Dataset Information

Intramyocardial Transplantation of Umbilical Cord Mesenchymal Stromal Cells in Chronic Ischemic Cardiomyopathy: A Controlled, Randomized Clinical Trial (HUC-HEART Trial).

ABSTRACT: Background and objectives: The HUC-HEART Trial (ClinicalTrials.gov Identifier: NCT02323477) was a controlled, prospective, phase I/II, multicenter, single-blind, three-arm randomized study of intramyocardial delivery of human umbilical cord-derived mesenchymal stromal cells (HUC-MSCs) combined with coronary artery bypass-grafting (CABG) in patients with chronic ischemic cardiomyopathy (CIC). The trial aimed to assess (i) the safety and the efficacy of cell transplantation during one-year follow-up, (ii) to compare the efficacy of HUC-MSCs with autologous bone-marrow- derived mononuclear cells (BM-MNCs) in the same clinical settings.

Methods and results: Fifty-four patients who were randomized to receive HUC-MSCs (23×10⁶) (n=26) or BM-MNCs (70×10⁷) (n=12) in combination with CABG surgery. The control patients (n=16) received no cells/vehicles but CABG intervention. All patients were screened at baseline and 1, 3, 6, 12 months after transplantation. Forty-six (85%) patients completed 12 months follow-up. No short/mid-term adverse events were encountered. Decline in NT-proBNP (baseline? 6 months) in both cell-treated groups; an increase in left ventricular ejection fraction (LVEF) (5.4%) and stroke volume (19.7%) were noted (baseline?6 or 12 months) only in the HUC-MSC group. Decreases were also detected in necrotic myocardium as 2.3% in the control, 4.5% in BM-MNC, and 7.7% in the HUC-MSC groups. The 6-min walking test revealed an increase in the control (14.4%) and HUC-MSC (23.1%) groups.

Conclusions: Significant findings directly related to the intramyocardial delivery of HUC-MSCs justified their efficacy in CIC. Stricter patient selection criteria with precisely aligned cell dose and delivery intervals, rigorous follow-up by detailed diagnostic approaches would further help to clarify the responsiveness to the therapy.

SUBMITTER: Ulus AT

PROVIDER: S-EPMC7691850 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Intramyocardial Transplantation of Umbilical Cord Mesenchymal Stromal Cells in Chronic Ischemic Cardiomyopathy: A Controlled, Randomized Clinical Trial (HUC-HEART Trial).

Ulus A Tulga AT Mungan Ceren C Kurtoglu Murat M Celikkan Ferda Topal FT Akyol Mesut M Sucu Merve M Toru Mustafa M Gul Serdar Savas SS Cinar Ozgur O Can Alp A

International journal of stem cells 20201101 3

<h4>Background and objectives</h4>The HUC-HEART Trial (ClinicalTrials.gov Identifier: NCT02323477) was a controlled, prospective, phase I/II, multicenter, single-blind, three-arm randomized study of intramyocardial delivery of human umbilical cord-derived mesenchymal stromal cells (HUC-MSCs) combined with coronary artery bypass-grafting (CABG) in patients with chronic ischemic cardiomyopathy (CIC). The trial aimed to assess (i) the safety and the efficacy of cell transplantation during one-year ...[more]

PMID: 32840230

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Project description:ObjectiveTo investigate the curative effects of HUC-MSCs combined with USW on spinal cord injury (SCI) and the effects on inflammatory microenvironment and to explore the regulatory mechanisms of MK2/TTP signalling pathway and NLRP3 inflammasome.MethodsThe SCI rat model was established using the modified Allen method; rats were administered with USW, HUC-MSCs, and combination therapy of USW and HUC-MSCs; the therapeutic efficacies in each group of rats were monitored and represented in BBB score. SCI levels were observed using HE staining and IF. The microglia polarisation state and released contents of inflammatory factors were detected. IF and Western Blotting were performed on to detect the expression levels of MK2/TTP signalling pathway and NLRP3 inflammasome-related proteins. Furthermore, the regulatory mechanisms of MK2/TTP pathway and NLRP3 were explored by performing on the in vitro study.ResultsCombination therapy of USW and HUC-MSCs was found of significant efficacy on improving motor functions of SCI rats, and it was further proved that this combination therapy can reduce spinal cord injury in SCI rats, of which USW plays a more important role. While transplantation of HUC-MSCs can promote microglial cells developing to SCI repair, and M2 microglial cells were taking advantages gradually. The combination therapy can inhibit the expression of MK2; downregulate NLRP3 inflammasome; suppress the expression levels of pro-caspase-1, pro-IL-1β, and pro-IL-18; and simultaneously suppress the release of IL-1β and IL-18, thereby reducing spinal cord neurons apoptosis. It was found that the steady state of microglial polarisation maintained by combined treatment of USW and HUC-MSCs was destroyed with the upregulation of MK2 expression in cells, of which, M1 type microglial cell was dominant and the increased contents of inflammatory factors were detected. However, overexpressed MK2 relieved the inhibition of NLRP3 expression by TTP.ConclusionsCombination therapy of USW and HUC-MSCs can downregulate NLRP3 expression, relieve inflammatory responses, improve immune microenvironment, and rescue spinal cord injury via suppressing phosphorylation level of MK2.

Project description:BACKGROUND:The therapeutic role of mesenchymal stem cells (MSCs) has been widely confirmed in several animal models of premature infant diseases. Micromolecule peptides have shown promise for the treatment of premature infant diseases. However, the potential role of peptides secreted from MSCs has not been studied. The purpose of this study is to help to broaden the knowledge of the hUC-MSC secretome at the peptide level through peptidomic profile analysis. METHODS:We used tandem mass tag (TMT) labeling technology followed by tandem mass spectrometry to compare the peptidomic profile of preterm and term umbilical cord MSC (hUC-MSC) conditioned medium (CM). Gene Ontology (GO) enrichment analysis and ingenuity pathway analysis (IPA) were conducted to explore the differentially expressed peptides by predicting the functions of their precursor proteins. To evaluate the effect of candidate peptides on human lung epithelial cells stimulated by hydrogen peroxide (H2O2), quantitative real-time PCR (qRT-PCR), western blot analysis, and enzyme-linked immunosorbent assay (ELISA) were, respectively, adopted to detect inflammatory cytokines (TNF-?, IL-1?, and IL-6) expression levels at the mRNA and protein levels. RESULTS:A total of 131 peptides derived from 106 precursor proteins were differentially expressed in the preterm hUC-MSC CM compared with the term group, comprising 37 upregulated peptides and 94 downregulated peptides. Bioinformatics analysis showed that these differentially expressed peptides may be associated with developmental disorders, inflammatory response, and organismal injury. We also found that peptides 7118TGAKIKLVGT7127 derived from MUC19 and 508AAAAGPANVH517 derived from SIX5 reduced the expression levels of TNF-?, IL-1?, and IL-6 in H2O2-treated human lung epithelial cells. CONCLUSIONS:In summary, this study provides further secretomics information on hUC-MSCs and provides a series of peptides that might have antiinflammatory effects on pulmonary epithelial cells and contribute to the prevention and treatment of respiratory diseases in premature infants.

Project description:Stroke is the second leading cause of death worldwide, claims six lives every 60 seconds, and is a leading cause of adult disability across the globe. Tissue plasminogen activator, the only United States Food and Drug Administration (FDA)-approved drug currently available, has a narrow therapeutic time window of less than 5 hours. In the past decade, cells derived from the human umbilical cord (HUC) have emerged as a potential therapeutic alternative for stroke; however, the most effective HUC-derived cell population remains unknown.We compared three cell populations derived from the human umbilical cord: cord blood mononuclear cells (cbMNCs); cord blood mesenchymal stromal cells (cbMSCs), a subpopulation of cbMNCs; and cord matrix MSCs (cmMSCs). We characterized these cells in vitro with flow cytometry and assessed the cells' in vivo efficacy in a 2-hour transient middle cerebral artery occlusion (MCAo) rat model of stroke. cbMNCs, cbMSCs, and cmMSCs were each transplanted intraarterially at 24 hours after stroke.A reduction in neurologic deficit and infarct area was observed in all three cell groups; however, this reduction was significantly enhanced in the cbMNC group compared with the cmMSC group. At 2 weeks after stroke, human nuclei-positive cells were present in the ischemic hemispheres of immunocompetent stroke rats in all three cell groups. Significantly decreased expression of rat brain-derived neurotrophic factor mRNA was observed in the ischemic hemispheres of all three cell-treated and phosphate-buffered saline (PBS) group animals compared with sham animals, although the decrease was least in cbMNC-treated animals. Significantly decreased expression of rat interleukin (IL)-2 mRNA and IL-6 mRNA was seen only in the cbMSC group. Notably, more severe complications (death, eye inflammation) were observed in the cmMSC group compared with the cbMNC and cbMSC groups.All three tested cell types promoted recovery after stroke, but cbMNCs showed enhanced recovery and fewer complications compared with cmMSCs.

Project description:ObjectiveWe tested the hypothesis that direct intramyocardial injection of bone marrow mononuclear cells in patients with non-ischemic dilated cardiomyopathy can improve left ventricular function and physical capacity.MethodsThirty non-ischemic dilated cardiomyopathy patients with left ventricular ejection fraction <35% were randomized at a 1:2 ratio into two groups, control and treated. The bone marrow mononuclear cells group received 1.06±108 bone marrow mononuclear cells through mini-thoracotomy. There was no intervention in the control group. Assessment was carried out through clinical evaluations as well as a 6-min walk test, nuclear magnectic resonance imaging and echocardiogram.ResultsThe bone marrow mononuclear cells group showed a trend toward left ventricular ejection fraction improvement, with magnectic resonance imaging - at 3 months, showing an increase from 27.80±6.86% to 30.13±9.06% (P=0.08) and returning to baseline at 9 months (28.78%, P=0.77). Magnectic resonance imaging showed no changes in left ventricular ejection fraction during follow-up of the control group (28.00±4.32%, 27.42±7.41%, and 29.57±4.50%). Echocardiogram showed left ventricular ejection fraction improved in the bone marrow mononuclear cells group at 3 months, 25.09±3.98 to 30.94±9.16 (P=0.01), and one year, 30.07±7.25% (P=0.001). The control group showed no change (26.1±4.4 vs 26.5±4.7 and 30.2±7.39%, P=0.25 and 0.10, respectively). Bone marrow mononuclear cells group showed improvement in New York Heart Association functional class, from 3.40±0.50 to 2.41±0.79 (P=0.002); patients in the control group showed no change (3.37±0.51 to 2.71±0.95; P=0.17). Six-minute walk test improved in the bone marrow mononuclear cells group (348.00±93.51m at baseline to 370.41±91.56m at 12 months, P=0.66) and there was a non-significant decline in the control group (361.25±90.78m to 330.00±123.42m after 12 months, P=0.66). Group comparisons were non-significant.ConclusionThe trend of intragroup functional and subjective improvement was not confirmed when compared to the control group. Direct intramyocardial application of bone marrow mononuclear cells in non-ischemic dilated cardiomyopathy was not associated with significant changes in left ventricular function. Differences observed within the bone marrow mononuclear cells group could be due to placebo effect or low statistical power.

Project description:Importance:Cell therapy may be helpful for cardiac disease but has been fraught with poor cell retention and survival after transplantation. Objective:To determine whether cell-laden hydrogel treatment is safe and feasible for patients with chronic ischemic heart disease (CIHD). Design, Setting, and Participants:This randomized, double-blind clinical trial was conducted between March 1, 2016, and August 31, 2019, at a single hospital in Nanjing, China. Among 115 eligible patients with CIHD, 50 patients with left ventricular ejection fraction of 45% or less were selected to receive elective coronary artery bypass grafting (CABG) and additionally randomized to cell-plus-collagen treatment (collagen/cell group), cell treatment alone (cell group), or a control group. Sixty-five patients were excluded because of severe comorbidities or unwillingness to participate. Forty-four participants (88%) completed the study. The last patient completed 12 months of follow-up in August 2019. Analyses were prespecified and included all patients with available data. Interventions:During CABG, patients in the collagen/cell group were treated with human umbilical cord-derived mesenchymal stromal cell (hUC-MSC)-laden collagen hydrogel intramyocardial injection, and the cell group was treated with hUC-MSCs alone. Patients in the control group underwent CABG alone. Main Outcomes and Measures:The primary outcome was safety of the cell-laden collagen hydrogel assessed by the incidence of serious adverse events. The secondary end point was the efficacy of treatment, according to cardiovascular magnetic resonance imaging-based left ventricular ejection fraction and infarct size. Results:Fifty patients (mean [SD] age, 62.6 [8.3] years; 38 men [76%]) were enrolled, of whom 18 were randomized to the collagen/cell group, 17 to the cell group, and 15 to the control group. Patient characteristics did not differ among groups at baseline. For the primary end point, no significant differences in serious adverse events, myocardial damage markers, and renal or liver function were observed among all groups after treatment; the collagen/cell and cell groups each had 1 case of hospitalization because of heart failure, and no serious adverse events were seen in the control group. At 12 months after treatment, the mean infarct size percentage change was -3.1% (95% CI, -6.20% to -0.02%; P?=?.05) in the collagen/cell group, 5.19% (-1.85% to 12.22%, P?=?.35) in the cell group, and 8.59% (-3.06% to 20.25%, P?=?.21) in the control group. Conclusions and Relevance:This study provides, to our knowledge, the first clinical evidence that the use of collagen hydrogel is safe and feasible for cell delivery. These findings provide a basis for larger clinical studies. Trial Registration:ClinicalTrials.gov Identifier: NCT02635464.

Dataset Information

Intramyocardial Transplantation of Umbilical Cord Mesenchymal Stromal Cells in Chronic Ischemic Cardiomyopathy: A Controlled, Randomized Clinical Trial (HUC-HEART Trial).

Publications

Intramyocardial Transplantation of Umbilical Cord Mesenchymal Stromal Cells in Chronic Ischemic Cardiomyopathy: A Controlled, Randomized Clinical Trial (HUC-HEART Trial).

Similar Datasets

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