Safety and Efficacy of the Intravenous Infusion of Umbilical Cord Mesenchymal Stem Cells in Patients With Heart Failure: A Phase 1/2 Randomized Controlled Trial (RIMECARD Trial [Randomized Clinical Trial of Intravenous Infusion Umbilical Cord Mesenchymal Stem Cells on Cardiopathy])

Abstract

Rationale: Umbilical cord-derived mesenchymal stem cells (UC-MSC) are easily accessible and expanded in vitro, possess distinct properties, and improve myocardial remodeling and function in experimental models of cardiovascular disease. Although bone marrow-derived mesenchymal stem cells have been previously assessed for their therapeutic potential in individuals with heart failure and reduced ejection fraction, no clinical trial has evaluated intravenous infusion of UC-MSCs in these patients.

Objective: Evaluate the safety and efficacy of the intravenous infusion of UC-MSC in patients with chronic stable heart failure and reduced ejection fraction.

Methods and results: Patients with heart failure and reduced ejection fraction under optimal medical treatment were randomized to intravenous infusion of allogenic UC-MSCs (Cellistem, Cells for Cells S.A., Santiago, Chile; 1×10⁶ cells/kg) or placebo (n=15 per group). UC-MSCs in vitro, compared with bone marrow-derived mesenchymal stem cells, displayed a 55-fold increase in the expression of hepatocyte growth factor, known to be involved in myogenesis, cell migration, and immunoregulation. UC-MSC-treated patients presented no adverse events related to the cell infusion, and none of the patients tested at 0, 15, and 90 days presented alloantibodies to the UC-MSCs (n=7). Only the UC-MSC-treated group exhibited significant improvements in left ventricular ejection fraction at 3, 6, and 12 months of follow-up assessed both through transthoracic echocardiography (P=0.0167 versus baseline) and cardiac MRI (P=0.025 versus baseline). Echocardiographic left ventricular ejection fraction change from baseline to month 12 differed significantly between groups (+7.07±6.22% versus +1.85±5.60%; P=0.028). In addition, at all follow-up time points, UC-MSC-treated patients displayed improvements of New York Heart Association functional class (P=0.0167 versus baseline) and Minnesota Living with Heart Failure Questionnaire (P<0.05 versus baseline). At study completion, groups did not differ in mortality, heart failure admissions, arrhythmias, or incident malignancy.

Conclusions: Intravenous infusion of UC-MSC was safe in this group of patients with stable heart failure and reduced ejection fraction under optimal medical treatment. Improvements in left ventricular function, functional status, and quality of life were observed in patients treated with UC-MSCs.

Clinical trial registration: URL: https://www.clinicaltrials.gov/ct2/show/NCT01739777. Unique identifier: NCT01739777.

Keywords: cardiomyopathies; clinical trial; heart failure; mesenchymal stromal cells; umbilical cord.

Figure 1.

Umbilical cord–derived mesenchymal stem cells (UC-MSCs) and marrow–derived mesenchymal stem cells (BM-MSCs) displayed different cardiac differentiation potential and paracrine factors profile. Cardiac differentiation was induced in UC-MSCs and BM-MSCs by cultured with 5-azacytidine (5-AZA) 10 µmol/L during 25 d. Cardiac differentiation potential was evaluated through mRNA relative expression of cardiac gene (NCx2.5, GATA-4, MEF2C, MYH7B, GJA1, and TNNT2) by real time polymerase chain reaction (RT-PCR) with B2M as a housekeeping gene (A) and by detection of cardiac proteins using indirect immunofluorescence staining troponin and connexin-43 (B), the respective graphs show the quantification of positive cells in the each staining. TGFβ3 expression was quantitated by quantitative RT-PCR (C). Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) levels were evaluated by ELISA assay (C). Data shown in the graphs are the mean±SEM of at least 3 individual experiments. *P<0.05, ***P<0.001, UC-MSCs compared with BM-MSCs. +P<0.05, ++P<0.001 UC-MSC-4 compared with UC-MSCs-1, 2, and 3.

Figure 2.

Umbilical cord–derived mesenchymal stem cells (UC-MSCs) and marrow–derived mesenchymal stem cells (BM-MSCs) display the same suppressive capacities to inhibit proinflammatory T-cells. PHA-activated peripheral blood mononuclear cells (PBMC) obtained from dilated cardiomyopathy patients with heart failure and reduced ejection fraction (HFrEF) labeled with 5(6)-carboxyfluorescein diacetate N-succinimidyl (CFSE) were coculture with or without mesenchymal stem cells (MSCs) at a 1:10 ratio (MSCs:PBMC). A, T-cell proliferation was evaluated by the reduction in CFSE intensity at 72 h after culture, the graphs in the left is a representative CFSE proliferation panel (light color histogram represents activated PBMCs and dark color histogram to activated PBMC cocultured with MSCs). B, Th1, Th2, CD8, and regulatory T cells subsets analysis from coculture of PBMC and MSCs. Results are represented as mean±SEM of at least 3 independent experiments using at least 3 different donors for PBMC (healthy donor and HF patient), UC-MSCs, and BM-MSCs. ***P<0.001 UC-MSCs or BM-MSCs with respect to PHA.

Figure 3.

Umbilical cord–derived mesenchymal stem cells (UC-MSCs) possess a superior migration capacity compared with marrow–derived mesenchymal stem cells (BM-MSCs). Migration capacity of MSCs was evaluated by transwell assay in response to serum from patients with heart failure and reduced ejection fraction after 16 h. The pictures show the representative staining with violet crystal and the left graph the quantification of % of migrated cells under the different conditions. Data shown in the graphs are the mean±SEM of at least 3 serum donors, UC-MSCs, and BM-MSCs. *P<0.05 UC-MSCs vs BM-MSCs.

Figure 4.

Study flow chart. UC-MSC indicates umbilical cord–derived mesenchymal stem cell.

Figure 5.

Changes in CMR measurements from baseline to 12-mo post-treatment in studied groups. A, Left ventricular ejection fraction (LVEF). B, Left ventricular end-diastolic volume (LVEDV). C, Left ventricular end-systolic volume (LVESV). Continuous line represents umbilical cord–derived mesenchymal stem cell group (n=14 per protocol). Dashed line represents placebo group (n=13 per protocol; withdrawal of consent from 1 patient). Statistical analysis is based on mixed effect maximum likelihood regression between baseline and follow-up measures for each group and variability between groups.