Source Future Medicine

Mesenchymal stem cells (MSCs) are in development for many clinical indications, based both on ‘stem’ properties (tissue repair or regeneration) and on signaling repertoire (immunomodulatory and antiinflammatory effects). Potential conflation of MSC properties with those of tissue-derived stromal cells presents difficulties in comparing study outcomes and represents a source of confusion in cell therapy development. Cultured MSCs demonstrate significant heterogeneity in clonogenicity and multi-lineage differentiation potential. However in vivo biology of MSCs includes native functions unrelated to regenerative medicine applications, so do nomenclature and heterogeneity matter? In this perspective we examine some consequences of the nomenclature debate and heterogeneity of MSCs. Regulatory expectations are considered, emphasizing that product development should prioritize detailed characterization of therapeutic cell populations for specific indications.

Variation is a fundamental concept in biology. While conservation of genes over evolutionary time spans allows for the preservation of essential processes common to all life it is variation that enables adaptation and survival. Within species, biological and behavioral traits exhibit a continuous spectrum of variation which are likely to be based in part on variations in gene expression. Even highly conserved RNA genes exhibit both species differences and variations in expression across different tissues. Within a clonal population of cells, variations in gene expression between individual cells arise due to both extrinsic and intrinsic factors which determine the exact profile of gene expression and biological activities. Since changes in signaling activity will impact upon the environment of other cells in the population, heterogeneity is inevitable even when the cells are genetically identical. Heterogeneity in cell communities may in fact be critical to many biological processes, but is generally not considered in the routine characterization of cell populations, where properties are frequently reported on an averaged basis. Although variation is inevitable, limitations in our ability to detect and control heterogeneity brings with it challenges for the production of cell therapies in which cells are the active substance in a medicinal product. Increasingly sophisticated techniques allow elucidation of expression profiles at the single cell level which may provide insights useful for the optimization of cell culture for regenerative medicine products. Since one of the goals of medicinal product manufacture is consistency, can we reconcile variation at the individual cell level, for example as detected in RNA sequencing or microfluidics, with the population-based measurements currently used to characterize cells for regenerative medicine? How closely should we seek to control cell phenotype and expression profile to achieve a therapeutic goal? Are there benefits of population heterogeneity for the therapeutic effects of the product? The regulatory frameworks for medicinal products, which includes cell therapies, require developers to define and produce consistently a specific product which is controlled in terms of its quality attributes. Developers need to consider how to achieve routine manufacture of safe and efficacious cell therapies when the very nature of the starting material seems to undermine this objective. Mesenchymal stem/stromal cells (MSCs) represent a significant fraction of the current efforts to develop cellbased treatments for a range of diseases. There are at present 98 clinical trials involving mesenchymal stem/stromal cells as the investigational medicinal product registered with the European clinical trials database EudraCT. The colony-forming fibroblastic adherent cell population originally described by Friedenstein et al. have become the cell of choice for many regenerative medicine applications, and the literature expands daily. In this perspective we consider the impact of biological heterogeneity on some of the regulatory requirements to which MSC-based therapies are subject, and discuss how these factors might impact upon the use of MSC in regenerative medicine.

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