Mesenchymal Stem Cells In Patients Research Articles

Treatment of erectile dysfunction by intracavernosal administration of mesenchymal stem cells in patients with diabetes mellitus.

The purpose of study is to assess and analyse the effectiveness of their use in the treatment of erectile dysfunction in patients with diabetes mellitus. The literature search was conducted using systematic methods and analysis in databases such as Web of Science, Scopus, PubMed, Elsevier, and Springer, with 41 sources included for further review. The study highlights microangiopathic and neuropathic links as key factors in erectile dysfunction development in diabetic patients, stemming from endothelial dysfunction and conductivity disturbances. Mesenchymal stem cell therapy from bone marrow, adipose tissue, and umbilical cord mitigates pathogenic impact through regenerative and anti-apoptotic effects. Due to this, most studies indicate high efficacy of the treatment and rapid therapeutic action through intracavernosal administration. Some studies suggest an increase in the body's receptor sensitivity to other drugs, such as sildenafil. From the perspective of further research on this issue, standardising the preparation of stem cells and the treatment method using a large sample size is essential to introduce such a method as an extremely promising therapy for this delicate issue in men into practical medicine. The practical value of the study lies in the systematisation of information on different sources of mesenchymal stem cells for treating erectile dysfunction.

Characterization of the biological and transcriptomic landscapes of bone marrow-derived mesenchymal stem cells in patients with multiple myeloma

BackgroundMesenchymal stem/stromal cells (MSCs) have been acknowledged as the most important stromal cells in the bone marrow (BM) microenvironment for physiologic hematopoiesis and the concomitant hematologic malignancies. However, the systematic and detailed dissection of the biological and transcriptomic signatures of BM-MSCs in multiple myeloma (MM) are largely unknown.MethodsIn this study, we isolated and identified BM-MSCs from 10 primary MM patients and 10 healthy donors (HD). On the one hand, we compared the multifaceted biological characteristics of the indicated two BM-MSCs, including biomarker expression pattern, multilineage differentiation potential, stemness and karyotyping, together with the cellular vitality and immunosuppressive property. On the other hand, we took advantage of RNA-SEQ and bioinformatics analysis to verify the similarities and differences at the transcriptomic level between MM-MSCs and HD-MSCs.ResultsAs to biological phenotypes and biofunctions, MM-MSCs revealed conservation in immunophenotype, stemness and differentiation towards adipocytes and chondrocytes with HD-MSCs, whereas with impaired osteogenic differentiation potential, cellular vitality and immunosuppressive property. As to transcriptomic properties, MM-MSCs revealed multidimensional alterations in gene expression profiling and genetic variations.ConclusionsOverall, our date systematic and detailed reflected the multifaceted similarities and variations between MM-MSCs and HD-MSCs both at the cellular and molecular levels, and in particular, the alterations of immunomodulation and cellular viability of MM-MSCs, which wound benefit the further exploration of the pathogenesis and new drug application (NDA) of multiple myeloma from the view of BM-MSCs.

Intrathecal administration of mesenchymal stem cells in patients with adrenomyeloneuropathy.

X-linked adrenomyeloneuropathy (AMN) is an inherited neurodegenerative disorder associated with mutations in the ABCD1 gene and the accumulation of very long-chain fatty acids (VLFCAs) in plasma and tissues. Currently, there is no effective treatment for AMN. We have aimed to evaluate the therapeutic effects of mesenchymal stem cell (MSC) transplantation in patients with AMN. This is a small cohort open-label study with patients with AMN diagnosed and treated at the University Hospital in Olsztyn, Poland. All patients met clinical, biochemical, MRI, and neuropsychological criteria for AMN. MSCs derived from Wharton jelly, 20 × 106 cells, were administered intrathecally three times every 2 months, and patients were followed up for an additional 3 months. The primary outcome measures included a blinded assessment of lower limb muscle strength with the Medical Research Council Manual Muscle Testing scale at baseline and on every month visits until the end of the study. Additional outcomes included measurements of the timed 25-feet walk (T25FW) and VLFCA serum ratio. Three male patients with AMN with an age range of 26-37 years participated in this study. All patients experienced increased muscle strength in the lower limbs at the end of the study versus baseline. The power grade increased by 25-43% at the baseline. In addition, all patients showed an improvement trend in walking speed measured with the T25FW test. Treatment with MSCs in patients with AMN appeared to be safe and well tolerated. The results of this study demonstrated that intrathecal administration of WJ-MSC improves motor symptoms in patients with AMN. The current findings lend support to the safety and feasibility of MSC therapy as a potentially viable treatment option for patients with AMN.

Efficacy and safety of mesenchymal stem cells in patients with acute ischemic stroke: a meta-analysis

ObjectiveThis meta-analysis and systematic review were conducted to comprehensively evaluate the efficacy and safety of mesenchymal stem cells in patients with acute ischemic stroke.MethodWe conducted a manual search of electronic databases, including PubMed, Embase, the Cochrane Library, and Web of Science, with a search deadline set for February 1, 2023. Data analysis was performed using Stata version 15.0.ResultA total of 9 randomized controlled studies were included, involving a total of 316 people, including 159 mesenchymal stem cells and 147 control groups. Results of meta-analysis: Compared to a placebo group, the administration of mesenchymal stem cells resulted in a significant reduction in the National Institutes of Health Stroke Scale (NIHSS) scores among patients diagnosed with acute ischemic stroke [SMD=-0.99,95% CI (-1.93, -0.05)]. Compared to placebo, barthel index [SMD = 0.48,95% CI (-0.55,1.51)], modified rankin score [SMD = 0.45, 95% CI (1.11, 0.21)], adverse events (RR = 0.68, 95% CI (0.40, 1.17)] the difference was not statistically significant.ConclusionBased on current studies, mesenchymal stem cell transplantation can ameliorate neurological deficits in patients with ischemic stroke to a certain extent without increasing adverse reactions. However, there was no significant effect on Barthel index and Modified Rankin score.

METTL3-Mediated m6A Modification Regulates the Osteogenic Differentiation through LncRNA CUTALP in Periodontal Mesenchymal Stem Cells of Periodontitis Patients.

Periodontitis is a chronic inflammatory disease that causes loss of periodontal support tissue. Our objective was to investigate the mechanism by which METTL3-mediated N6-methyladenosine modification regulates the osteogenic differentiation through lncRNA in periodontal mesenchymal stem cells in patients with periodontitis (pPDLSCs). Material and Methods. We carried out a series of experiments, including methylated RNA immunoprecipitation-PCR, quantitative real-time polymerase chain reaction, and western blotting. The expressions of alkaline phosphatase (ALP), Runx2, Col1, Runx2 protein level, ALP staining, and Alizarin red staining were used to demonstrate the degree of osteogenic differentiation. We found that METTL3 was the most significantly differentially expressed methylation-related enzyme in pPDLSCs and promoted osteogenic differentiation of pPDLSCs. METTL3 regulated the stability and expression of lncRNA CUTALP, while lncRNA CUTALP promoted osteogenic differentiation of pPDLSCs by inhibiting miR-30b-3p. At different time points of osteogenic differentiation, lncRNA CUTALP expression was positively correlated with Runx2, while miR-30b-3p showed the opposite pattern. The attenuated osteogenic differentiation induced by METTL3 knockdown was recovered by lncRNA CUTALP overexpression. The attenuated osteogenic differentiation induced by lncRNA CUTALP knockdown could be reversed by the miR-30b-3p inhibitor. In summary, METTL3/lncRNA CUTALP/miR-30b-3p/Runx2 is a regulatory network in the osteogenic differentiation of pPDLSCs.

The Safety and Efficacy of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Patients With Heart Failure and Myocardial Infarction: A Meta-Analysis of Clinical Trials.

Evidence from preclinical and clinical studies suggests that human umbilical cord-derived mesenchymal stromal cells (HUC-MSCs) may be useful in treating heart failure and acute myocardial infarction (MI). However, the effects of stem cell therapy on patients with heart failure remain the subject of ongoing controversy, and the safety and effectiveness of HUC-MSCs therapy have not yet been proven. To date, there has been no systematic overview and meta-analysis of clinical studies using HUC-MSCs therapy for heart failure and MI. The purpose of this study is to assess the safety and efficacy of HUC-MSC therapy versus a placebo in patients with heart failure and MI. While preparing this systematic review and meta-analysis, we adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A computer literature search of PubMed was performed. We considered randomized controlled trials (RCTs) that reported data on the safety and efficacy of HUC-MSC transplantation in patients with heart failure and MI. Two investigators independently searched the literature, extracted data, and rated the quality of the included research. Pooled data were analyzed using the fixed-effect model or the random-effect model in Review Manager 5.3. The Cochrane risk of bias tool was used to assess the bias of included studies. The primary outcome was ejection fraction (EF), whereas the secondary outcomes were readmission and mortality rates. Three RCTs (201 patients) were included in this meta-analysis. The overall effect did not favor either of the two groups in terms of risk of readmission (risk ratio = 0.5, 95% confidence interval (CI) = 0.22-1.15, p = 0.10) as well as mortality rate (risk ratio = 0.44, 95% CI = 0.14-1.44, p = 0.18). However, there was an improvement in EF in patients who received HUC-MSCs compared to placebo after 12 months of transplantation (mean difference (MD) = 3.21, 95% CI = 2.91-3.51, p < 0.00001). At the six-month follow-up period, there was no significant improvement in EF (MD = 1.30, 95% CI = -1.94-4.54), p = 0.43), indicating that the duration of follow-up can shape the response to therapy. Our findings indicate that HUC-MSC transplantation can improve EF but has no meaningful effect on readmission or mortality rates. Existing evidence is insufficient to confirm the efficacy of HUC-MSCs for broader therapeutic applications. Therefore, additional double-blind RCTs with larger sample sizes are required.

Subcutaneous and Intravenous Administration of Human Umbilical Cord Mesenchymal Stem Cells in Patient With Multiple Foot Ulcers Complicated by Scleroderma- A Case Report with One Year Follow Up

We treated a patient with progressive, refractory scleroderma with multiple ulcers on her feet with a combination of intravenous and a subcutaneous injection at the periphery of the ulcers using Umbilical Cord-Derived Mesenchymal Stem Cells (UCMSCs). The patient improved subjectively and objectively and we have followed up with the patient for 1 year. The combination was well tolerated and effective, suggesting a large-scale study may be warranted for progressive, refractory scleroderma ulcer treatment.

Alteration in apoptosis and ataxia telangiectasia mutated (ATM) gene expression in mesenchymal stem cells in patients with idiopathic acquired aplastic anemia

Alteration in apoptosis and ataxia telangiectasia mutated (ATM) gene expression in mesenchymal stem cells in patients with idiopathic acquired aplastic anemia

Icariin promotes the proliferation and osteogenic differentiation of bone-derived mesenchymal stem cells in patients with osteoporosis and T2DM by upregulating GLI-1

BackgroundThe function of mesenchymal stem cells (MSCs) from patients with osteoporosis (OP) is impaired and worsens in patients with type 2 diabetes mellitus (T2DM). Icariin (ICA) is the major active flavonoid glucoside isolated from traditional Chinese herbal Epimedium pubescens, and confirmed able to improve bone mass of OP patients.ObjectiveTo investigate the effect of ICA on the proliferation and osteogenic differentiation of bone-derived MSCs (BMSCs) from patients with OP and T2DM and uncover the potential mechanism.MethodsBMSCs were treated with ICA, and proliferation and osteogenic potency were evaluated using the 2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and detection of osteogenic markers (ALP, RUNX2, SPP1, COL1A1, and mineralized nodules) was performed. RNA sequencing and bioinformatic analysis were performed to identify differentially expressed genes (DEGs) after ICA treatment and screen proliferation- and osteogenic differentiation-related processes. Gene gain and loss were performed to confirm the role of the key candidate gene.ResultsICA significantly promoted the proliferation and osteogenic differentiation of BMSCs. A total of 173 DEGs were identified after ICA treatment. Six DEGs (GLI-1, IGF2, BMP6, WNT5A, PTHLH, and MAPK14) enriched in both proliferation- and osteogenic differentiation-related processes were screened; GLI-1 had the highest validated |log2FC| value. Overexpression of GLI-1 enhanced the proliferation and osteogenic differentiation of BMSCs, and knockdown of GLI-1 weakened the positive effect of ICA on BMSCs.ConclusionICA promoted the proliferation and osteogenic differentiation of impaired BMSCs by upregulating GLI-1.

Effect and safety of mesenchymal stem cells for patients with COVID-19: Systematic review and meta-analysis with trial sequential analysis.

The objective of this study was to assess whether mesenchymal stem cells (MSCs) therapy could offer survival advantages for patients with novel coronavirus disease 2019 (COVID-19). An electronic search of PubMed, Embase, Cochrane Library, Web of Science, WanFang, and CNKI was performed from December 1, 2019 to December 25, 2022. The primary outcome was all-cause mortality. Trial sequential analysis (TSA) was conducted in this meta analysis. Besides, subgroup analysis and meta-regression was performed using a random-effects model to find the potential sources of heterogeneity. Seventeen randomized controlled trials (RCTs) involving a total of 1073 patients with COVID-19 were included in this study. Compared with the control group, patients in the MSCs groups were associated with significantly reduced all-cause mortality (MSCs 18.4% vs. control 25.5%; risk ratio [RR] 0.73; 95% confidence interval [CI] 0.59-0.90; p = 0.004; I² = 0%). For all secondary outcomes, there wasn't significant improvement in the experimental group versus the control group regarding symptom remission rate (53.2%, 201/378 vs. 46.5%, 164/353; RR 1.15; 95% CI 1.00-1.32; p = 0.05; I² = 43%), but the pooled analysis revealed significant differences between the groups in length of hospital stay(MD: -3.82, 95% CI: -5.87 to -1.77; p = 0.0003, I2 = 0%), requirement of invasive mechanical ventilation(RR 0.52; 95% CI 0.33-0.82; p = 0.005; I2 = 0%) and post-CRP level (MD: -31.61; 95% CI -46.74 to -16.49; p < 0.0001). Moreover, regarding the incidence of adverse events (AEs) (RR 0.73; 95% CI 0.35-1.52; p = 0.39; I² = 44%) and serious adverse events (sAEs) (RR 0.87; 95% CI 0.40-1.92; p = 0.73; I² = 39%), no significant differences were observed between MSCs and control groups. The TSA analysis showed that the result of all-cause mortality might be false-positive result. Based on the pooled results in this study, compared with standard treatment, MSCs therapy may reduce all-cause mortality of patients with COVID-19 with no increase risk of AEs and sAEs, but may not improve symptom remission rate. Further more high-quality and large-sample RCTs should be performed to confirm these findings.

Smoking Status Impacts Mitochondrial Function in Peripheral Arterial Disease Patient-Derived Mesenchymal Stem Cells

INTRODUCTION: Patient mesenchymal stem cells (MSCs) present a new regenerative medicine tool to treat peripheral arterial disease (PAD). Mitochondrial function, i.e., bioenergetics, and turnover via mitophagy are key regulators of “stemness” and may impact regenerative potential of MSCs. Patient smoking status is known to impact MSC proliferation, but the effect on mitochondrial function is unknown. We hypothesize that smoking status impacts mitophagy and mitochondrial bioenergetics in MSCs. METHODS: Non-PAD MSCs were purchased from ATCC. PAD MSCs were obtained after major amputation under our IRB-approved project, Learning from Failure. Mitochondria were stained with Mitotracker Green FM and lysosomes with Lysotracker Deep Red for co-localization in live cells using confocal microscopy. Co-localization was quantified using FIJI software and reported using Spearman’s Rank correlation coefficient. Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were measured using the Seahorse XFe96 Analyzer. RESULTS: Two PAD patient lines were from smokers and two from non-smokers. Mitophagy (co-localization of mitochondria with lysosomes) did not differ significantly by smoking status in PAD MSCs. PAD MSCs also did not differ in mitophagy when compared with the non-PAD control. Maximal mitochondrial respiration (maximal OCR) differed significantly among the smoking PAD, non-smoking PAD, and non-PAD control MSCs (p < .0001). Glycolytic capacity (ECAR) also differed significantly between groups (p < .0001) (Figure). CONCLUSION: Active smoking status affected mitochondrial bioenergetics in patient MSCs, suggesting a potential impact on “stemness.” Further characterization of the impact of smoking on regenerative capacity of patient MSCs will inform optimal development of stem cell-based therapies to treat PAD.Figure

Topical and intravenous administration of human umbilical cord mesenchymal stem cells in patients with diabetic foot ulcer and peripheral arterial disease: a phase I pilot study with a 3-year follow-up

BackgroundDiabetic foot ulcer (DFU) is a serious chronic complication of diabetes mellitus that contributes to 85% of nontraumatic lower extremity amputations in diabetic patients. Preliminary clinical benefits have been shown in treatments based on mesenchymal stem cells for patients with DFU or peripheral arterial disease (PAD). However, the long-term safety and benefits are unclear for patients with both DFU and PAD who are not amenable to surgical revascularization.MethodsIn this phase I pilot study, 14 patients with PAD and incurable DFU were enrolled to assess the safety and efficacy of human umbilical cord mesenchymal stem cell (hUC-MSC) administration based on conservative treatments. All patients received topical and intravenous administrations of hUC-MSCs at a dosage of 2 × 105 cells/kg with an upper limit of 1 × 107 cells for each dose. The adverse events during treatment and follow-up were documented for safety assessments. The therapeutic efficacy was assessed by ulcer healing status, recurrence rate, and 3-year amputation-free rate in the follow-up phase.ResultsThe safety profiles were favorable. Only 2 cases of transient fever were observed within 3 days after transfusion and considered possibly related to hUC-MSC administration intravenously. Ulcer disclosure was achieved for more than 95% of the lesion area for all patients within 1.5 months after treatment. The symptoms of chronic limb ischaemia were alleviated along with a decrease in Wagner scores, Rutherford grades, and visual analogue scale scores. No direct evidence was observed to indicate the alleviation of the obstruction in the main vessels of target limbs based on computed tomography angiography. The duration of rehospitalization for DFU was 2.0 ± 0.6 years. All of the patients survived without amputation due to the recurrence of DFU within 3 years after treatments.ConclusionsBased on the current pilot study, the preliminary clinical benefits of hUC-MSCs on DFU healing were shown, including good tolerance, a shortened healing time to 1.5 months and a favorable 3-year amputation-free survival rate. The clinical evidence in the current study suggested a further phase I/II study with a larger patient population and a more rigorous design to explore the efficacy and mechanism of hUC-MSCs on DFU healing.Trial registration: The current study was registered retrospectively on 22 Jan 2022 with the Chinese Clinical Trial Registry (ChiCTR2200055885), http://www.chictr.org.cn/showproj.aspx?proj=135888Graphical

RNA Sequencing Reveals the Expression Profiles of circRNAs and Indicates Hsa_circ_0070562 as a Pro-osteogenic Factor in Bone Marrow-Derived Mesenchymal Stem Cells of Patients With Ankylosing Spondylitis.

Recent studies have reported that circular RNAs (circRNAs) play a crucial regulatory role in a variety of human diseases. However, the roles of circRNAs in pathological osteogenesis in ankylosing spondylitis (AS) remain unclear. We conducted circRNA and miRNA expression profiling of osteogenically differentiated bone marrow-derived mesenchymal stem cells (BMSCs) of patients with AS compared with those of healthy donors (HDs) by RNA sequencing (RNA-seq). Results showed that a total of 31806 circRNAs were detected in the BMSC samples, of which 418 circRNAs were significantly differentially expressed (DE) with a fold change ≥2 and p value <0.05. Among these, 204 circRNAs were upregulated, and 214 were downregulated. GO and KEGG analyses demonstrated that the DE circRNAs were mainly involved in the regulation of biological processes of the cell matrix adhesion and the TGF-beta signaling pathway, which are closely related to AS. circRNA-miRNA interaction networks related to the TGF-beta signaling pathway were established. The results of qRT-PCR showed that has_circ_0070562 was significantly up-regulated in AS-MSCs. In vitro experiments showed that silencing of has_circ_0070562 weakened osteogenesis of AS-BMSCs. In conclusion, we identified numerous circRNAs that were dysregulated in AS-BMSCs compared with HD-BMSCs. Bioinformatic analyses suggested that these dysregulated circRNAs might play important functional roles in AS-BMSCs osteogenesis. Circ_0070562 functioned as a pro-ostegenic factor and might serve as a potential biomarker and a therapeutic target for AS.

Combination of Haploidentical Hematopoietic Stem Cell Transplantation with Umbilical Cord-Derived Mesenchymal Stem Cells in Patients with Severe Aplastic Anemia: A Retrospective Controlled Study

Objective:We retrospectively compared the outcomes of patients with severe aplastic anemia (SAA) who received haploidentical hematopoietic stem cell transplantation (haplo-HSCT) combined or not combined with umbilical cord-derived mesenchymal stem cells (UC-MSCs).Materials and Methods:A total of 101 patients with SAA were enrolled in this study and treated with haplo-HSCT plus UC-MSC infusion (MSC group, n=47) or haplo-HSCT alone (non-MSC group, n=54).Results:The median time to neutrophil engraftment in the MSC and non-MSC group was 11 (range: 8-19) and 12 (range: 8-23) days, respectively (p=0.049), with a respective cumulative incidence (CI) of 97.82% and 97.96% (p=0.101). Compared to the non-MSC group, the MSC group had a lower CI of chronic graft-versus-host disease (GVHD) (8.60±0.25% vs. 24.57±0.48%, p=0.048), but similar rates of grades II-IV acute GVHD (23.40±0.39% vs. 24.49±0.39%, p=0.849), grades III-IV acute GVHD (8.51±0.17% vs. 10.20±0.19%, p=0.765), and moderate-severe chronic GVHD (2.38±0.06% vs. 7.45±0.18%, p=0.352) were observed. The estimated 5-year overall survival (OS) rates were 78.3±6.1% and 70.1±6.3% (p=0.292) while the estimated 5-year GVHD-free, failure-free survival (GFFS) rates were 76.6±6.2% and 56.7±6.9% (p=0.045) in the MSC and non-MSC groups, respectively.Conclusion:In multivariate analysis, graft failure was the only adverse predictor for OS. Meanwhile, graft failure, grades III-IV acute GVHD, and moderate-severe chronic GVHD could predict worse GFFS. Our results indicated that haplo-HSCT combined with UC-MSCs infusion was an effective and safe option for SAA patients.

Cell therapy for destructive pancreatitis

To evaluate therapeutic efficacy of mesenchymal stem cells in patients with severe acute pancreatitis. There were 60 patients with severe acute pancreatitis randomized into 2 groups: the first group (n=30) - endoscopic surgical treatment, mean age 44.7±2.93 years (18 (60.0%) males and 12 (40.0%) females); the second group (n=30) - complex therapy (standard treatment + cell therapy), mean age 50.8±3.8 years (16 (53.3%) men and 14 (46.7%) women). Taxation of endogenous intoxication, immunity state and regional microcirculation were assessed. Genetic analysis of eNOS (C774T) gene polymorphism was also carried out. Early period of acute severe pancreatitis is accompanied by significant disorders of homeostasis (endogenous intoxication, immune imbalance, severe disorders of regional microcirculation). Genetic analysis showed that polymorphic genotype (T774T) of the endothelial NO synthase gene in a larger percentage (66.7-71.6%, p=0.001) occur in patients with severe acute pancreatitis and more severe homeostatic disorders (p<0.05). Inclusion of mesenchymal stem cells into standard therapy in early phase of acute severe pancreatitis makes it possible to purposefully and relatively quickly exert its effect on abnormal processes of homeostasis, inhibiting toxemic phenomenon, restoring immune response, and improving microcirculation. A particularly positive therapeutic effect of the drug is observed in patients with the eNOS gene mutation (T774T). Mesenchymal stem cell drugs are advisable in early period of acute pancreatitis, mainly in patients with severe forms of disease.

Safety and Efficacy of Repeat Doses of Allogeneic Mesenchymal Stem Cells in Patients with Age Related Frailty

Cognitive decline and impairment among older adults have become an important public health issue. Previous research shows older women have a greater prevalence of Alzheimer's disease than Men. Among women, breast cancer is one of the most common types of cancer. Over half of breast cancer deaths occur in women aged 65 and older. Therefore, early detection of breast cancer through mammogram screening is important among older women. This study aimed to examine the influence of cognitive function on adherence to mammogram breast cancer screening among older American women aged 65 and older. Data from the Health and Retirement Study (2012-2016) was obtained and analyzed. The independent variable of the study was cognitive function (normal, not normal). Adherence to mammogram (low, moderate, high) was the dependent variable. Multinomial regression was performed to examine the association between cognitive function and adherence to mammogram after controlling for demographic covariates. In the study, 33.3% of respondents had impaired cognitive function and 21.7% showed low adherence to mammogram screening. Regression results found that older women with impaired cognitive function were more likely to be in low adherence group (OR=1.30, p=0.01) or moderate adherence group (OR=1.47, p<0.001) relatively to be in high adherence group compared to older women with normal cognitive function. The development and implementation of interventions are needed for reducing barriers to accessing cancer screening services in high-risk vulnerable populations. This submission is considered late-breaking research because study findings were obtained from a recently completed student's master's project.

METTL14 benefits the mesenchymal stem cells in patients with steroid-associated osteonecrosis of the femoral head by regulating the m6A level of PTPN6.

Imbalanced osteogenic/adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is considered the core pathological characteristic of steroid-associated osteonecrosis of the femoral head (SONFH). N6-Methyladenosine (m6A) is the most common type of RNA modification in eukaryotic cells and participates in various physiological and pathological processes. However, the relationship between m6A modification and SONFH has not been reported. In the present study, we aimed to explore the roles of m6A modifications and methyltransferase METTL14 in SONFH. Our results showed that the m6A levels were down-regulated in femoral head tissues and BMSCs from SONFH patients, and this effect was attributed to the reduction of METTL14. Furthermore, METTL14 overexpression in BMSCs from SONFH patients enhanced cell proliferation and osteogenic differentiation. We further identified PTPN6 as the downstream target of METTL14 by mRNA sequencing. Mechanistically, METTL14 regulated PTPN6 expression by increasing PTPN6 mRNA stability in an m6A-dependent manner. Moreover, PTPN6 knockdown abrogated the beneficial effects of METTL14 overexpression on BMSCs. Additionally, we found that METTL14 activated the Wnt signaling pathway, and this effect was caused by the interaction of PTPN6 and GSK-3β. In conclusion, we elucidated the functional roles of METTL14 and m6A methylation in SONFH BMSCs and identified a novel RNA regulatory mechanism, providing a potential therapeutic target for SONFH.

Potential Use of Umbilical Cord Mesenchymal Stem Cells for Improving Patients with COVID-19: A Review

The SARS-CoV-2 virus is a member of the coronavirus family that caused the COVID-19 respiratory disease epidemic in China before the global pandemic of the disease in late 2019. The virus's genome is of 79% similarity to that of the SARS-CoV virus, using the ACE2 receptor to enter its target cells. The most common symptoms of this disease include fever, cough, pulmonary involvement, and sometimes gastrointestinal symptoms. A decline in both the number and function of lymphocytes and a severe increase in leukocyte inflammatory activity are among the most obvious immunological complications of this disease. If the immune system response to the virus is inadequate, the disease can become acute. Immune cells activity leads to a sharp increase in the number of blood cytokines, causing storm, which in turn can cause systematic damages to the heart, lungs, and kidneys, and ultimately may lead to death. Mesenchymal stem cell therapy offers a promising approach to reducing the destructive impacts of infection in patients with COVID-19. Mesenchymal stem cells can secrete immune-modulating factors that suppress cytokine storms. Furthermore, the role of mesenchymal stem cells in preventing cell death and inhibiting tissue fibrosis has been well demonstrated. This review shows available clinical trials that have tapped into the therapeutic potential of the umbilical cord mesenchymal stem cells in patients with COVID-19. *Corresponding Author: Seyed Hadi Mousavi; Email: hmousavi@tums.ac.ir; ORCID iD: 0000-0002-0163-5839 Please cite this article as: Motallebzadeh Khanmiri J, Khani-Eshratabadi M, Nasirzadeh A, Nematzade M, Talebpour M, Mousavi H. Potential Use of Umbilical Cord Mesenchymal Stem Cells for the Improving Patients with COVID-19. Arch Med Lab Sci. 2021;7:1-12 (e20). https://doi.org/10.22037/amls.v7.35373

Characterization of Urine-Derived Stem Cells from Patients with End-Stage Liver Diseases and Application to Induced Acute and Chronic Liver Injury of Nude Mice Model.

Urine-derived stem cells (USCs) are adult stem cells isolated from urine with strong proliferative ability and differentiation potentials. Cell transplantation of USCs could partly repair liver injury. It has been reported that the proliferative ability of bone mesenchymal stem cells in patients with chronic liver failure is significantly lower than in patients without liver disease. The aim of this study was therefore to evaluate the biological characteristics of USCs from end-stage liver disease patients (LD-USCs, USCs from patients with liver disease) compared with those from normal healthy individuals (N-USCs, USCs from normal individuals), with a view to determining whether autologous USCs can be applied to the treatment of liver disease. In this study USCs were isolated from urine samples of male patients with end-stage liver disease. Adherent USCs exhibit a spindle- or rice grain-like morphology, and express CD24, CD29, CD73, CD90, and CD146 surface markers, but not CD31, CD34, CD45, and CD105. We observed no differences in cell morphology or cell surface marker profile between LD-USCs and N-USCs. LD-USCs exhibited similar proliferative, colony-forming, apoptotic, and migratory abilities to N-USCs. Both USCs demonstrated similar capacities for osteogenic, adipogenic, and chondrogenic differentiation. When USCs were transplanted into CCl4 treatment-induced acute and chronic liver fibrosis mouse models, we observed a decrease in liver index, recovery of alanine aminotransferase and aspartate aminotransferase levels, alleviation of liver tissue injury, and dramatic improvement of liver tissue structure. USC transplantation can effectively recover liver function and improve liver tissue damage in acute or chronic liver injury mouse models. According to the results, we concluded that the biological characteristics of LD-USCs are not affected by basic liver disease. This study provides further evidence of the stem cell characteristics and liver repair function of LD-USCs, which may serve as a theoretical and experimental foundation for autologous USC transplantation technology in the treatment of liver failure and end-stage liver diseases.

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.