Over the past two decades, there has been an explosion in the numbers of clinical trials using mesenchymal stem cells (MSCs). While the safety profile of MSC therapy has been excellent, therapeutic success has not been as robust as expected. In addition to variabilities inherent in all live-cell products because of donor-specific differences and manufacturing practices, MSCs may have an additional layer of complexity due to the availability of many tissues/organ sources for isolation. Since first isolation from the bone marrow (BM) over 50 years ago, human MSCs have been robustly found in multiple tissues/organs. The increased variety of MSC sources is reflected in clinical trials: while BMMSCs was used in nearly all trials prior to 2008, they are used in less than 50% of clinical trials in recent years. While the majority of single-source MSC preclinical data accumulated over the past several decades do reveal biological differences between tissue-specific sources of MSCs, studies directly comparing different MSC sources are relatively rare. In this Review, we summarise these past findings and also specifically focus on studies comparing MSCs isolated from the most commonly utilised sources of BM, adipose tissue and post-partum discarded extraembryonic tissue. The MSC functions discussed here include paraxial mesodermal trilineage differentiation capacity, and also other well-studied and translationally relevant MSC functions of haematopoietic support, immunomodulation and paracrine capacities. Finally, we will discuss the implications of tissue-specific MSC functional differences on future research avenues, manufacturing practices, as well as clinical implementation.
