsOverexpression of c-Met promotes the homing of BMSCs to injured hepatic sites in a rat model of ALF, thereby improving the efficacy of BMSC therapy for ALF repair.

Effect of mesenchymal stem cells on induced skeletal muscle chemodenervation atrophy in adult male albino rats

The present research was conducted to evaluate the effect of bone marrow derived mesenchymal stem cells (BM-MSCs) as a potential therapeutic tool for improvement of skeletal muscle recovery after induced chemodenervation atrophy by repeated local injection of botulinum toxin-A in the right tibialis anterior muscle of adult male albino rats. Forty five adult Wistar male albino rats were classified into control and experimental groups. Experimental group was further subdivided into 3 equal subgroups; induced atrophy, BM-MSCs treated and recovery groups. Biochemical analysis of serum LDH, CK and Real-time PCR for Bcl-2, caspase 3 and caspase 9 was measured. Skeletal muscle sections were stained with H and E, Mallory trichrome, and Immunohistochemical reaction for Bax and CD34. Improvement in the skeletal muscle histological structure was noticed in BM-MSCs treated group, however, in the recovery group, some sections showed apparent transverse striations and others still affected. Immunohistochemical reaction of Bax protein showed strong positive immunoreaction in the cytoplasm of muscle fibers in the induced atrophy group. BM-MSCs treated group showed weak positive reaction while the recovery group showed moderate reaction in the cytoplasm of muscle fibers. Immunohistochemical reaction for CD34 revealed occasional positive CD34 stained cells in the induced atrophy group. In BM-MSCs treated group, multiple positive CD34 stained cells were detected. However, recovery group showed some positive CD34 stained cells at the periphery of the muscle fibers. Marked improvement in the regenerative capacity of skeletal muscles after BM-MSCs therapy. Hence, stem cell therapy provides a new hope for patients suffering from myopathies and severe injuries.

Heparin improves BMSC cell therapy: Anticoagulant treatment by heparin improves the safety and therapeutic effect of bone marrow-derived mesenchymal stem cell cytotherapy.

Systemic infusion of bone marrow-derived mesenchymal stem cells (BMSCs) has become a promising strategy for disease treatment and tissue regeneration. Strategies to enhance the efficiency of BMSC cell therapy are crucial to promote its clinical application. Here, we aimed to improve BMSC cell therapy by inhibiting the BMSC-induced coagulation reaction. Intravenous injection of gradient BMSCs into mice showed that BMSCs were not fully compatible with blood. Large doses of BMSCs induced a series of symptoms of respiratory failure and heart failure. Histological and homeostasis analysis confirmed that large doses of BMSCs induced disseminated intravascular thrombosis, exhaustion of platelets and coagulation factors, and prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT). Similar to mouse BMSCs, goat and human BMSCs also induced coagulation reactions in vitro and in vivo. The coagulation was induced mostly by tissue factor, the overexpression of which enhanced the procoagulant activity of BMSCs during in vitro culture. Notably, clinical doses of BMSCs in cell therapy also induced mild and reversible coagulation, which increased BMSC lung embolism and clearance. Anticoagulation treatment by heparin (400 U/kg) prevented BMSC-induced coagulation and the acute adverse effects of large-dose BMSCs infusion efficiently. Importantly, heparin treatment led to decreased BMSC lung embolism and enhanced migration and maintenance of BMSCs to target organs in cell therapy. Based on an experimental colitis model, we confirmed that heparin treatment enhanced the effect of BMSC therapy efficiently to reduce mortality, prevent weight loss, suppress inflammation reaction and alleviate tissue injury. In conclusion, BMSCs possess procoagulant activity that could induce disseminated coagulation and thrombosis in recipients. Anticoagulation treatment by heparin is a practical strategy to improve both the safety and therapeutic effect of BMSC therapy.

Mesenchymal stem cells: a future experimental exploration for recession of diabetic nephropathy

Background: The progresses made in stem cell therapy offer an innovative approach and exhibit great potential for the repair of damaged organs and tissues. This study was conducted with a view to find the mechanisms responsible for the effectiveness of bone marrow-derived mesenchymal stem cells (BM-MSCs) in the suppression of diabetes and experimentally-induced diabetic nephropathy.Methods: To realize this objective, diabetic and diabetic nephropathy subject groups that underwent MSC treatment were studied through numerous biochemistry and molecular genetics analyses.Results: The findings show that, relative to the control groups, the rats in the diabetic and diabetic nephropathy groups treated with stem cells infused with BM-MSCs showed a significant reversal in the levels of their insulin, glucose, heme-oxygenase-1 (HO-1) serum, and advanced glycation end product (AGEP). Moreover, BM-MSC therapy was also found to have a definite positive effect on the kidney functions. In addition, it also corresponded with a significant decrease in the availability of certain growth factors, namely the fibroblast growth factor (FGF), the platelet-derived growth factor (PDGF), and the transforming growth factor-β (TGF-β). BM-MSC treatment also improved the levels of expression of monocyte chemoatractant-1 (MCP-1) and interleukin-8 (IL-8) genes within kidney tissues. Lastly, the treatment recovered the organizational structure of the kidney and pancreas, a result demonstrated by a histopathological analysis. These results greatly coincide with those obtained through the biochemistry and molecular genetics analyses.Conclusion: Treatment using BM-MSCs is determined to be definitely effective in cases of diabetes and diabetic nephropathy.

Evaluation of Simvastatin and Bone Marrow-Derived Mesenchymal Stem Cell Combination Therapy on Airway Remodeling in a Mouse Asthma Model.

The effect of bone marrow-derived mesenchymal stem cells (BMSCs) on asthma treatment was shown in our previous study. Several studies have shown the effect of statins on BMSC preservation and migration to sites of inflammation. In this study, the effects of simvastatin and BMSC combination therapy in an ovalbumin-induced asthma model in mouse were examined. Four groups of BALB/c mice were studied including control group (animals were not sensitized), asthma group (animals were sensitized by ovalbumin), asthma+simvastatin group (asthmatic animals were treated with simvastatin), and asthma+BMSC+simvastatin group (asthmatic animals were treated with simvastatin and BMSCs). BMSCs were isolated, characterized, labeled with BrdU, and transferred into asthmatic mice. BMSC migration, airways histopathology, and total and differential white blood cell (WBC) count in bronchoalveolar lavage (BAL) fluid were evaluated. A significant increase in the number of BrdU-BMSCs was found in the lungs of mice treated with simvastatin+BMSCs compared to mice treated with BMSCs. The histopathological changes, BAL total WBC counts, and the percentage of neutrophils and eosinophils were increased in asthma group compared to the control group. Treatment with simvastatin significantly decreased airway inflammation and inflammatory cell infiltration. Combination therapy improved all measured parameters higher than simvastatin. Goblet cell hyperplasia and subepithelial fibrosis were also decreased in combination therapy group. These results indicated that simvastatin and BMSC combination therapy was superior to simvastatin therapy and BMSC therapy alone in reduction of airway remodeling and lung inflammation in the ovalbumin-induced asthma model in mouse.

Mesenchymal stem cell therapy for the streptozotocin-induced neurodegeneration in rats

Background and Aim: Bone marrow-derived mesenchymal stem cells (BM-MSCs) are one of the sources of adult stem cells being explored for potential use in repairing neurodegenerative disorders. In this study, it was aimed to investigate the useful effects of BM-MSCs therapy on the streptozotocin-induced neurodegeneration in rats.Materials and Methods: Adult female Wistar rats were bilaterally injected intra-cerebroventricularly with streptozotocin (3 mg/kg) for neurodegeneration. Water maze tests were used to monitor spatial learning and memory. One or two intravenous injections of BM-MSCs were administrated to rat via the tail veins. At the end of the study, all rats were sacrificed for histological evaluation and immunohistochemistry.Results: Streptozotocin group demonstrated a significant increase in escape latency in comparison with both control groups (Sham and Saline), whereas rats treated with BM-MSCs exhibited a decrease in escape latency in comparison with streptozotocin group. The percentage of time spent in the target quadrant and the mean number of platform crossings did not change in all the groups. BM-MSCs administration improved spatial learning but not memory. However, improvement in neuronal cells in hippocampal CA1 region was only observed in the rats treated with BM-MSCs twice as opposed to the rats treated with BM-MSCs once or with saline.Conclusions: In this study, mesenchymal stem cells therapy failed to improve the streptozotocin-induced neurodegeneration like Alzheimer’s disease in rats.

Effect of bone marrow derived mesenchymal stem cells on lung pathology and inflammation in ovalbumin-induced asthma in mouse.

Bone marrow-derived mesenchymal stem cells (BMSCs) have attracted significant interest to treat asthma and its complication. In this study, the effects of BMSCs on lung pathology and inflammation in an ovalbumin-induced asthma model in mouse were examined. BALB/c mice were divided into three groups: control group (animals were not sensitized), asthma group (animals were sensitized by ovalbumin), asthma+BMSC group (animals were sensitized by ovalbumin and treated with BMSCs). BMSCs were isolated and characterized and then labeled with Bromodeoxyuridine (BrdU). After that the cells transferred into asthmatic mice. Histopathological changes of the airways, BMSCs migration and total and differential white blood cell (WBC) count in bronchoalveolar lavage (BAL) fluid were evaluated. A large number of BrdU-BMSCs were found in the lungs of mice treated with BMSCs. The histopathological changes, BAL total WBC counts and the percentage of neutrophils and eosinophils were increased in asthma group compared to the control group. Treatment with BMSCs significantly decreased airway pathological indices, inflammatory cell infiltration, and also goblet cell hyperplasia. The results of this study revealed that BMSCs therapy significantly suppressed the lung pathology and inflammation in the ovalbumin induced asthma model in mouse.