Marrow-derived Mesenchymal Stem Cell Therapy Research Articles

Bone marrow transplantation and bone marrow-derived mesenchymal stem cell therapy in epidermolysis bullosa: A systematic review.

Epidermolysis bullosa (EB) is a genodermatosis that lacks effective treatments and requires supportive care for its severe, life-threatening manifestations. Bone marrow transplantation (BMT) and its derived cells have been suggested to improve clinical symptoms and quality of life. A comprehensive search was conducted for publications evaluating BMT and bone marrow-derived mesenchymal stem cell (BM-MSC) therapy for EB in PubMed/MEDLINE, Google Scholar, and Cochrane databases from inception until June 2023. A total of 55 participants with severe forms of EB had BMT and/or BM-MSCs, with recessive dystrophic EB as the most common EB type; 53 (96.4%) patients had better wound healing, and 3 (5.5%) patients died of sepsis. The most common adverse events reported were graft failure, sepsis, graft-versus-host disease, and renal insufficiency. Allogeneic BMT is a high-risk procedure with possible benefits and adverse events. BM-MSCs revealed favorable outcomes to improve the safety of EB cell-based therapy by minimizing the risk of serious adverse events, reducing blisters, and accelerating wound healing. Further studies are needed to assess the treatment's long-term effects and clarify the risk/benefit ratio of procedure versus conventional therapy.

Bone Marrow-derived Mesenchymal Stem Cell Therapy in Retinitis Pigmentosa.

To determine the effectiveness of bone marrow-derived mesenchymal stem cell therapy on visual acuity and visual field in patients with retinitis pigmentosa. Stem cell treatment in retinitis pigmentosa provides improvement in visual acuity and visual field. Forty-seven eyes of 27 patients diagnosed with retinitis pigmentosa were included in our study. Allogeneic bone marrow-derived mesenchymal stem cells were administered by deep subtenon injection. Complete routine ophthalmological examinations, optical coherence tomography (Zeiss, Cirrus HD-OCT) measurements, and visual field (Humphrey perimetry, 30-2) tests were performed on all patients before the treatment and on the 1st, 3rd, and 6th month after treatment. The best corrected visual acuities of the patients were determined by the Snellen chart and converted to logMAR. Visual evoked potential (VEP) and electroretinogram (ERG) examinations of the patients before the treatment and on the 6th month after the treatment were performed (Metrovision) data were compared. Visual acuities were 0.74 ± 0.49 logMAR before treatment and 0.61 ± 0.46 logMAR after treatment. Visual acuity had a statistically significant increase (p < 0.001). The visual field deviation was found to be -27.16 ± 5.77 dB before treatment and -26.59 ± 5.96 dB after treatment (p = 0.005). The ganglion cell layer was 46.26 ± 12.87 μm before treatment and 52.47 ± 12.26 μm after treatment (p = 0.003). There was a significant improvement in Pattern VEP 120º P100 amplitude compared to that before the treatment (4.43 ± 2.42 μV) and that after the treatment (5.09 ± 2.86 μV) (p = 0.013). ERG latency measurements were 18.33 ± 15.39 μV before treatment and 20.87 ± 18.64 μV after treatment for scotopic 0.01 (p = 0.02). ERG latency measurements for scotopic 3.0 were 20.75 ± 26.31 μV before treatment and 23.10 ± 28.60 μV after treatment (p = 0.014). Retinitis pigmentosa is a progressive, inherited disease that can result in severe vision loss. In retinitis pigmentosa, the application of bone marrow-derived mesenchymal stem cells by deep subtenon injection has positive effects on visual function. No systemic or ophthalmic side effects were detected in the patients during the 6-month follow-up period.

Mechano-responsive hydrogel for direct stem cell manufacturing to therapy.

Bone marrow-derived mesenchymal stem cell (MSC) is one of the most actively studied cell types due to its regenerative potential and immunomodulatory properties. Conventional cell expansion methods using 2D tissue culture plates and 2.5D microcarriers in bioreactors can generate large cell numbers, but they compromise stem cell potency and lack mechanical preconditioning to prepare MSC for physiological loading expected in vivo. To overcome these challenges, in this work, we describe a 3D dynamic hydrogel using magneto-stimulation for direct MSC manufacturing to therapy. With our technology, we found that dynamic mechanical stimulation (DMS) enhanced matrix-integrin β1 interactions which induced MSCs spreading and proliferation. In addition, DMS could modulate MSC biofunctions including directing MSC differentiation into specific lineages and boosting paracrine activities (e.g., growth factor secretion) through YAP nuclear localization and FAK-ERK pathway. With our magnetic hydrogel, complex procedures from MSC manufacturing to final clinical use, can be integrated into one single platform, and we believe this 'all-in-one' technology could offer a paradigm shift to existing standards in MSC therapy.

Intra-amniotic mesenchymal stem cell therapy improves the amniotic fluid microenvironment in rat spina bifida aperta fetuses.

Spina bifida aperta (SBA) is one of the most common neural tube defects. Neural injury in SBA occurs in two stages involving failed neural tube closure and progressive degeneration through contact with the amniotic fluid. We previously suggested that intra-amniotic bone marrow-derived mesenchymal stem cell (BMSC) therapy for fetal rat SBA could achieve beneficial functional recovery through lesion-specific differentiation. The aim of this study is to examine whether the amniotic fluid microenvironment can be improved by intra-amniotic BMSC transplantation. The intra-amniotic BMSC injection was performed using in vivo rat fetal SBA models. The various cytokine expressions in rat amniotic fluid were screened by protein microassays. Intervention experiments were used to study the function of differentially expressed cytokines. A total of 32 cytokines showed significant upregulated expression in the BMSC-injected amniotic fluid. We focused on Activin A, NGF, BDNF, CNTF, and CXCR4. Intervention experiments showed that the upregulated Activin A, NGF, BDNF, and CNTF could inhibit apoptosis and promote synaptic development in fetal spinal cords. Inhibiting the activity of these factors weakened the anti-apoptotic and pro-differentiation effects of transplanted BMSCs. Inhibition of CXCR4 activity reduced the engraftment rate of BMSCs in SBA fetuses. BMSC transplantation can improve the amniotic fluid environment, and this is beneficial for SBA repair.

Treatment of Pulmonary Sarcoidosis Using Allogenic Bone Marrow-Derived Mesenchymal Stem Cell Therapy is Safe: A Case Report

Mesenchymal stem cells have a proven potent immunomodulatory effect both in vitro and in vivo. We report a case of a 67-year-old male patient, first diagnosed with sarcoidosis in 2005, that responded well clinically and biologically to ImmunoARTTM (developed by Educell Ltd.) allogenic, HLA-incompatible, and non-related bone marrow-derived MSCs in a dose of 106/kg. The patient presented to St. Catherine Specialty Hospital in 2021 with an exacerbation of respiratory symptoms. After a clinical and radiological examination with laboratory workup, radiological findings were consistent with pulmonary sarcoidosis, while laboratory work revealed increased leucocytes at 14.2 g/L, CRP at 51.2 mg/L, and lymphocytes at 4.25 g/L. The patient was then administered intravenous application of MSCs on three occasions in the out-patient clinic. MSC doses were prepared from a young, healthy donor who agreed to donate bone marrow for allogeneic treatment and who was negative for viral markers (HBs Ag, HBc Ab, HCV Ab, HIV 1-2 Ab, TPHA, HBV NAT, HCV NAT, HIV NAT) according to EU legislation. Cells were prepared in a controlled and verified laboratory for “Hospital exemption” cell preparation in the cleanroom facility in safety cabinet class A and expressed CD105, CD 73, and CD 90 but lacked the expression of CD45 and CD34. Before the treatment, standard print and detailed verbal information were provided to patients undergoing treatment. Immediately after the informed consent form (ICF) was signed by the patient. Throughout MSC therapy, the patient showed an improvement clinically and biologically with a decrease in inflammatory parameters. Laboratory values were assessed on days 2, 5, and 7. On day 7, leucocytes were 11.2 g/L, CRP 5.1 mg/L, and lymphocytes 4.0 g/L. In the follow-up period, the patient felt subjectively better, without any side effects of the MSC therapy. Unfortunately, the patient dropped out from follow-up, therefore, the prolonged effects of this therapy were not able to be assessed. Therefore, systemic MSC therapy presents an opportunity to treat sarcoidosis that needs to be further researched.

Treatment of Pulmonary Sarcoidosis Using Allogenic Bone Marrow-Derived Mesenchymal Stem Cell Therapy is Safe: A Case Report

Treatment of Pulmonary Sarcoidosis Using Allogenic Bone Marrow-Derived Mesenchymal Stem Cell Therapy is Safe: A Case Report

Human allogeneic bone marrow-derived mesenchymal stem cell therapy for cerebellar ataxia: A case report

To date, there is no curable treatment option for non-hereditary degenerative cerebellar ataxia. Here we report the case of a patient with sporadic adult-onset ataxia (SAOA) who underwent allogeneic bone marrow-derived mesenchymal stem cell (MSC) therapy via the intrathecal route.

Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease Using Commercial Mesenchymal Stem Cell Products.

Acute graft-versus-host disease (GVHD) is a life-threatening complication that can develop after allogeneic hematopoietic stem cell transplantation. In particular, the prognosis of patients with steroid-refractory acute GVHD is extremely poor. Ryoncil™ (remestemcel-L), a human bone marrow-derived mesenchymal stem cell (MSC) product, failed to show superiority over placebo in patients with steroid-refractory acute GVHD, but it was approved for use in pediatric patients in Canada and New Zealand based on the results of a subgroup analysis. Temcell®, an equivalent manufactured MSC product to remestemcel-L, was approved in Japan based on small single-arm studies by using a regulation for regenerative medicine in 2016. The efficacy of Temcell was evaluated in 381 consecutive patients treated with Temcell during the initial 3 years after its approval. Interestingly, its real-world efficacy was found to be equivalent to that observed in a prospective study of remestemcel-L with strict eligibility criteria. In this article, the potential of MSC therapy in the treatment of acute GVHD is discussed. A meticulous comparison of studies of remestemcel-L and Temcell, remestemcel-L/Temcell and ruxolitinib, and remestemcel-L/Temcell and thymoglobulin showed that the precise position of remestemcel-L/Temcell therapy in the treatment of acute GVHD remains to be determined.

The Interdisciplinary Stem Cell Institute's Use of Food and Drug Administration-Expanded Access Guidelines to Provide Experimental Cell Therapy to Patients With Rare Serious Diseases.

The U.S. Food and Drug Administration (FDA) provides guidance for expanded access to experimental therapies, which in turn plays an important role in the Twenty-first Century Cures Act mandate to advance cell-based therapy. In cases of incurable diseases where there is a lack of alternative treatment options, many patients seek access to cell-based therapies for the possibility of treatment responses demonstrated in clinical trials. Here, we describe the use of the FDA’s expanded access to investigational new drug (IND) to address rare and emergency conditions that include stiff-person syndrome, spinal cord injury, traumatic brain stem injury, complex congenital heart disease, ischemic stroke, and peripheral nerve injury. We have administered both allogeneic bone marrow-derived mesenchymal stem cell (MSC) and autologous Schwann cell (SC) therapy to patients upon emergency request using Single Patient Expanded Access (SPEA) INDs approved by the FDA. In this report, we present our experience with 10 completed SPEA protocols.

Compassionate mesenchymal stem cell treatment in a severe COVID-19 patient: a case report

COVID-19 presentations range from cold-like symptoms to severe symptoms with the development of acute respiratory distress syndrome (ARDS). We report on a severe COVID-19 patient who was mechanically ventilated and who developed ARDS and bacterial infection. Because of rapid clinical deterioration and the exhaustion of other treatment options, the family and attending physicians requested a compassionate use of adult allogeneic bone marrow-derived mesenchymal stem cells (MSC) in addition to commonly used immunosuppressive, antiviral, and supportive therapy. The clinical course is discussed thoroughly, with a special emphasis on the safety and effect of MSC therapy. Compassionate MSC treatment, given in three rounds, affected ARDS regression. The patient was discharged from the intensive care unit after 31 days and from hospital after 49 days in a good general condition. MSC treatment was not associated with any side effects and was well tolerated in a three-week period; therefore, it should be studied in larger trials and considered for compassionate use.

Compassionate mesenchymal stem cell treatment in a severe COVID-19 patient: a case report

COVID-19 presentations range from cold-like symptoms to severe symptoms with the development of acute respiratory distress syndrome (ARDS). We report on a severe COVID-19 patient who was mechanically ventilated and who developed ARDS and bacterial infection. Because of rapid clinical deterioration and the exhaustion of other treatment options, the family and attending physicians requested a compassionate use of adult allogenic bone marrow-derived mesenchymal stem cells (MSC) in addition to commonly used immunosuppressive, antiviral, and supportive therapy. The clinical course is discussed thoroughly, with a special emphasis on the safety and effect of MSC therapy. Compassionate MSC treatment, given in three rounds, affected ARDS regression. The patient was discharged from the intensive care unit after 31 days and from hospital after 49 days in a good general condition. MSC treatment was not associated with any side effects and was well tolerated in a three-week period; therefore, it should be studied in larger trials and considered for compassionate use.

Off-the-shelf bone marrow-derived mesenchymal stem cell treatment for acute graft-versus-host disease: real-world evidence.

Temcell is a cryopreserved, human bone marrow-derived mesenchymal stem cell (MSC) product approved for the treatment of patients of all ages with acute graft-versus-host disease (GVHD). Initial experience with Temcell in a real-world setting from a cellular therapy registry in Japan is presented. A total of 381 consecutive patients were enrolled since its approval in 2016. The median cell number infused was 2.00 × 106/kg. The most common number of infusions was 8 in 100 patients. Of the 306 evaluable patients, the overall response rate (ORR) on day 28 after the start of MSC therapy was 56%. Of the 151 evaluable patients who received it as second-line therapy following first-line steroid therapy for classic acute GVHD, the ORR was 61%. Liver involvement of GVHD and ≥14 days from first-line steroid therapy to second-line MSC therapy was associated with a lower ORR. Day 28 ORR, patient age, GVHD grade, GVHD organ involvement, and a number of GVHD therapies before MSC therapy were associated with nonrelapse mortality. Overall survival at 6 months in 381 patients was 40%. This study suggests that Temcell is one of the treatment options for steroid-refractory acute GVHD until a new treatment with survival benefit is developed.

Autologous bone marrow derived mesenchymal stem cell therapy for osteonecrosis of femoral head: A systematic overview of overlapping meta-analyses

Study designSystematic Review. ObjectivesWe performed this systematic overview on the overlapping meta-analyses that analyzed autologous bone marrow-derived mesenchymal stem cell(BM-MSC) therapy along with core decompression(CD) for the management of osteonecrosis of the femoral head(ONFH) and identify which study provides the current best evidence on the topic and generate recommendations for the same. Materials and methodsWe conducted independent and duplicate electronic database searches in PubMed, Web of Science, Embase, Cochrane Database of Systematic Reviews, and the Database of Abstracts of Reviews of Effects till September 2020 for meta-analyses that analyzed the efficacy of BM-MSC therapy along with CD for ONFH. Methodological quality assessment was made using Oxford Levels of Evidence, AMSTAR scoring, and AMSTAR 2 grades. We then utilized the Jadad decision algorithm to identify the study with the highest quality to represent the current best evidence to generate the recommendation. Results6 meta-analyses fulfilling the eligibility criteria were included. The AMSTAR scores of the included studies varied from 4 to 9 (mean:7) and all the included studies had critically low reliability in their summary of results due to their methodological flaws according to AMSTAR 2 grades. The current best evidence showed that utilization of BM-MSC therapy along with CD for ONFH resulted in significant improvement in Harris hip scores at 12 and 24 months along with a significant reduction in the necrotic area of the femoral head and the rate of conversion to total hip arthroplasty(THA) without a significant rise in adverse events due to the procedure. ConclusionBased on this systematic overview, we give a Level II recommendation that BM-MSC therapy is more efficacious along with CD in the management of ONFH compared to CD alone. BM-MSC therapy provides better pain relief with significant functional improvement and delaying the collapse of the femoral head thereby preventing further treatment such as THA.

Transamniotic mesenchymal stem cell therapy for neural tube defects preserves neural function through lesion-specific engraftment and regeneration

Neural tube defects (NTDs) lead to prenatal mortality and lifelong morbidity. Currently, surgical closure of NTD lesions results in limited functional recovery. We previously suggested that nerve regeneration was critical for NTD therapy. Here, we report that transamniotic bone marrow-derived mesenchymal stem cell (BMSC) therapy for NTDs during early development may achieve beneficial functional recovery. In our ex vivo rat embryonic NTD model, BMSCs injected into the amniotic cavity spontaneously migrated into the defective neural tissue. Hepatocyte growth factor and its receptor c-MET were found to play critical roles in this NTD lesion-specific migration. Using the in vivo rat fetal NTD model, we further discovered that the engrafted BMSCs specifically differentiated into the cell types of the defective tissue, including skin and different types of neurons in situ. BMSC treatment triggered skin repair in fetuses, leading to a 29.9 ± 5.6% reduction in the skin lesion area. The electrophysiological functional recovery assay revealed a decreased latency and increased motor-evoked potential amplitude in the BMSC-treated fetuses. Based on these positive outcomes, ease of operation, and reduced trauma to the mother and fetus, we propose that transamniotic BMSC administration could be a new effective therapy for NTDs.

Influence of Bone Marrow-Derived Mesenchymal Stem Cell Therapy on Oxidative Stress Intensity in Minimally Conscious State Patients.

Neurological disorders, including minimally conscious state (MCS), may be associated with the presence of high concentrations of reactive oxygen species within the central nervous system. Regarding the documented role of mesenchymal stem cells (MSCs) in oxidative stress neutralization, the aim of this study is to evaluate the effect of bone marrow-derived MSC (BM-MSC) transplantation on selected markers of oxidative stress in MCS patients. Antioxidant capacity was measured in cerebrospinal fluid (CSF) and plasma collected from nine patients aged between 19 and 45 years, remaining in MCS for 3 to 14 months. Total antioxidant capacity, ascorbic acid and ascorbate concentrations, superoxide dismutase, catalase, and peroxidase activity were analyzed and the presence of tested antioxidants in the CSF and plasma was confirmed. Higher ascorbic acid (AA) content and catalase (CAT) activity were noted in CSF relative to plasma, whereas superoxide dismutase (SOD) activity and total antioxidant capacity were higher in plasma relative to CSF. Total antioxidant capacity measured in CSF was greater after BM-MSC transplantations. The content of ascorbates was lower and CAT activity was higher both in CSF and plasma after the administration of BM-MSC. The above results suggest that MSCs modulate oxidative stress intensity in MCS patients, mainly via ascorbates and CAT activity.

Effect of Mesenchymal Stem Cells Therapy on Cardiovascular Risk in Experimental Diabetic Kidney Disease

Abstract Background Bone Marrow-derived Mesenchymal stem cells (MSC)s were experimentally used in treating diabetes mellitus (DM) and its complications, particularly, diabetic kidney disease (DKD). Cardiovascular diseases are the leading cause of mortality in diabetic patients, which has been strongly associated with progression of DKD. Aim This study was designed to explore the effect of MSCs in modulating cardiovascular risk factors that develop with DKD. Study Design 60 adult female albino rats were allocated into three groups: control group, untreated diabetic kidney disease group (un-DKD) and MSCs treated diabetic kidney disease group (MSC-DKD). DM was induced by a single dose of Streptozotocin at a dose of 35mg/kg, then rats were sacrificed 8 weeks later. MSC-DKD rats were treated by IV injection of bone marrow-derived MSCs 4 weeks after DM induction. DKD establishment was confirmed by histopathological kidney changes and elevated plasma creatinine and urea in both un-DKD and MSC-DKD rats. Methods Blood Pressure and lipid profile were measured, and atherogenic index was calculated to assess cardiovascular risk accompanying the progression of the diabetic renal damage. Moreover, aortic reactivity studies were performed in vitro. Results A single MSCs injection to MSC-DKD rats resulted in significant decrease in final blood glucose, mean arterial blood pressure and atherogenic index, together with a significant increase in plasma HDL level compared to untreated rats, thus minimizing cardiovascular risk factors. MSC-DKD aortae also exhibited significant enhancement of vascular reactivity parameters, particularly vasorelaxation which could partially explain the improvement of blood pressure. On the other hand, DKD didn’t improve by MSCs therapy. These results conformed to tracking labelled MSCs which were found in abundance in both aortic and pancreatic tissues and absent in kidneys. Conclusion MSCs therapy holds hope of improving cardiovascular risk and mortality for diabetic patients with diabetic Kidney disease.

Intrauterine Infusion of Human Platelet-Rich Plasma Improves Endometrial Regeneration and Pregnancy Outcomes in a Murine Model of Asherman's Syndrome.

Asherman’s syndrome (AS) is characterized by intrauterine adhesion or fibrosis resulting from damage to the endometrium, often leading to amenorrhea, infertility, or recurrent pregnancy loss. Although various therapeutic strategies for AS have been proposed, the options remain limited. New strategies such as bone marrow-derived mesenchymal stem cell (BM-MSC) therapy aim to potentiate the intrinsic capacity of endometrial regeneration. However, BM-MSC therapy has not been widely adopted mainly because it involves invasive and expensive procedures such as bone marrow biopsy and cell storing. On the other hand, platelet-rich plasma (PRP) is considered safe and affordable because it involves the less invasive procedure of blood collection from peripheral veins to produce PRP. To assess the effectiveness of human PRP infusion for endometrial regeneration, we established a murine model of injury-induced AS and evaluated endometrial morphology, expression of fibrosis-related factors, implantation sites (IS), and pregnancy outcomes associated with human PRP treatment. We found that treatment with human PRP was associated with improved endometrial morphology, reduced degree of fibrosis, and down-regulated expression of fibrosis-related factors in murine model of AS. Furthermore, human PRP treatment was associated with a higher number of IS and live-births. Our results suggest that human PRP treatment may become a valuable strategy to promote the regeneration of damaged endometrium and thus improve fertility and pregnancy outcomes in clinical practice.

The significant suppressive effect of intravenous injection of autologous bon marrow-derived mesenchymal stem cells on the gene expression and plasma level of CCL5 in patients with refractory rheumatoid arthritis

Background:Rheumatoid arthritis (RA) is the most prevalent autoimmune disease, in which CCL2 and CCL5 are critically involved. The objective was to evaluate the therapeutic effects of bone marrow-derived mesenchymal stem cells (MSCs) on the foregoing chemokines in RA patients.Materials and Methods:Thirteen RA patients were evaluated in terms of clinical manifestations, paraclinical factors, gene expression, and plasma levels of CCL2 and CCL5 prior to treatment and 1 and 6 months after intervention. Real-time-polymerase chain reaction and enzyme-linked immunosorbent assay were employed to assess the gene expression and plasma levels of CCL2 and CCL5 at different time points after MSC therapy. Statistical analysis was performed by SPSS 16 and Prism 7.Results:The CCL2 gene expression had statistically significantly increased (P = 0.034), and its plasma level had insignificantly reduced after 1 month. Furthermore, the gene expression and plasma level of CCL5 had statistically significantly decreased (P = 0.032, P < 0.001). The CCL5 gene expression had statistically significantly increased after 6 months (P = 0.001) and its plasma level had insignificantly reduced.Conclusion:The most significant inhibitory effects of MSC therapy on the gene expression and plasma level of CCL5 were observed at the end of 1 month. The differences between the gene expression and protein levels during the treatment might be related to microRNA effects or the insufficient number of MSC injection.

Bone Marrow Mesenchymal Stem Cell Therapy and Related Bone Marrow-Derived Orthobiologic Therapeutics.

The purpose of the current article is to review the available literature related to bone marrow-derived mesenchymal stem cell therapy in the management of musculoskeletal pathologies and demonstrate the critical need for additional well-designed clinical studies. In recent years, there has been a rapid increase in interest regarding the use of bone marrow-derived mesenchymal stem cells in the treatment of musculoskeletal injury and disease. The clinical use of BM-MSCs and other forms of stem cell therapy has far outpaced the basic and translational science evidence required to elucidate the potential efficacy of this orthobiologic treatment approach. Early studies have demonstrated potential clinical benefit of utilizing bone marrow-derived mesenchymal stem cell therapy in the management of knee osteoarthritis, focal chondral lesions, shoulder pathology including rotator cuff tears and glenohumeral arthritis, and degenerative disk disease in the spine. To date, most published studies are small case series often lacking a control group or a standardized method of treatment. Bone marrow-derived mesenchymal stem cell therapy is becoming an increasingly common treatment for musculoskeletal injuries and disease. Although early clinical studies have shown promising outcomes, methodological flaws and lack of standardization among trials have limited the conclusions that can be drawn from the existing literature. A better understanding of the underlying mechanism of action and more carefully designed clinical trials will help reveal the efficacy and utility of BM-MSCs as a treatment modality for various orthopedic pathologies.

The Anti-fibrotic and Anti-inflammatory Potential of Bone Marrow-Derived Mesenchymal Stem Cells and Nintedanib in Bleomycin-Induced Lung Fibrosis in Rats.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by progressive lung damage. Tyrosine kinase inhibitors are approved to treat people with IPF while bone marrow-derived mesenchymal stem cell therapy was previously suggested to inhibit pulmonary fibrosis through the alveolar epithelial cell repair. The present study aimed to evaluate the anti-inflammatory and anti-fibrotic effect of the bone marrow-derived mesenchymal stem cell (BM-MSC) therapy in comparison with nintedanib, a tyrosine kinase inhibitor, on improving survival in bleomycin-induced lung fibrosis in rats. Moreover, the combined therapy of BM-MSCs and nintedanib will be evaluated. In the present study, IPF was induced through intra-tracheal instillation of bleomycin (5mg/kg) in rats then treatments were administered 14days thereafter. Nintedanib (100mg/kg, I.P.) was administered daily for 28days, while BM-MSCs were injected once intravenously in tail vein in the dose 1 × 106cells/ml/rat. In the present study, both treatment regimens effectively inhibited lung fibrosis through several pathways, suppressing tumor growth factor-β (TGF-β)/SMAD3 expression which is considered the master signaling pathway. Nintedanib and BLM-MSCs exerted their anti-inflammatory effect through minimizing the expression of TNF-α and IL-6. In addition, the histopathological examination of the lung tissue showed a significant decrease in the alveolar wall thickening, in the inflammatory infiltrate, and in the collagen fiber deposition in response to either nintedanib or BM-MSC and their combination. In conclusion, the therapeutic pulmonary anti-fibrotic activity of nintedanib or BM-MSC is mediated through their anti-inflammatory properties and inhibition of SMAD-3/TGF-β expression.