Mesenchymal stromal cells: are they ready for prime time?

Mesenchymal stromal cells (MSCs), originally referred to as colony-forming unit–fibroblasts (CFU-F) were first isolated from marrow almost 50 years ago as a population of rare, plastic-adherent, nonhematopoietic stromal cells with osteogenic potential.1 The term mesenchymal stem cells was subsequently coined because of their additional potential for differentiating into adipocytes and chondrocytes. Over the past decade and a half, MSCs have sparked tremendous interest among the scientific community because 1) they can be isolated from various tissue sources with relative ease, 2) they are poorly immunogenic thus making allogeneic MSCs ideal for therapeutic use, and 3) they have powerful immunomodulatory activity in a variety of potential therapeutic indications. It is becoming increasingly clear that their therapeutic effects in enhancing tissue repair and regeneration result from “paracrine” properties mediated by their ability to secrete tissue factors and not directly from their multidifferentiation or cell replacement potential. These factors stimulate endogenous progenitor cells and angiogenesis, suppress apoptosis of vulnerable cells, and induce remodeling of the extracellular matrix.2 A search of the ClinicalTrials.gov website for clinical trials involving the administration of MSCs yields more than 300 such trials ranging from Phase I to Phase III trials. As of the time of writing, no therapeutic product containing MSCs has been FDA approved for use in the United States although there are a limited number of such cellular products approved for use outside the United States. Early-phase studies have clearly shown that MSC infusions are generally safe with few infusion-related toxicities. A few recent Phase II and Phase III clinical trials of MSCs have yielded favorable results suggesting that one or more of these cellular therapy products will become approved for clinical use in a limited number of indications in the next few years. So while they are not yet ready for prime time, there is widespread optimism that MSCs will become part of the therapeutic armamentarium based on their immunomodulatory and tissue regeneration inducing properties. A day-long workshop entitled “MSCs: Are They Ready for Prime Time?” was held just before the 2015 annual meeting of AABB in Anaheim, California, featuring several presentations highlighting the biology and heterogeneity of MSCs, the manufacturing and regulatory challenges faced by academic investigators and pharmaceutical companies, results of preclinical studies highlighting their therapeutic potential, and results of contemporary clinical trials in stroke and graft-versus-host disease. One of the major issues facing the field is the question of how the potency of MSCs can be measured because of the large variability in tissue sources and methods of isolation and processing and the significant heterogeneity in the cells that are actually being administered to patients in different clinical trials. Without some consensus on how potency is defined or can be assessed, it will be difficult to analyze and compare results from different trials. One of the presentations addressed the potential for genetically engineered MSCs to deliver bioactive factors such as vascular endothelial growth factor (VEGF) to damaged tissues to take advantage of the ability of MSCs to traffic to such sites and promote angiogenesis by extending the duration of local expression of VEGF. In another presentation, the potential role of MSCs as therapy in severe trauma and other critical care conditions was discussed. While the available laboratory and preclinical data suggest that MSCs may have potent positive effects in this setting, many confounding factors and variables will need to be considered, studied, and paid attention to before clinical trials can be designed and conducted. In a supplement to this issue of TRANSFUSION, summaries of these workshop presentations are being published to provide the reader with concise reviews of the latest developments in this exciting field along with emerging data of outcomes of clinical trials and potential future applications of gene-modified MSCs in human disease. The author is an AABB employee. Naynesh R. Kamani e-mail: nkamani@aabb.org Center for Cellular Therapies and Research AABB Bethesda, MD