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As a result of over five decades of investigation, mesenchymal stromal/stem cells (MSCs) have emerged as a versatile and frequently utilized cell source in the fields of regenerative medicine and tissue engineering. In this review, we summarize the history of MSC research from the initial discovery of their multipotency to the more recent recognition of their perivascular identity in vivo and their extraordinary capacity for immunomodulation and angiogenic signaling. As well, we discuss long-standing questions regarding their developmental origins and their capacity for differentiation toward a range of cell lineages. We also highlight important considerations and potential risks involved with their isolation, ex vivo expansion, and clinical use. Overall, this review aims to serve as an overview of the breadth of research that has demonstrated the utility of MSCs in a wide range of clinical contexts and continues to unravel the mechanisms by which these cells exert their therapeutic effects.

Significance Robust and predictive in vitro models of human cardiac tissue function could have transformative impact on our ability to test new drugs and understand cardiac disease. Despite significant effort, the generation of high-fidelity adult-like human cardiac tissue analogs remains challenging. In this paper, we systematically explore the design criteria for pluripotent stem cell-derived engineered cardiac tissue. Parameters such as biomechanical stress during tissue remodeling, input-cell composition, electrical stimulation, and tissue geometry are evaluated. Our results suggest that a specified combination of a 3D matrix-based microenvironment, uniaxial mechanical stress, and mixtures of cardiomyocytes and fibroblasts improves the performance and maturation state of in vitro engineered cardiac tissue.