Bone Marrow-derived Stem Cell Therapy Research Articles

Efficacy and Safety of Bone Marrow Derived Stem Cell Therapy for Ischemic Stroke: Evidence from Network Meta-analysis.

Several types of stem cells are available for the treatment of stroke patients. However, the optimal type of stem cell remains unclear. To analyze the effects of bone marrow-derived stem cell therapy in patients with ischemic stroke by integrating all available direct and indirect evidence in network meta-analyses. We searched several databases to identify randomized clinical trials comparing clinical outcomes of bone marrow-derived stem cell therapy vs. conventional treatment in stroke patients. Pooled relative risks (RRs) and mean differences (MDs) were reported. The surface under the cumulative ranking (SUCRA) was used to rank the probabilities of each agent regarding different outcomes. Overall, 11 trials with 576 patients were eligible for analysis. Three different therapies, including mesenchymal stem cells (MSCs), mononuclear stem cells (MNCs), and multipotent adult progenitor cells (MAPCs), were assessed. The direct analysis demonstrated that stem cell therapy was associated with significantly reduced all-cause mortality rates (RR 0.55, 95% CI 0.33 to 0.93; I2=0%). Network analysis demonstrated MSCs ranked first in reducing mortality (RR 0.42, 95% CrI 0.15 to 0.86) and improving modified Rankin Scale score (MD -0.59 95% CI -1.09 to -0.09), with SUCRA values 80%, and 98%, respectively. Subgroup analysis showed intravenous transplantation was superior to conventional therapy in reducing all-cause mortality (RR 0.53, 95% CrI 0.29 to 0.88). Using stem cell transplantation was associated with reduced risk of death and improved functional outcomes in patients with ischemic stroke. Additional large trials are warranted to provide more conclusive evidence.

The Effects of Colchicum Dispert and Bone Marrow-Derived Mesenchymal Stem Cell Therapy on Skeletal Muscle Injury in a Rat Aortic Ischemia-Reperfusion Model.

Abdominal aortic aneurysms and peripheral artery disease pose significant health risks, ranking third after heart attacks and cerebral strokes. Surgical interventions often involve temporary aortic clamping, leading to ischemia-reperfusion injury and tissue damage. Colchicine and mesenchymal stem cells have shown promise, individually, in mitigating ischemia-reperfusion injury, but their combined effects remain understudied. This study utilized 42 male Wistar rats, divided into six groups: Control, Sham, Ischemia-Reperfusion, Colchicine, Mesenchymal stem cell, and Mix (colchicine and mesenchymal stem cell). The ischemia-reperfusion model involved clamping the abdominal aorta for 60 min, followed by 120 min of reperfusion. Colchicine and mesenchymal stem cell treatments were administered as pre- and post-ischemia interventions, respectively. Mesenchymal stem cells were cultured, characterized by flow cytometry, and verified for specific surface antigens. Blood and tissue samples were analyzed for oxidative stress markers, nitric oxide metabolites, and apoptosis using TUNEL. There were significant differences between the groups in terms of the serum total antioxidant capacity (p < 0.001) and inflammation markers (ischemia-modified albumin, p = 0.020). The combined therapy group (Mix) exhibited the lowest inflammation levels. Arginine levels also showed significant variation (p = 0.028), confirming the ischemia-reperfusion injury model. In muscle tissues, the total antioxidant capacity (p = 0.022), symmetric dimethylarginine, and citrulline levels (p < 0.05) indicated nitric oxide metabolism. Apoptosis was notably high in the ischemia-reperfusion injury group as anticipated. It appeared to be reduced by colchicine, mesenchymal stem cells, and their combination, with the most significant decrease observed in the Mix group (p < 0.001). This study highlights the potential of using combined colchicine and mesenchymal stem cell therapy to reduce muscle damage caused by ischemia-reperfusion injury. Further research is needed to understand the underlying mechanisms and confirm the clinical significance of this approach in treating extremity ischemia-reperfusion injuries.

Therapeutic Effect of Stem Cells from Different Sources on Diabetic Foot Ulcers: Systematic Review and Network Meta-Analysis.

To evaluate the efficacy of stem cell therapy from different sources on the ankle-brachial index, wound closure percentage, and wound closure time in the treatment of diabetic foot ulcers (DFUs). A literature search was conducted in PubMed, Embase, Cochrane Library's Central Register of Controlled Trials, and Web of Science, extending through June 29, 2023. Quality evaluation was done using the Cochrane's bias risk assessment tool (RoB 2.0). Employing a Bayesian approach, the statistical computations was executed with the JAGS software, leveraging the gemtc 0.8-2 and rjags 4-10 libraries, within the R environment 4.1.2. The included interventions came from peripheral blood, bone marrow, placenta, umbilical cord blood, adipose tissue, or others. A preliminary search identified 2286 articles, of which 23 randomized controlled trials met the inclusion criteria and were ultimately included. The analysis findings indicated that mesenchymal stem cells derived from the umbilical cord (HUCMSCs) led to a notable enhanced the ankle-brachial index in patients with DFUs compared to standard treatment (MD: 0.2; 95% CI [0.01, 0.36]). HUCMSCs were found to be the optimal therapeutic approach for enhancing the ankle-brachial index (SUCRA = 82.7%). Research on the wound closure percentage revealed that compared to platelet-rich plasma (PRP), processed microvascular tissue (PMVT), peripheral blood stem cells (PBSCs), microfragmented adipose tissue (MFAT), autologous bone marrow-derived stem cell therapy (ABMSCT), adipose-derived stem cells (ASCs), and dehydrated human umbilical cord allograft (EpiCord), Huoxue Shengji Decoction (HXSJD) + ABMSCT (H_Group_hematopoietic) significantly increased the wound closure percentage in DFU patients (P < 0.05). According to the SUCRA ranking, HXSJD + ABMSCT was the best therapeutic method to increase the percentage of wound closure (SUCRA = 93.8%). This study employed a network meta-analysis method, combining direct and indirect comparisons, to analyze the latest clinical data and concluded that umbilical cord mesenchymal stem cells and the combination of HXSJD + autologous bone marrow hematopoietic stem cell treatment as adjunctive therapies for DFUs may have beneficial effects. Future research needs to focus on this.

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.

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

Differentiation of Adipose Tissue-Derived Stem Cells into Cardiomyocytes: An Overview

Cardiovascular diseases, including congenital and acquired cardiovascular diseases, impose a severe burden on healthcare systems worldwide. Although bone marrow-derived stem cells (BMSCs) therapy can be an effective therapeutic strategy for the heart disease, relatively low abundance, difficult accessibility, and small tissue volume hinder the clinical usefulness. Adipose tissue-derived stem cells (ADSCs) show similar potential with BMSCs to differentiate into lineages and tissues, such as smooth muscle cells, endothelial cells, and adipocytes, with attractiveness of obtaining adipose tissue easily and repeatedly, and a simple separation procedure. We briefly summarize the current understanding of the cardiomyocytes differentiated from ADSCs

Bone Marrow-Derived Stem Cells for Patients with Liver Cirrhosis: A Systematic Review and Meta-analysis.

To date, studies have shown inconsistent results of treatment with bone marrow-derived stem cells (BMDSC) for patients with liver cirrhosis. This study aims to compare the efficacy and safety of BMDSC and standard therapy for liver cirrhosis. Articles from PubMed, Embase, and the Cochrane library were searched from inception to April 2018. The index included Model for End-stage Liver Disease (MELD), alanine aminotransferase (ALT), albumin, total bilirubin (TBIL), prothrombin time (PT), Child-Pugh score, and all-cause mortality. A total of 9 studies with a total of 424 patients with liver cirrhosis were included in final meta-analysis. BMDSC therapy was associated with lower MELD within 3 months (P = .010), while it had no significant impact on MELD after 6 months (P = .074). There were no differences between BMDSC and standard therapy for ALT within 3 months (P = .336) and after 6 months (P = .379). BMDSC did not affect albumin level within 3 months (P = .196) and after 6 months (P = .840). BMDSC reduced the TBIL level within 3 months (P = .037) and was not associated with the TBIL level after 6 months (P = .914). There were no differences between BMDSC and standard therapy for PT within 3 months (P = .167) and after 6 months (P = .484). The Child-Pugh scores within 3 months (P = .342) and after 6 months (P = .133) were not associated with BMDSC treatment for liver cirrhosis patients. Finally, the BMDSC was not associated with the risk of all-cause mortality, as compared with standard therapy (P = .622). BMDSC treatment for patients with liver cirrhosis could improve short-term MELD and TBIL, but not the risk of mortality, as compared with standard therapy.

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.

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.

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.

Efficacy of Stem Cell Therapy for Tendon Disorders: A Systematic Review.

Background:Stem cell therapy is an emerging treatment for tendon disorders.Purpose:To systematically review the efficacy of stem cell therapy for patients with tendon disorders.Study Design:Systematic review; Level of evidence, 4.Methods:MEDLINE/PubMed, EMBASE, CINAHL, CENTRAL, PEDro, and SPORTDiscus; trial registers; and gray literature were searched to identify randomized controlled trials (RCTs) and non-RCTs, cohort studies, and case series with 5 or more cases. Studies investigating any type of stem cell therapy for patients with tendon disorders were eligible if they included patient-reported outcome measures or assessed tendon healing. Risk of bias was assessed through use of the Cochrane risk of bias tools.Results:This review included 8 trials (289 patients). All trials had moderate to high risk of bias (level 3 or 4 evidence). In Achilles tendon disorders, 1 trial found that allogenic-derived stem cells led to a faster recovery compared with platelet-rich plasma. Another study found no retears after bone marrow–derived stem cell therapy was used in addition to surgical treatment. There were 4 trials that studied the efficacy of bone marrow–derived stem cell therapy for rotator cuff tears. The controlled trials reported superior patient-reported outcomes and better tendon healing. A further 2 case series found that stem cell therapy improved patient-reported outcomes in patients with patellar tendinopathy and elbow tendinopathy.Conclusion:Level 3 evidence is available to support the efficacy of stem cell therapy for tendon disorders. The findings of available studies are at considerable risk of bias, and evidence-based recommendations for the use of stem cell therapy for tendon disorders in clinical practice cannot be made at this time. Stem cell injections should not be used in clinical practice given the lack of knowledge about potentially serious adverse effects.

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.

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.

Autologous Bone Marrow-Derived Stem Cell Therapy for Asherman's Syndrome and Endometrial Atrophy: A 5-Year Follow-up Study.

Background:Based on the role of bone marrow (BM) stem cells in regeneration of endometrium, refractory cases of Asherman's syndrome (AS) and endometrial atrophy (EA) may benefit with BM-derived intrauterine stem cell instillation. Aims and Objectives: To evaluate the role of BM-derived autologous stem cell therapy in endometrial regeneration and restoration of menstruation and fertility in refractory cases of AS and EA.Setting:This study was conducted at a tertiary care center.Design:This was a prospective, single-arm longitudinal study.Materials and Methods:Twenty-five cases with refractory AS or EA were included. BM-derived mononuclear stem cells were instilled into the subendometrial zone followed by oral estrogen therapy for 3 months. Menstrual flow and endometrial thickness (ET) were assessed at 3, 6, and 9 months and 5 years.Results:Statistical analysis was carried out using statistical software STATA version 12.0. Mean prestem cell transfer ET (mm) was 3.3 ± 1.0. At the end of 3 months, there was a significant increase in ET (mm) to 5.1 ± 1.9 (P = 0.001), but there was no significant change at 6 months (5.6 ± 1.5; P = 0.164), at 9 months (6.1 ± 1.7; P = 0.135), or at the end of 5 years. Six of the seven amenorrheic patients resumed menses. Three patients had a successful pregnancy outcome.Conclusion:Intrauterine stem cell treatment is a promising novel approach for refractory cases of AS and EA.

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.