Intravenous Mesenchymal Stem Cells Research Articles

Systematic Intravenous Administration of Autologous Mesenchymal Stem Cells Is Safe.

Background: Mesenchymal stem cells (MSCs) have drawn significant attention for their regenerative potential and therapeutic applicability across a range of conditions, including cardiovascular diseases and age-related frailty. Despite extensive preclinical studies, there remain gaps in understanding the long-term safety and efficacy of MSC therapy in humans. This study aimed to assess the safety of intravenous MSC administration, evaluate the mean major adverse cardiac and cerebrovascular event (MACCE)-free period, and identify potential risk factors for MACCE development in patients receiving MSC therapy for various indications. Methods: A retrospective observational study was conducted on 2504 patients (mean age: 54.09 ± 11.65 years) who received intravenous adipose-derived MSC (AD-MSC) therapy between October 2014 and December 2023 at the Omotesando Helene Clinic, Tokyo, Japan. Patients received MSC doses ranging from 100 million to 2 billion cells, with the majority receiving 1-2 billion cells per treatment. Statistical analyses included multivariate Cox proportional hazards regression and Kaplan-Meier survival analysis to evaluate MACCE risk factors and event-free duration. Results: Over the follow-up period, the MACCE rate was exceptionally low at 0.2%. Multivariate analysis identified age as a significant risk factor for MACCE (hazard ratio: 1.127; 95% CI: 1.0418-1.219; p = 0.0029), while sex and MSC dose showed no significant association. Minor adverse events occurred in 0.8% of patients, with no severe adverse events reported. The study found MSC therapy to be safe, with a low adverse event rate and minimal risk of MACCE. Conclusions: This study demonstrates the safety of intravenous MSC therapy in a large cohort of patients, with a low incidence of MACCE and minimal adverse effects. Age was the only significant predictor of MACCE risk. Further prospective randomized studies are needed to validate these findings and explore the potential of MSC therapy in reducing MACCE risk and improving clinical outcomes across diverse indications.

Repeated Infusions of Bone-Marrow-Derived Mesenchymal Stem Cells over 8 Weeks for Steroid-Refractory Chronic Graft-versus-Host Disease: A Prospective, Phase I/II Clinical Study.

Chronic graft-versus-host disease (cGVHD) is a long-term complication of allogeneic hematopoietic stem cell transplantation associated with poor quality of life and increased morbidity and mortality. Currently, there are several approved treatments for patients who do not respond to steroids, such as ruxolitinib. Nevertheless, a significant proportion of patients fail second-line treatment, indicating the need for novel approaches. Mesenchymal stem cells (MSCs) have been considered a potential treatment approach for steroid-refractory cGVHD. To evaluate the safety and efficacy of repeated infusions of MSCs, we administered intravenous MSCs every two weeks to ten patients with severe steroid-refractory cGVHD in a prospective phase I clinical trial. Each patient received a total of four doses, with each dose containing 1 × 106 cells/kg body weight from the same donor and same passage. Patients were assessed for their response to treatment using the 2014 National Institutes of Health (NIH) response criteria during each visit. Ten patients with diverse organ involvement were enrolled, collectively undergoing 40 infusions as planned. Remarkably, the MSC infusions were well tolerated without severe adverse events. Eight weeks after the initial MSC infusion, all ten patients showed partial responses characterized by the amelioration of clinical symptoms and enhancement of their quality of life. The overall response rate was 60%, with a complete response rate of 20% and a partial response (PR) rate of 40% at the last follow-up. Overall survival was 80%, with a median follow-up of 381 days. Two patients died due to relapse of their primary disease. Immunological analyses revealed a reduction in inflammatory markers, including Suppression of Tumorigenicity 2 (ST2), C-X-C motif chemokine ligand (CXCL)10, and Secreted phosphoprotein 1(SPP1), following the MSC treatment. Repeated MSC infusions proved to be both feasible and safe, and they may be an effective salvage therapy in patients with steroid-refractory cGVHD. Further large-scale clinical studies with long-term follow-up are needed in the future to determine the role of MSCs in cGVHD.

Efficacy and safety of mesenchymal stem cell-derived microvesicles in mouse inflammatory arthritis

ObjectiveTo determine the effective and safe intravenous doses of mesenchymal stem cells (MSCs)-derived microvesicles (MVs) and to elucidate the possible causes of death in mice receiving high-dose MVs. MethodsMVs were isolated from human MSCs by gradient centrifugation. Mice with collagen-induced arthritis were treated with different doses of intravenous MVs or MSCs. Arthritis severity, white blood cell count, and serum C-reactive protein levels were measured. To assess the safety profile of MSCs and MVs, mice were treated with different doses of MSCs and MVs, and LD50 was calculated. Mouse lungs and heart were assessed by live fluorescence imaging, histopathological measurements, and immunohistochemistry to explore the possible causes of death. Serum concentrations of cTnT, cTnI, and CK-MB were determined by ELISA. With the H9C2 cardiomyocyte cell line, cellular uptake of MVs was observed using confocal microscopy and cell toxicity was assessed by CCK-8 and flow cytometry. ResultsIntravenous treatment with MSCs and MVs alleviated inflammatory arthritis, while high doses of MSCs and MVs were lethal. Mice receiving a maximum dose of MSCs (0.1 mL of MSCs at 109/mL) died immediately, while mice receiving a maximum dose of MVs (0.1 mL of MVs at 1012/mL) exhibited tears, drooling, tachycardia, shortness of breath, unbalanced rollover, bouncing, circular crawling, mania, and death. Some mice died after exhibiting convulsions and other symptoms. All mice died shortly after injecting the maximum dose of MSCs. Histologically, mice receiving high doses of MSCs frequently developed pulmonary embolism, while those receiving high doses of MVs died of myocardial infarction. Consistently, the serum levels of cTnT, cTnI, and CK-MB were significantly increased in the MVs-treated group (P < 0.05). The LD50 of intravenous MVs was 1.60 × 1012/kg. Further, MVs could enter the cell. High doses of MVs induced cell apoptosis, though low concentrations of MVs induced cell proliferation. ConclusionsAppropriate dosages of MVs and MSCs are effective treatments for inflammatory arthritis while MVs and MSCs overdose is unsafe by causing cardiopulmonary complications.

Effectiveness of mesenchymal stem cell therapy in cats with chronic gingivostomatitis

PICO Question In cats with chronic gingivostomatitis, does using intravenous mesenchymal stem cell therapy, compared to not using it, lead to the improvement of clinical signs? Clinical bottom line Category of research Treatment. Number and type of study designs reviewed Five interventional studies (clinical trials). Strength of evidence None. Outcomes reported The reviewed studies indicate intravenous mesenchymal stem cell (MSC) therapy is safe to administer and can be effective in remission or alleviating the clinical signs of refractory, chronic gingivostomatitis in cats that have undergone full-mouth tooth extraction. Conclusion The collective evidence supports the intravenous administration of mesenchymal stem cell (MSC) therapy in cats with chronic gingivostomatitis following dental extraction. However, conducted clinical trials are prone to different degrees of bias due to the lack of independent control groups, the small number of subjects, and enrolling subjects with various severity of the disease. Therefore, more robust evidence can be obtained through well-designed randomised controlled trials to confirm the observed positive effects of the treatment in cats with a broader range of characteristics. How to apply this evidence in practice The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources. Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.

Efficacy and safety of intravenous mesenchymal stem cells for ischemic stroke patients, a systematic review and meta-analysis

BackgroundClinical trials have evaluated the efficacy of intravenous mesenchymal stem cells (MSCs) for acute and subacute ischemic stroke. Therefore, we conducted this meta-analysis to investigate the efficacy and safety of intravenous MSC treatments compared to placebo for acute and subacute ischemic stroke patients.MethodsWe searched PubMed, SCOPUS, Web of Science, and Cochrane CENTRAL for randomized controlled trials evaluating any clinical trials of intravenous MSCs for acute and subacute ischemic stroke patients. The efficacy outcomes of this study were the rates of improvement in National Institutes of Health Stroke Scale (NIHSS) scores, good scores on the modified Rankin Scale (mRS), and Barthel Index (BI) scores, while the safety outcomes were the rates of mortality and stroke recurrence. We compared intravenous MSC and placebo treatments on a fixed-effect meta-analysis model in R software.ResultsFour randomized controlled studies involving 97 patients were included in the analysis. In the meta-analysis, MSC treatments were superior to placebo treatments in good mRS (MD −0.95, 95% CI [−1.39, −0.52]) or BI (MD 21.36, 95% CI [9.96, 32.75]) scores, and MSC treatments were not superior to placebo treatments in the rate of improvement of the NIHSS scores (MD −1.81, 95% CI [−4.123, 0.494]). MSCs were associated with neither decreased mortality nor stroke recurrence (risk ratio 0.58 and 0.59, respectively; p-value = 0.51 and p-value = 0.533, respectively).ConclusionFor patients with acute and subacute ischemic stroke who are eligible for further damage to neural tissue, MSCs achieve high efficacy and acceptable safety.Systematic review registrationProspero, unique ID: CRD42023457655.

Intravenous human dental pulp-derived mesenchymal stem cell therapy for ischemic stroke in rats: an analysis of functional and ischemic brain areas outcomes

Cellular therapies have been implicated in treating and rehabilitating ischemic stroke (IS), involving the basic experimental and preclinical areas. Using mesenchymal stem cells (MSC) derived from human dental pulp has shown promising results in animal models, but still with mechanisms and consequences that are not entirely clear. The study aims to evaluate the effects of intravenous MSC on rats with IS regarding neurological function and histological areas of ischemia. Thirty-two male Wistar rats underwent temporary occlusion of the middle cerebral artery (TOMCA) for 60 minutes and were divided into two groups of 16 animals each. One group received dental pulp MSC intravenously, and another received saline 2 hours after TOMCA. The animals were then evaluated using the neurological functionality scales for 15 days, and at the end of the experiment period, the histological areas of cerebral ischemia were analysed. All animals presented ischemic areas and neurological deficits compatible with IS. There was partial recovery of the functionality scores over the evaluation period, and all animals presented focal cerebral ischemia measured by histological analysis; however, there was no statistical difference between the groups. The TOMCA model was effective in reproducing IS. Although we found no difference between treatment groups, our results were useful in showing the pattern of neurological recovery presented by animals treated with dental pulp MSC and the need to extend the evaluation time for a longer period and use more sensitive functional tests. The results add valuable data for improving research with dental pulp MSC in the murine model of IS.

Utero-Vesical Fistula Closure after 3 Weeks Treatment with Intravenous Mesenchymal Stem Cells Infusion: Case Report

Objective: To describe the evolution of Utero-Vesical Fistula (UVF) of one patient who received conservative treatment using intravenous (IV) infusion of 120x106 Adipose tissue Mesenchymal Stem Cells (ADMSCs). Clinical case report: A 36-year-old female presented with postcesarean hematuria 3 hours after an emergency c-section was performed consequently to placental abruption during labor. The primary measure was to use a transurethral Silastic 18F Foley catheter to prevent bladder expansion. The catheter remained for 21 days. Evaluation through Computerized Tomography Cystography (Cysto-CT) revealed failure to close the fistula. The decision to inject ADMSCs as an IV single dose was done. Three weeks after this intervention no blood was seen in the urine drainage bag. Complete resolution of UVF was confirmed with a control CT urogram. Result: Total closure of UVF. Conclusions: The IV infusion of ADMSCs proved to be a plausible and effective conservative treatment of UVF.

Utero-Vesical Fistula Closure After 3 Weeks Treatment with Intravenous Mesenchymal Stem Cells Infusion: Case Report

Objective: To describe the evolution of Utero-Vesical Fistula (UVF) of one patient who received conservative treatment using intravenous (IV) infusion of 120x106 Adipose tissue Mesenchymal Stem Cells (ADMSCs). Clinical case report A 36-year-old female presented with post-cesarean hematuria 3 hours after an emergency c-section was performed consequently to placental abruption during labour. The primary measure was to use a transurethral Silastic 18F Foley catheter to prevent bladder expansion. The catheter remained for 21 days. Evaluation through Computarized Tomography Cystography (Cisto-CAT) revealed failure to close the fistula. The decision to inject ADMSCs as an IV single dose was done. Three weeks after this intervention no blood was seen in the urine drainage bag. Complete resolution of UVF was confirmed with a control CT urogram. Result: Total closure of UVF. Conclusions: The IV infusion of ADMSCs proved to be a plausible and effective conservative treatment of UVF.

Recent clinical trials with stem cells to slow or reverse normal aging processes.

Aging is associated with a decline in the regenerative potential of stem cells. In recent years, several clinical trials have been launched in order to evaluate the efficacy of mesenchymal stem cell interventions to slow or reverse normal aging processes (aging conditions). Information concerning those clinical trials was extracted from national and international databases (United States, EU, China, Japan, and World Health Organization). Mesenchymal stem cell preparations were in development for two main aging conditions: physical frailty and facial skin aging. With regard to physical frailty, positive results have been obtained in phase II studies with intravenous Lomecel-B (an allogeneic bone marrow stem cell preparation), and a phase I/II study with an allogeneic preparation of umbilical cord-derived stem cells was recently completed. With regard to facial skin aging, positive results have been obtained with an autologous preparation of adipose-derived stem cells. A further sixteen clinical trials for physical frailty and facial skin aging are currently underway. Reducing physical frailty with intravenous mesenchymal stem cell administration can increase healthy life expectancy and decrease costs to the public health system. However, intravenous administration runs the risk of entrapment of the stem cells in the lungs (and could raise safety concerns). In addition to aesthetic purposes, clinical research on facial skin aging allows direct evaluation of tissue regeneration using sophisticated and precise methods. Therefore, research on both conditions is complementary, which facilitates a global vision.

Utero Vesical Fistula Closure After 3 Weeks Treatment with Intravenous Mesenchymal Stem Cells Infusion Case Report

Utero Vesical Fistula Closure After 3 Weeks Treatment with Intravenous Mesenchymal Stem Cells Infusion Case Report

Does Mesenchymal Stem Cell therapy affect clinical outcomes in COVID-19-associated ARDS?

To retrospectively investigate the effects of intravenous mesenchymal stem cell therapy on mortality, ventilator-free days, acute phase reactants, and respiratory parameters in moderate-severe ARDS patients dependent on mechanical ventilation.

Intravenous Mesenchymal Stem Cell Administration Modulates Monocytes/Macrophages and Ameliorates Asthmatic Airway Inflammation in a Murine Asthma Model.

Although asthma is a common chronic airway disease that responds well to anti-inflammatory agents, some patients with asthma are unresponsive to conventional treatment. Mesenchymal stem cells (MSCs) have therapeutic potential for the treatment of inflammatory diseases owing to their immunomodulatory properties. However, the target cells of MSCs are not yet clearly known. This study aimed to determine the effect of human umbilical cord-derived MSCs (hUC-MSCs) on asthmatic lungs by modulating innate immune cells and effector T cells using a murine asthmatic model. Intravenously administered hUC-MSCs reduced airway resistance, mucus production, and inflammation in the murine asthma model. hUC-MSCs attenuated not only T helper (Th) 2 cells and Th17 cells but also augmented regulatory T cells (Tregs). As for innate lymphoid cells (ILC), hUC-MSCs effectively suppressed ILC2s by downregulating master regulators of ILC2s, such as Gata3 and Tcf7. Finally, regarding lung macrophages, hUC-MSCs reduced the total number of macrophages, particularly the proportion of the enhanced monocyte-derived macrophage population. In a closer examination of monocyte-derived macrophages, hUC-MSCs reduced the M2a and M2c populations. In conclusion, hUC-MSCs can be considered as a potential anti- asthmatic treatment given their therapeutic effect on the asthmatic airway inflammation in a murine asthma model by modulating innate immune cells, such as ILC2s, M2a, and M2c macrophages, as well as affecting Tregs and effector T cells.

Therapeutic role of intravenous mesenchymal stem cells infusion in a rat model of induced acute myocardial infarction

Therapeutic role of intravenous mesenchymal stem cells infusion in a rat model of induced acute myocardial infarction

First-in-human pilot trial of combined intracoronary and intravenous mesenchymal stem cell therapy in acute myocardial infarction.

BackgroundAcute ST-elevation myocardial infarction (STEMI) elicits a robust cardiomyocyte death and inflammatory responses despite timely revascularization.ObjectivesThis phase 1, open-label, single-arm, first-in-human study aimed to assess the safety and efficacy of combined intracoronary (IC) and intravenous (IV) transplantation of umbilical cord-derived mesenchymal stem cells (UMSC01) for heart repair in STEMI patients with impaired left ventricular ejection fraction (LVEF 30-49%) following successful reperfusion by percutaneous coronary intervention.MethodsConsenting patients received the first dose of UMSC01 through IC injection 4-5 days after STEMI followed by the second dose of UMSC01 via IV infusion 2 days later. The primary endpoint was occurrence of any treatment-related adverse events and the secondary endpoint was changes of serum biomarkers and heart function by cardiac magnetic resonance imaging during a 12-month follow-up period.ResultsEight patients gave informed consents, of whom six completed the study. None of the subjects experienced treatment-related serious adverse events or major adverse cardiovascular events during IC or IV infusion of UMSC01 and during the follow-up period. The NT-proBNP level decreased (1362 ± 1801 vs. 109 ± 115 pg/mL, p = 0.0313), the LVEF increased (52.67 ± 12.75% vs. 62.47 ± 17.35%, p = 0.0246), and the wall motion score decreased (26.33 ± 5.57 vs. 22.33 ± 5.85, p = 0.0180) at the 12-month follow-up compared to the baseline values. The serial changes of LVEF were 0.67 ± 3.98, 8.09 ± 6.18, 9.04 ± 10.91, and 9.80 ± 7.56 at 1, 3, 6, and 12 months, respectively as compared to the baseline.ConclusionThis pilot study shows that combined IC and IV transplantation of UMSC01 in STEMI patients with impaired LVEF appears to be safe, feasible, and potentially beneficial in improving heart function. Further phase 2 studies are required to explore the effectiveness of dual-route transplantation of UMSC01 in STEMI patients.

Abstract P1022: Intravenously Transplanted Mesenchymal Stem Cells--- A New Endocrine Reservoir For Cardioprotection

Aims: Intravenous mesenchymal stem cells (MSCs) confer considerable cardiovascular benefits to patients. The lung, but not the heart, is the main trapped site for intravenous MSCs. It remains unclear how intravenous MSCs bridge this spatial gap between the lung and the heart to achieve cardiac repair. To investigate how intravenous MSCs, like an endocrine reservoir, secrete specific miRNA-enriched extracellular vesicles (EVs) gradually and continuously to alleviate doxorubicin (Dox)-induced cardiotoxicity. Methods and results: MSCs were isolated from human placenta tissue, and multiple molecular imaging was generated by modifying MSCs-DF or MSCs-Gluc transduced with firefly luciferase ( Fluc ) / enhanced green fluorescence protein (eGFP) or Gaussia luciferase (Gluc) lactadherin fusion protein. The Dox-induced cardiotoxicity murine model was constructed and an equal sum of MSCs was infused into mice by single high dose (5 х 10 6 MSCs) or repeated low dose (1 х 10 6 MSCs, 5 times) intravenously. Dox-induced cardiotoxicity, characterized by cardiac atrophy, left ventricular dysfunction, and injured myocardium, was alleviated by low doses of repeated MSCs. These cardioprotective effects were attributed to the suppression of GRP78 triggering stress-induced apoptosis of the endoplasmic reticulum (ER) in cardiomyocytes. Our results confirmed that miR-181a-5p in EVs derived from MSCs (MSC-EVs) inhibited GRP78. Intravenous MSCs-DF were trapped in the lung vasculature, secreted EVs into serum, which was confirmed by the detection of eGFP + EVs. Gluc activity increased in serum EVs from mice administrated with MSCs-Gluc. MiR-181a-5p, which inhibits GRP78 with high efficacy, expressed an increase in serum EVs and myocardium after injecting repeated low-dose MSCs. Up-regulation or down-regulation of miR-181a-5p levels in MSC-EVs had enhanced or weakened therapeutic effects on Dox-induced cardiotoxicity by modulating ER stress-induced apoptosis. Conclusion: This study identifies intravenous MSCs, recognized as an endocrine reservoir, secrete EVs enriched with miR-181a-5p in the blood to confer indirect cardioprotection against Dox-induced cardiotoxicity.

Effect of Stem Cell Infusion Therapy on Sexual Function in Women with Type 2 Diabetes and Metabolic Syndrome: Post-Hoc Analysis of Randomized Controlled Trials

ABSTRACT Introduction There is a growing interest in restorative therapies for sexual function, yet there exists a paucity of human research into potential therapeutic applications of stem cell therapy (SCT). Mesenchymal Stem Cells (MSCs) and their effect on sexual function have not yet been explored in women with Type 2 Diabetes Mellitus (DM) and Metabolic Syndrome (MetS). Objective To determine the safety and efficacy of intravenous mesenchymal stem cell infusion therapy on sexual function in women with DM or MetS. Methods Female participants enrolled in the ACESO (NCT02886884) and CERES (NCT03059355) clinical trials completed the Sexual Quality of Life Questionnaire-Female (SQOL-F). SQOL-F is a validated 18-item self-assessment questionnaire rated on a six-point scale ranging from “completely agree” to “completely disagree” in which higher scores reflect better sexual quality of life. Participants were enrolled in the trials based on diagnosis of DM or MetS, respectively. Intervention in both trials was peripheral intravenous infusion of allogeneic MSCs. Follow-up was for 1 year. Questionnaires were collected at baseline and 1-, 3-, 6-, and 12-months post-infusion. Participants received 20 or 100 million MSCs from either bone marrow (n=5) or umbilical cord (n=2). Results Data was pooled from 7 women who participated in the two trials; 5 were from ACESO and 2 were from CERES. Three received high dose MSCs (100 million) and four received low dose (20 million) MSCs. The women in the ACESO trial received MSCs derived from healthy allogeneic donor bone marrow, and both women in the CERES trial received umbilical cord tissue derived MSCs. Median age was 73 [IQR=55-74] years. Six of the seven (86%) had past medical history of hypertension. Median SQOL score among all women at baseline was 30 [IQR=19-50], 25 [IQR=23-36] at 1 month, 34 [IQR=19-46] at 3 months, 29 [IQR=21-32] at 6 months, and 34 [IQR=26-49] at the end of 12 months. Improvements in SQOL from baseline through follow up did not meet level of statistical significance. Limitations of this study include the absence of a placebo-control group, the small sample size, and that sexual function was not a primary endpoint of the original trials. Conclusions SQOL did not appear to improve following peripheral infusion of MSCs in women with DM or MetS, but nevertheless appears to be safe with no decline in sexual function over the following 1 year. Larger clinical trials with placebo-controls are needed to further investigate the optimal dose, source, and route administration of SCT to enact a meaningful change in sexual function in women with DM or MetS. Disclosure Yes, this is sponsored by industry/sponsor: This work was supported by National Institutes of Health Grant R01 DK130991 and Clinician Scientist Development Grant from the American Cancer Society to RR. JMH is supported by National Institutes of Health grants 1R01 HL137355, 1R01 HL107110, 1R01 HL134558, 5R01 CA136387, and 5UM1 HL113460 and Soffer Family Foundation. Clarification Industry funding only - investigator initiated and executed study Any of the authors act as a consultant, employee or shareholder of an industry for: JMH discloses a relationship with Vestion Inc. that includes equity, board membership, and consulting. Neither Longeveron, Vestion, or any other companies participated in the funding of this work. All other authors indicated no potential conflicts of interest.

Anti-inflammatory effect of mesenchymal stem cells on hepatocellular carcinoma in the xenograft mice model.

BackgroundHepatocellular carcinoma (HCC) is the fifth most diagnosed cancer and the second leading cause of cancer‐related deaths worldwide. Sorafenib is the standard treatment used in the advanced stages of HCC. Cell therapy with mesenchymal stem cells (MSCs)‐based cell therapy has proven effective in immune regulation and tumour growth inhibition.ObjectivesIn this study, we investigated the anti‐inflammatory effect of MSCs on HCC xenografts.MethodsHuman HepG2 cell lines were subcutaneously implanted into the flank of 12 nude mice, divided into three groups: the control group, the IV group (intravenous MSCs injection) and the local group (local MSCs injection). Mice were sacrificed 6 weeks after tumour implantation, and tumours were resected entirety. Quantitative real‐time polymerase chain reaction (qRT‐PCR) measured the gene expression of inflammatory markers, including tumour necrosis factor‐α (TNF‐α), interleukin (IL)‐1α and IL‐10. Aspartate transaminase (AST), alanine transaminase (ALT) and urea levels were measured using spectrophotometry to ensure the safety of MSC therapy.ResultsGene expressions for all three inflammatory markers were reduced in both MSCs groups compared to the control group. AST, ALT and urea levels remained in normal ranges.ConclusionsMSC therapy can reduce inflammation in HCC xenograft mouse models.

Effectiveness of cell- and colony stimulating factor-based therapy for liver cirrhosis: a network meta-analysis of randomized controlled trials

Background aimsCirrhosis is the 11th leading cause of death worldwide. Because of the limitations of liver transplantation, cell- and granulocyte colony-stimulating factor (G-CSF)-based therapies are considered potential treatment methods. This work analyzes the effectiveness of cell- and G-CSF-based therapies by network meta-analysis. MethodsA literature search was performed in four databases from inception to September 10, 2021. Registered randomized controlled trials (RCTs) evaluating cell-based therapies and/or G-CSF-based therapies for cirrhosis patients were included. Traditional and network meta-analyses were analyzed in terms of survival, model for end-stage liver disease (MELD) score, Child–Turcotte–Pugh (CTP) score, alanine aminotransferase levels and aspartate aminotransferase levels. ResultsTwenty-four studies were included in this analysis. The results showed that G-CSF-based therapies (odds ratio [OR], 2.38, 95% confidence interval [CI], 1.49–3.79, P < 0.01) and cell-based therapies (OR, 1.54, 95% CI, 1.00–2.40, P = 0.048) improved the transplantation-free survival rate compared with standard medical treatment. Network analysis results showed that G-CSF combined with erythropoietin (EPO) and growth hormone (GH) had a therapeutic advantage, and cell-based therapy with mononuclear cell (MNC) hepatic artery injection and intravenous mesenchymal stem cells (MSCs) combined with G-CSF also had a relative advantage in terms of survival outcome. For the MELD score, G-CSF plus GH and MSC portal vein injection had relative advantages. G-CSF plus GH and G-CSF plus EPO had advantages in terms of CTP scores. The included strategies demonstrated no obvious improvement in liver injury indicators. ConclusionsCell-based therapy has potential therapeutic effects for liver cirrhosis. Among cell-based therapies, intravenous MSCs and hepatic artery injection of MNCs have advantageous therapeutic effects. The use of G-CSF was also noted in regimens that improved survival outcomes. However, more well-designed, large-scale RCTs are needed to confirm this conclusion.

Efficacy of Intravenous Mesenchymal Stem Cells for Motor Recovery After Ischemic Stroke: A Neuroimaging Study.

Stem cell-based therapy is a promising approach to repair brain damage after stroke. This study was conducted to investigate changes in neuroimaging measures using stem cell-based therapy in patients with ischemic stroke. In this prospective, open-label, randomized controlled trial with blinded outcome evaluation, patients with severe middle cerebral artery territory infarct were assigned to the autologous mesenchymal stem cell (MSC) treatment or control group. Of 54 patients who completed the intervention, 31 for the MSC and 13 for the control groups were included in this neuroimaging analysis. Motor function was assessed before the intervention and 90 days after randomization using the Fugl-Meyer assessment scale. Neuroimaging measures included fractional anisotropy values of the corticospinal tract and posterior limb of the internal capsule from diffusion tensor magnetic resonance imaging and strength of connectivity, efficiency, and density of the motor network from resting-state functional magnetic resonance imaging. For motor function, the improvement ratio of the Fugl-Meyer assessment score was significantly higher in the MSC group compared with the control group. In neuroimaging, corticospinal tract and posterior limb of the internal capsule fractional anisotropy did not decrease in the MSC group but significantly decreased at 90 days after randomization in the control group. Interhemispheric connectivity and ipsilesional connectivity significantly increased in the MSC group. Change in interhemispheric connectivity showed a significant group difference. Stem cell-based therapy can protect corticospinal tract against degeneration and enhance positive changes in network reorganization to facilitate motor recovery after stroke. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01716481.

Safety of Intravenous Autologous Bone Marrow-Derived Mesenchymal Cell Transplantation in 5 Patients With Reduced Left Ventricular Ejection Fraction.

Background: Although intracardiac injection or intracoronary delivery of mesenchymal stem cells (MSCs) has been reported, there have been few studies on the intravenous injection of MSCs, particularly in Japan.Methods and Results: Five patients with left ventricular ejection fraction (LVEF) ≤45% received 1.0×108 MSCs intravenously. The procedure did not induce significant changes in vital signs. One patient had an elevated body temperature after 1 day, but recovered spontaneously. Laboratory tests remained normal for 1 month after cell delivery. Computed tomography was performed after 1–2 years, and there was no evidence of malignancy.Conclusions: In this pilot study of patients with reduced LVEF, intravenous MSC delivery had no adverse effects.