Abstract
Human mesenchymal stem cells gather special interest as a universal and feasible add-on therapy for myocardial infarction (MI). In particular, human umbilical cord matrix-derived mesenchymal stromal cells (UCM-MSC) are advantageous since can be easily obtained and display high expansion potential. Using isolation protocols compliant with cell therapy, we previously showed UCM-MSC preserved cardiac function and attenuated remodeling 2 weeks after MI. In this study, UCM-MSC from two umbilical cords, UC-A and UC-B, were transplanted in a murine MI model to investigate consistency and durability of the therapeutic benefits. Both cellular products improved cardiac function and limited adverse cardiac remodeling 12 weeks post-ischemic injury, supporting sustained and long-term beneficial therapeutic effect. Donor associated variability was found in the modulation of cardiac remodeling and activation of the Akt-mTOR-GSK3β survival pathway. In vitro, the two cell products displayed similar ability to induce the formation of vessel-like structures and comparable transcriptome in normoxia and hypoxia, apart from UCM-MSCs proliferation and expression differences in a small subset of genes associated with MHC Class I. These findings support that UCM-MSC are strong candidates to assist the treatment of MI whilst calling for the discussion on methodologies to characterize and select best performing UCM-MSC before clinical application.
Highlights
Cardiovascular diseases are the leading cause of morbidity and mortality worldwide (Benjamin et al, 2019), with ischemic heart disease representing the largest single cause of death in countries of all income levels (Nowbar et al, 2019)
Cardiac cell-based therapies aimed at regeneration and/or instructing a more favorable repair have been explored in clinical settings, including skeletal myoblasts, embryonic stem cells (ESCs), bone marrow mononuclear cells (BMMNCs), cardiac stem cells (CSCs), hematopoietic stem cells (HSCs), mesenchymal stromal cells (MSCs), and recently, induced pluripotent stem cells-derived cardiomyocytes in preclinical studies (Madigan and Atoui, 2018)
Using the same murine Myocardial Infarction (MI) model, the efficiency of UC-A and umbilical cord blood (UCB) was evaluated in a long-term scenario of 12 weeks
Summary
Cardiovascular diseases are the leading cause of morbidity and mortality worldwide (Benjamin et al, 2019), with ischemic heart disease representing the largest single cause of death in countries of all income levels (Nowbar et al, 2019). To other candidates for cell therapy, MSCs do not express MHC Class II and display low levels of MHC Class I proteins, as such seen as immune evasive (Ankrum et al, 2014) and suitable for MHC mismatched allogeneic transplantation. These cells can be procured from a variety of adult sources as the bone marrow and adipose tissue, and neonatal sources, including the placenta, umbilical cord blood or umbilical cord matrix (UCM; Wharton’s Jelly). UCM-MSC are attractive since the source tissue can be obtained in a non-invasive and more efficient fashion, have higher expansion potential, higher differentiation range and were shown to be stronger immunomodulators by repressing Tcell activation and promoting Treg expansion more efficiently (Santos et al, 2013)
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