Umbilical Cord Matrix (Wharton Jelly) Mesenchymal Stem Cells in Next-Generation Myocardial Repair and Regeneration: Mechanisms and Pre-Clinical Evidence.

Chronic ischemic heart failure (CIHF), caused by myocardial injury and cell loss, is a growing public health concern. Despite substantial investments in pharmaco- and device therapies for acute myocardial infarction and CIHF over the past decades, long-term prognosis has shown little improvement. There is a clear need to develop novel therapeutic strategies capable of attenuating progression from acute to chronic myocardial damage, reducing adverse myocardial remodeling, and enhancing myocardial contractility. Cell-based approaches are an important direction in basic and clinical research. Nevertheless, candidate cell types tested to-date in experimental and human studies show several fundamental limitations, including insufficient quantities and potency, poor myocardial uptake, immunogenicity and/or risk of tumorigenicity. Human umbilical cord matrix is a rich source of mesenchymal stem cells (Wharton's jelly mesenchymal stem cells, WJMSCs). WJMSCs are naturally low-immunogenic, demonstrate high plasticity and proliferation capacity, and exhibit an absence of tumorigenic potential. Moreover, by producing specific anti-inflammatory cytokines and chemokines, they reduce the inflammatory response (hence their use in graft-versus-host disease) and have pro-angiogenic, antiapoptotic, and anti-fibrotic properties, making them a natural player in myocardial repair and regeneration. Furthermore, WJMSCs can be expanded ex vivo with high genomic stability and full clonogenic potential and can be standardized as an "off-the-shelf" next-generation advanced therapy medicinal product (ATMP). This review aggregates essential, contemporary information on the properties and fundamental mechanisms of WJMSCs, addressing the process of infarct healing and chronic myocardial injury. It discusses outcomes from pre-clinical studies, such as improvements in myocardial function and reductions in fibrosis in animal models, paving the way for human ATMP trials.