Paracrine Effects of Mesenchymal Stromal Cells Cultured in Three-Dimensional Settings on Tissue Repair

Mesenchymal stromal cells (MSCs) are a promising cell source for promoting tissue repair, due to their ability to release growth, angiogenic, and immunomodulatory factors. However, when injected as a suspension, these cells suffer from poor survival and localization, and suboptimal release of paracrine factors. While there have been attempts to overcome these limitations by modifying MSCs themselves, a more versatile solution is to grow them in three dimensions, as aggregates or embedded into biomaterials. Here we review the mechanisms by which 3D culture can influence the regenerative capacity of undifferentiated MSCs, focusing on recent examples from the literature. We further discuss how knowledge of these mechanisms can lead to strategic design of MSC therapies that overcome some of the challenges to their effective translation.