Stem Cell Therapy In Patients Research Articles

The differentiation of mesenchymal bone marrow stem cells into nerve cells induced by Chromolaena odorata extracts

Background: Mesenchymal stem cells (MSCs) can differentiate into nerve cells with an induction from chemical compounds in medium culture. Chromolaena odorata contains active compounds, such as alkaloids and flavonoids, that can initiate the transformation of MSCs into nerve cells. The aim of this study was to determine the potential of methanol extracted C. odorata leaf to induce the differentiation of bone marrow MSCs into nerve cells. Methods: A serial concentration of C. odorata leaf extract (0.7-1.0 mg/mL) with two replications was used. The parameters measured were the number of differentiated MSCs into nerve cells (statistically analyzed using ANOVA) and cell confirmation using reverse transcription polymerase chain reaction (RT-PCR). Results: The results showed that the C. odorata extract had a significant effect on the number MSCs differentiating into nerve cells ( p < 0.05) on the doses of 0.8 mg/ml with 22.6%. Molecular assay with RT-PCR confirmed the presence of the nerve cell gene in all of the samples. Conclusions: In conclusion, this study showed the potential application of C. odorata leaf extract in stem cell therapy for patients experiencing neurodegeneration by inducing the differentiation of MSCs into nerve cells.

Controlled Subretinal Injection Pressure Prevents Damage in Pigs

Introduction: Administration of retinal gene and stem cell therapy in patients with retinal degenerative diseases is in many cases dependent on a subretinal approach. It has been indicated that manual subretinal injection is associated with outer retinal damage, which may be explained by a high flow rate in the injection cannula. In the present porcine study, we evaluated flow-related retinal damage after controlled subretinal injection at different flow rates. Methods: The flow rate through a 41G cannula was estimated at different injection pressures (6–48 pounds per square inch [PSI]) in an in vitro setup. A linear correlation between the flow rate and injection pressure was found from 6 to 32 PSI. In full anesthesia, 12 pigs were vitrectomized and received a controlled subretinal injection of 300 μL balanced saline solution at injection pressures of 14, 24, and 32 PSI (four in each group). Prior to surgery and 2 and 4 weeks after surgery, the eyes were examined by multifocal electroretinogram (mfERG) and fundus photographs. At the end of follow-up, the eyes were enucleated for histology. Results: The in vitro flow study determined that the flow in a 41G cannula shifts from laminar to turbulent at 32 PSI and that the manual injection flow is turbulent. In the porcine study, we showed a significant difference in retinal pigment epithelium (RPE) damage between the three pressure groups (p = 0.0096). There was no significant difference in damage to the outer retina (p = 0.1526), but the high-pressure group (32 PSI) had the most outer retinal damage. The middle-pressure group (24 PSI) showed minimum retinal damage. There was no significant change in the mfERG ratios during follow-up. Discussion/Conclusion: This study indicates that an injection pressure at approximately 24 PSI might be safe for subretinal delivery. Retinal damage at low injection pressures may be explained by mechanical damage to the RPE due to prolonged needle time in the subretinal space, while retinal damage at high pressures can be related to high flow in the injection cannula. Controlled subretinal injection pressure of 24 PSI showed minimum mechanical- and flow-related damage to the porcine retina.

Therapeutic Effects of Stem Cells for the Treatment of Diabetes Mellitus

Stem cell therapy may be the key to diabetes mellitus. In this study, we systematically retrieved the related studies and conducted this meta-analysis to evaluate the efficacy and safety of stem cell therapy for patients with diabetes mellitus. A systematic articles search was performed for eligible studies published up to April 28, 2021 through the PubMed, Cochrane library, ClinicalTrials.gov and Chinese National Knowledge Infrastructure database. The included articles were screened by using rigorous inclusion and exclusion criteria. All analyses were conducted using Review Manager 5.4. The quality of studies and risk of bias were evaluated. A total of 9 randomized controlled trials were included with a sample size of 326 subjects diagnosed with diabetes mellitus. Stem cells therapy was superior to placebo group in all of outcomes including hemoglobin A1c (mean deviation -0.51, 95 % confidence interval 0.70 to −0.32, p<0.00001), fasting plasma glucose (mean deviation -6.64, 95 % confidence interval -11.58 to -1.71, p=0.008), C-peptide (mean deviation 0.03, 95 % confidence interval 0.02 to 0.04, p<0.00001) and the requirement for insulin (mean deviation -10.34, 95 % confidence interval -16 to -4.67, p<0.00003). There was no significant difference in reported adverse events between stem cell therapy groups and placebo groups (Relative risk 1.77, 95 % confidence interval 0.89 to 3.51, p=0.10). Our results support stem cell therapy is a safe and effective therapeutic modality for diabetes mellitus. The best therapeutic outcome was achieved with bone marrow-mononuclear stem cells and hyperbaric oxygen therapy for type 2 diabetes mellitus, while the poorest outcome was observed with autologous bone marrowmesenchymal stromal cells for type 2 diabetes mellitus.

Human Umbilical Cord Blood Therapy for Diabetes Mellitus : A Review

Stem cell therapy for patients with diabetes mellitus is receiving great attention among scientists and clinicians. Although bone marrow is considered one of the rich sources of stem cells, its limited availability of donors precludes its use for all the suitable patients. Human umbilical cord blood mononuclear cells or its-derived mesenchymal cells are being increasingly used as an alternative source of stem cells for cell-based therapy for malignant and nonmalignant diseases. Human umbilical cord blood cells have low potential for graft-versus-host disease and tumorigenicity. Also, no immunosuppression is required. Experimental evidence has shown that human umbilical cord blood -derived stem cells can differentiate into insulin-secreting β-cells. Transplantation of Human umbilical cord blood cells has been shown to improve blood glucose levels, and ameliorate kidney as well as neuropathic complications in diabetic animal models. Although the first use of autologous Human umbilical cord blood transfusion in type 1 diabetic children had a short-term beneficial effect in reducing the daily requirement of insulin dose and the maintenance of near normoglycemia, subsequent studies have failed to show this beneficial effect. In this review, we will provide both experimental and clinical evidence in favor and against the beneficial effect of human umbilical cord blood cells and cord blood-derived mesenchymal cells in the management of diabetes mellitus.

A meta-analysis of randomized controlled trials on therapeutic efficacy and safety of autologous cell therapy for atherosclerosis obliterans

ObjectiveAtherosclerosis obliterans (ASO) is a chronic occlusive arterial disease and the most common type of peripheral arterial disease. Current treatment options like medication and vascularization have limited effects for “no-option” patients, and stem cell therapy is considered a viable option, although its application and efficacy have not been standardized. The objective of this review was to assess the safety and efficacy of autologous stem cell therapy in patients with ASO. MethodsWe performed a literature search of published randomized controlled trials (RCTs) for patients with ASO receiving stem cell therapy without a revascularization option. PubMed, Embase, and the Cochrane Library were searched. This study was conducted by a pair of authors independently and audited by a third author. Data were synthesized with a random-effects model. ResultsA total of 630 patients in 12 RCTs were included. The results showed that cell therapy significantly improved total amputation (relative risk [RR], 0.64; 95% confidence interval [CI], 0.47-0.87; P = .004), major amputation (RR, 0.69; 95% CI, 0.50-0.94; P = .02), ankle-brachial index (mean difference [MD], 0.08; 95% CI, 0.02-0.13; P = .004), transcutaneous oxygen tension (MD, 11.52; 95% CI, 3.60-19.43; P = .004), and rest pain score (MD, −0.64; 95% CI, −1.10 to −0.17; P = .007) compared with placebo or standard care. However, current studies showed cell therapy was not superior to placebo or standard care in all-cause death (RR, 0.75; 95% CI, 0.41-1.36; P = .34) and ulcer size (MD, −8.85; 95% CI, −29.05 to 11.36; P = .39). The number of trials included was limited. Moreover, most trials were designed for “no-option” patients, and thus the results should be applied with caution to other patients with peripheral arterial disease. ConclusionsPatients with ASO can benefit from autologous cell therapy in limb salvage, limb blood perfusion, and rest pain alleviation.

Efficient hepatic differentiation and regeneration potential under xeno-free conditions using mass-producible amnion-derived mesenchymal stem cells

BackgroundAmnion-derived mesenchymal stem cells (AM-MSCs) are an attractive source of stem cell therapy for patients with irreversible liver disease. However, there are obstacles to their use due to low efficiency and xeno-contamination for hepatic differentiation.MethodsWe established an efficient protocol for differentiating AM-MSCs into hepatic progenitor cells (HPCs) by analyzing transcriptome-sequencing data. Furthermore, to generate the xeno-free conditioned differentiation protocol, we replaced fetal bovine serum (FBS) with polyvinyl alcohol (PVA). We investigated the hepatocyte functions with the expression of mRNA and protein, secretion of albumin, and activity of CYP3A4. Finally, to test the transplantable potential of HPCs, we transferred AM-MSCs along with hepatic progenitors after differentiated days 11, 12, and 13 based on the expression of hepatocyte-related genes and mitochondrial function. Further, we established a mouse model of acute liver failure using a thioacetamide (TAA) and cyclophosphamide monohydrate (CTX) and transplanted AM-HPCs in the mouse model through splenic injection.ResultsWe analyzed gene expression from RNA sequencing data in AM-MSCs and detected downregulation of hepatic development-associated genes including GATA6, KIT, AFP, c-MET, FGF2, EGF, and c-JUN, and upregulation of GSK3. Based on this result, we established an efficient hepatic differentiation protocol using the GSK3 inhibitor, CHIR99021. Replacing FBS with PVA resulted in improved differentiation ability, such as upregulation of hepatic maturation markers. The differentiated hepatocyte-like cells (HLCs) not only synthesized and secreted albumin, but also metabolized drugs by the CYP3A4 enzyme. The best time for translation of AM-HPCs was 12 days from the start of differentiation. When the AM-HPCs were transplanted into the liver failure mouse model, they settled in the damaged livers and differentiated into hepatocytes.ConclusionThis study offers an efficient and xeno-free conditioned hepatic differentiation protocol and shows that AM-HPCs could be used as transplantable therapeutic materials. Thus, we suggest that AM-MSC-derived HPCs are promising cells for treating liver disease.

Mesenchymal Stem Cell-Conditioned Media Regulate Steroidogenesis and Inhibit Androgen Secretion in a PCOS Cell Model via BMP-2

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women. Previous studies have demonstrated the therapeutic efficacy of human bone marrow mesenchymal stem cells (BM-hMSCs) for PCOS; however, the regulatory mechanism remains unknown. Bone morphogenetic proteins (BMPs) secreted by BM-hMSCs may underlie the therapeutic effect of these cells on PCOS, based on the ability of BMPs to modulate androgen production and alter steroidogenesis pathway enzymes. In this study, we analyze the effect of BMP-2 on androgen production and steroidogenic pathway enzymes in H295R cells as a human PCOS in vitro cell model. In H295R cells, BMP-2 significantly suppressed cell proliferation, androgen production, and expression of androgen-synthesizing genes, as well as inflammatory gene expression. Furthermore, H295R cells treated with the BM-hMSCs secretome in the presence of neutralizing BMP-2 antibody or with BMP-2 gene knockdown showed augmented expression of androgen-producing genes. Taken together, these results indicate that BMP-2 is a key player mediating the favorable effects of the BM-hMSCs secretome in a human PCOS cell model. BMP-2 overexpression could increase the efficacy of BM-hMSC-based therapy, serving as a novel stem cell therapy for patients with intractable PCOS.

Long-term Results of Stem Cell Therapy for Acute and Chronic Limb Ischemia

Stem cell therapy (SCT) using intramuscular injections of autologous bone marrow mononuclear cells is shown to improve clinical symptoms and prevent major amputation in patients with chronic nonreconstructable peripheral arterial disease (PAD). However, there is limited data regarding the usage of SCT in patients presenting with acute limb ischemia. In an Indian setting, it is not uncommon to see delayed presentation of acute limb ischemia or acute on chronic embolism where revascularization would be suboptimal or not feasible.

Stem Cell Therapy for the Treatment of Myocardial Infarction: How Far Are We Now?

Myocardial infarction is one of the leading causes of death worldwide. Poor functional recovery of the myocardium is noticed after an event of myocardial infarction. Researchers and clinicians around the world have been engaged to regenerate the damaged human heart for a long time. Stem cell therapy is an exciting newer therapy to treat cardiovascular diseases.Various types of stem cells have been used to revive the damaged myocardium after myocardial infarction, and they have overall demonstrated safety and moderate efficacy. The specific mechanisms by which these cells help in improving cardiac function are still not completely known. There is growing evidence that intracoronary bone marrow cell transplantation in patients with myocardial infarction beneficially affects the remodeling of the damaged myocardium.Our systematic review article aims to assess the effects and the future of stem cell therapy in patients with myocardial Infarction. We searched articles in PubMed, ScienceDirect, and Google Scholar. Thirty-one studies that included 2171 patients in total were analyzed. Most of these studies showed stem cell therapy is safe and well tolerated in patients, and modest improvements are seen in left ventricular functions with no major adverse effects. However, some studies showed no positive and clinically significant outcomes. So, more high-quality studies on a larger scale are required to support and confirm its efficacy in remodeling damaged myocardium after myocardial infarction. We should also perform studies to determine the timing of cell delivery that is best suited for stem cell therapy.

The Feasibility and Applicability of Stem Cell Therapy for the Cure of Type 1 Diabetes.

Stem cell therapy using islet-like insulin-producing cells derived from human pluripotent stem cells has the potential to allow patients with type 1 diabetes to withdraw from insulin therapy. However, several issues exist regarding the use of stem cell therapy to treat type 1 diabetes. In this review, we will focus on the following topics: (1) autoimmune responses during the autologous transplantation of stem cell-derived islet cells, (2) a comparison of stem cell therapy with insulin injection therapy, (3) the impact of the islet microenvironment on stem cell-derived islet cells, and (4) the cost-effectiveness of stem cell-derived islet cell transplantation. Based on these various viewpoints, we will discuss what is required to perform stem cell therapy for patients with type 1 diabetes.

Stem Cell Therapy in Ischemic Stroke: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background and Objective:Stem cell therapy has emerged as a potential therapy for the treatment of stroke. We performed a systematic review and meta-analysis of published randomized controlled studies using various types of stem cell therapies in patients with ischemic stroke (IS).Method:Literature search was carried out using PubMed, Google Scholar, Cochrane library, and clinicaltrial.gov to identify studies on stem cell therapy in IS from its inception till January 2020. Data were extracted independently by two reviewers. STATA version 13 was used for carrying out meta- analysis. We included only randomized controlled trials (RCTs) if any of the stem cell therapy was used to treat patients with IS in any phase after the index stroke.Results:We included a total of eight randomized controlled studies involving 459 subjects (217 intervention and 242 controls) in the meta-analysis. We did not observe statistically significant reduction in mean NIHSS score in the intervention group (SMD - 0.34, 95% CI - 0.76 to 0.08) in patients with acute or sub-acute stroke. However, a statistically significant reduction (SMD - 1.57, 95% CI -2.22 to -0.92) was observed in patients with chronic ischemic stroke. Statistically non-significant reduction in mean mRS in the intervention group (SMD 0.04, 95% CI -0.20 to 0.28) in patients with acute or sub-acute ischemic stroke was observed, however a statistically significant reduction (SMD - 1.07, 95% CI - 1.94 to -0.19) was noted in patients with chronic stroke. We did not observe statistically significant reduction in mean Barthel index score (SMD 0.24, 95%CI -1.69 to 2.17) in chronic stroke. Statistically non-significant lower mortality rate was observed in intervention group compared to controls (Risk Ratio 0.84, 95% CI 0.43 to 1.66) among acute or sub-acute, as well as in the chronic stroke group (Risk Ratio 0.47, 95% CI 0.20 to 1.09).Conclusion:Our meta-analysis provides no clinically important evidence for efficacy of stem cells in reducing neurological deficit compared to control group. Well-designed large randomized controlled trials are required to provide more information on the efficacy of stem cell therapy in patients with IS.

Long Term Results of Stem Cell Therapy in Patients with Peripheral Arterial Disease (PAD)

Peripheral Arterial Disease (PAD) is still a challenging condition affecting millions of people and leading to amputation or death. In patients with non reconstructable disease or failed revascularization, stem cell therapy (SCT) could help in promoting angiogenesis and limb salvage. However, there is limited data about the long-term benefits of SCT in such patients. Aim of this study is to evaluate the long-term survival and clinical outcomes in PAD patients who underwent stem cell therapy. All patients who underwent stem cell therapy using intramuscular injections of autologous bone-marrow mononuclear cells (BM-MNCs) for the treatment of PAD between January 2011 and November 2020 were include in the study. Electronic medical records (EMRs) and Telephonic phone follow up was used to get baseline clinical characteristics and follow up data. Out of 3627 PAD patient, 41 patients underwent stem cell therapy procedure between January 2011 to November 2020. Mean age was 48 years (range, 21 to 75 years) and 37 patients (90.24%) were males. The median follow-up period was 4.66 years (range, 6 months – 9.9 years). Indication for SCT was rest pain, gangrene or non-healing ulcer due to either non reconstructable disease or failed revascularization. All patients were given antiplatelets and statin therapy. Out of 41 PAD patients, 7 patients were lost to follow up. In the remaining, 34 patients, 29 (70.73%) patients were alive, and 5 patients were dead. Overall, 10 (24.39%) patients underwent ipsilateral amputation and 4 patients had persistent claudication pain. In the remaining patients’ ulcers healed and has no residual pain. Amputation free survival was 75.61%. The benefits of Autologous BM-MNCs stem cell therapy are sustained even in the long term with overall survival rate was 85.29% and the amputation free survival was 75.61% and should be considered for all CLI patients irrespective of age.

Mesenchymal Stem Cell Therapy for Patients with Ischemic Heart Failure- Past, Present, and Future

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Safety and feasibility of mesenchymal stem cell therapy in patients with aqueous deficient dry eye disease

PurposeTo evaluate the safety and feasibility of injecting allogeneic adipose-derived mesenchymal stem cells (ASCs) into the lacrimal gland (LG) as a treatment of aqueous deficient dry eye disease (ADDE). MethodsIn this open-label, 5-visit clinical trial (baseline, treatment and weeks 1, 4 and 16) seven subjects with ADDE received one transconjunctival injection of allogeneic ASCs into the LG in one eye. The ASC product contained 22 million ASCs/ml and the injected volume was maximally 50% of the LG volume as determined on magnetic resonance imaging (MRI). Treatment related adverse events (AEs) were assessed at each visit (primary endpoint). Ocular Surface Disease Index (OSDI), tear osmolarity, tear film breakup time (TBUT), corneal staining (Oxford grade) and Schirmer's I test were assessed at each timepoint. ResultsNo AEs related to the study treatment were observed. Mean follow-up time was 126 days after treatment. The mean OSDI score decreased from 58.9 ± 20.6 at baseline to 34.1 ± 21.6 (p < 0.002). In the study eye mean tear osmolarity decreased from 312.9 ± 10.4 to 291.6 ± 10.9 mosm/l (p < 0.002), mean TBUT increased from 3.7 ± 1.5 to 7.1 ± 1.9 s (p < 0.002), mean Schirmer's I test increased from 4.6 ± 0.7 to 8.1 ± 3.1 mm/5 min (p < 0.03), while mean Oxford grade showed a trend towards a decrease from 2.4 ± 0.7 to 1.3 ± 1 (p < 0.10). ConclusionOur trial suggests that injection of allogeneic ASCs into the LG is a safe and feasible treatment of severe ADDE. A randomized placebo-controlled trial aimed at elucidating the therapeutic effect of allogeneic ASCs in a larger patient cohort from our research group is currently underway.

SAFEty and efficacy of autologous bone marrow – derived mononuclear stem cell therapy in patients with severe chronic ischemic Heart Failure – rationale and design

The main aim of this study is to explore the safety and efficacy of autologous bone marrow – derived mononuclear stem cell therapy in patients with severe chronic ischemic heart failure on short to medium-term (1-3 months). The SAFE-HF trial is a prospective, single center, two-arm, controlled trial with blind evaluation of endpoints. Target population will consist of patients with heart failure due to prior extensive myocardial infarction and left ventricle ejection fraction of less than 35% – namely the population with the highest risk of adverse events and the highest mortality. All patients will be treated with the state of the art reperfusion – primary percutaneous coronary intervention and also with guidelinebased optimal medical therapy. The stem cell injection will be performed 1 to 3 months after the acute event; evolution of stem cell treated patients will be compared with matched control–cases. Comprehensive assessment of outcomes will be done at 1 and 3 months follow-up; serum biomarkers, cardiac structural and physiological parameters, functional capacity and health-related quality of life will be evaluated. This pilot study possibly will serve as a foundation for designing future trials.

Efficacy and Safety of Stem Cell Therapy for T1DM: An Updated Systematic Review and Meta-Analysis.

Background The long-term insulin therapy for type 1 diabetes mellitus (T1DM) fails to achieve optimal glycemic control and avoid adverse events simultaneously. Stem cells have unique immunomodulatory capacities and have been considered as a promising interventional strategy for T1DM. Stem cell therapy in T1DM has been tried in many studies. However, the results were controversial. We thus performed a meta-analysis to update the efficacy and safety of stem cell therapy in patients with T1DM. Methods We systematically searched the Medline, EMBASE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, Web of Science, Wan Fang Data, China National Knowledge Infrastructure, VIP database, and the Chinese Biomedical Literature Database (SinoMed) for relevant studies published before March 19, 2019. The outcomes included parameters for glycemic control (i.e., glycosylated hemoglobin (HbA1c) levels and insulin dosages), β cell function (i.e., fasting C-peptide levels and area-under-curve of C-peptide concentration (AUCC)), and relative risk of adverse events. Statistical analysis was conducted by using RevMan 5.3 and Stata 12.0. Results Five randomized controlled trials (RCTs) and eight nonrandomized concurrent control trials (NRCCTs) with a total of 396 individuals were finally included into the meta-analysis. Among RCTs, stem cell therapy could significantly reduce HbA1c levels (MD = −1.20, 95% CI -1.91 to -0.49, P = 0.0009) and increase fasting C-peptide levels (MD = 0.25, 95% CI 0.04 to 0.45, P = 0.02) and AUCC (SMD = 0.66, 95% CI 0.13 to 1.18, P = 0.01). Stem cell therapy could also reduce insulin dosages (SMD = −2.65, 95% CI -4.86 to -0.45, P = 0.02) at 6 months after treatment. NRCCTs also had consistent results. Furthermore, RCTs showed stem cell therapy did not increase relative risk of gastrointestinal symptom (RR = 0.69, 95% CI 0.14 to 3.28, P = 0.64) and infection (RR = 0.97, 95% CI 0.40 to 2.34, P = 0.95). However, NRCCTs showed stem cell therapy increased relative risk of gastrointestinal symptom (RR = 44.49, 95% CI 9.20 to 215.18, P < 0.00001). Conclusion Stem cell therapy for T1DM may improve glycemic control and β cell function without increasing the risk of serious adverse events. Stem cell therapy may also have a short-term (3-6 months) effect on reducing insulin dosages.

Value of mesenchymal stem cell therapy for patients with septic shock: an early health economic evaluation.

This study estimates the maximum price at which mesenchymal stem cell (MSC) therapy is deemed cost-effective for septic shock patients and identifies parameters that are most important in making treatment decisions. We developed a probabilistic Markov model according to the sepsis care trajectory to simulate costs and quality-adjusted life years (QALYs) of septic shock patients receiving either MSC therapy or usual care over their lifetime. We calculated the therapeutic headroom by multiplying the gains attributable to MSCs with willingness-to-pay (WTP) threshold and derived the maximum reimbursable price (MRP) from the expected net monetary benefit and savings attributable to MSCs. We performed scenario analyses to assess the impact of changes to assumptions on the study findings. A value of information analysis is performed to identify parameters with greatest impact on the uncertainty around the cost-effectiveness of MSC therapy. At a WTP threshold of $50,000 per QALY, the therapeutic headroom and MRP of MSC therapy were $20,941 and $16,748, respectively; these estimates increased with the larger WTP values and the greater impact of MSCs on in-hospital mortality and hospital discharge rates. The parameters with greatest information value were MSC's impact on in-hospital mortality and the baseline septic shock in-hospital mortality. At a common WTP of $50,000/QALY, MSC therapy is deemed to be economically attractive if its unit cost does not exceed $16,748. This ceiling price can be increased to $101,450 if the therapy significantly reduces both in-hospital mortality and increases hospital discharge rates.

A Phase I Study of Allogeneic Mesenchymal Stem Cell Therapy in Patients with Heart Failure Secondary to Anthracycline-induced Cardiomyopathy: The Cctrn Stem Cell Injection in Cancer Survivors (Seneca) Trial

Background Anthracycline-induced cardiomyopathy (AIC) can be irreversible with a poor prognosis, and disproportionately affects women and young adults. Administration of allogeneic bone marrow-derived mesenchymal stromal cells (allo-MSCs) is a promising approach to heart failure treatment. Allo-MSCs are known to favorably affect fibrosis, apoptosis, and inflammation, which are key features of AIC. Methods This phase I study evaluated 37 adult cancer survivors (68% female) with left ventricular dysfunction secondary to chronic AIC. The study included a six-subject open-label, lead-in phase followed by 31 subjects randomized 1:1 to receive 1 × 108 allo-MSCs or vehicle via 20 transendocardial injections. Subjects were followed for 1 year to assess safety and feasibility (Fisher's test). Secondary efficacy measures included cardiac function/structure measured by magnetic resonance imaging (MRI), functional capacity, quality of life (MLHFQ), and biomarkers. These were assessed by ANCOVA adjusting for baseline values. Results Ninety-seven percent of subjects underwent successful study product injections, all allo-MSC-assigned subjects received the target dose. Follow-up visits were well attended (92%) with successful collection of endpoints in 94% at the 1-year visit. Although 58% of subjects had non-MRI compatible devices, MRI endpoints were successfully collected in 84% of subjects imaged at 1 year. No new tumors were reported. There were no significant differences between allo-MSC and vehicle groups with regard to clinical outcomes including major adverse cardiac events, other significant adverse events, and days alive and out of the hospital. Ten of the 13 efficacy measures numerically favored the allo-MSC group including a lower MLHFQ score (p = .048). Conclusion In this first-in-human study of cell therapy in patients with AIC, transendocardial administration of allo-MSCs appears safe and feasible and MRI was successfully performed in the majority of patients with devices. This study provides crucial information for designing Phase II trials aimed at assessing efficacy of cell therapy in patients with AIC.

Autologous bone-marrow mononuclear stem cell therapy in patients with stroke: a meta-analysis of comparative studies

BackgroundThere is a need to promote recovery after stroke with novel therapeutic interventions. Of them, bone-marrow mononuclear cell (BM-MNC) therapy offers promising outcomes in preclinical and clinical models.AimsTo investigate the efficacy and safety of BM-MNCs versus traditional medical care of stroke patients.Summary of reviewA meta-analysis was conducted involving controlled prospective studies and randomized clinical trials (RCTs) which investigated the changes in the scores of neurological functions (the National Institutes of Health Stroke Scale [NIHSS]), the indices of functional recovery (the Barthel Index [BI] and the modified Rankin scale [mRS]) at 3 and 6 month post-transplantation. A total of nine studies (five RCTs) recruited 469 stroke patients (65.5% males, 49.25% received the intervention). There were no significant differences in NIHSS, BI, or mRS scores after 3 months of follow-up. However, the BI indices of BM-MNCs-receiving patients improved significantly after 6 months (standardized mean difference = 1.17, 95% confidence interval, 0.23 to 2.10, P = 0.01) as compared to traditional treatment. The risk of mortality and adverse events and the proportion of patients with favorable outcomes (mRS ≤ 3) were similar in both groups.ConclusionBoth the BM-MNCs and medical stroke treatment have similar outcomes in terms of safety and short-term efficacy, while the effect of therapy is significant only after 6 months. More well-designed, large sized RCTs are needed to confirm the efficacy of stem cell therapy over long periods of follow-up.

Human umbilical cord-derived mesenchymal stem cell therapy in patients with COVID-19: a phase 1 clinical trial

No effective drug treatments are available for coronavirus disease 2019 (COVID-19). Host-directed therapies targeting the underlying aberrant immune responses leading to pulmonary tissue damage, death, or long-term functional disability in survivors require clinical evaluation. We performed a parallel assigned controlled, non-randomized, phase 1 clinical trial to evaluate the safety of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) infusions in the treatment of patients with moderate and severe COVID-19 pulmonary disease. The study enrolled 18 hospitalized patients with COVID-19 (n = 9 for each group). The treatment group received three cycles of intravenous infusion of UC-MSCs (3 × 107 cells per infusion) on days 0, 3, and 6. Both groups received standard COVID-treatment regimens. Adverse events, duration of clinical symptoms, laboratory parameters, length of hospitalization, serial chest computed tomography (CT) images, the PaO2/FiO2 ratio, dynamics of cytokines, and IgG and IgM anti-SARS-CoV-2 antibodies were analyzed. No serious UC-MSCs infusion-associated adverse events were observed. Two patients receiving UC-MSCs developed transient facial flushing and fever, and one patient developed transient hypoxia at 12 h post UC-MSCs transfusion. Mechanical ventilation was required in one patient in the treatment group compared with four in the control group. All patients recovered and were discharged. Our data show that intravenous UC-MSCs infusion in patients with moderate and severe COVID-19 is safe and well tolerated. Phase 2/3 randomized, controlled, double-blinded trials with long-term follow-up are needed to evaluate the therapeutic use of UC-MSCs to reduce deaths and improve long-term treatment outcomes in patients with serious COVID-19.