What's in a name: The trouble with mesenchymal stromal cell nomenclature

Mesenchymal stromal cells (MSCs), a.k.a. mesenchymal stem cells (MSCs), a.k.a. medicinal signalling cells (MSCs), are all terms that have been used to describe what is known to be a heterogeneous population of cells that can be derived from a myriad tissues, including adipose, bone marrow, and umbilical cord. According to Dominici et al, an MSC is described as plastic-adherent, having trilineage potential in vitro, i.e. the ability to differentiate chondro-, adipo-, and osteogenically, and exhibiting a number of surface markers. This position statement from 2006 sets these criteria expressly, but is very clear about this being a starting point for harmonisation within the field:

"While these criteria will probably require modification as new knowledge unfolds, we believe this minimal set of standard criteria will foster a more uniform characterization of MSC and facilitate the exchange of data among investigators."

14 years on, we still refer to the standards proposed in this statement as validation that the cells presented are indeed 'MSCs'. The problem becomes clear when the heterogeneity of the MSC population is considered. A bone marrow-derived MSC population will contain a significant percentage of non-differentiating cells, but will fulfil the plastic-adherence and surface marker criteria, and are therefore often passed as 'MSCs'.

This issue might be construed as pedantry, but it has ramifications on downstream applications of MSCs in therapy. The efficacy of MSC therapy is not guaranteed by the presence of the presented markers, the plastic adherence, and in vitro trilineage potential, as the cells might have different propensities to certain lineages and immunomodulatory effects potentially attenuating their action.

In 2015, James et al published a paper presenting the heterogeneity of marrow-derived stromal cells exhibiting surface marker profiles consistent with the proposed profile, but having wide variability in terms of immunomodulatory activity and differentiation capacity. Immortalised, clonal cell lines arising from this study represent subpopulations present in bone marrow derived stromal cells with different therapeutic potential, highlighting the need for more granularity in the classification of MSCs.

In a recent publication by Wilson et al, this heterogeneity is dissected from the point of view of MSC use in regenerative medicine. Here, it is pointed out the the surface marker profile is often used in publications and clinical trial applications as a de facto standard for MSC classification, whereas functionally, large variances were shown. The difficulty in nomenclature surrounding the use of 'stem' versus 'stromal' is also highlighted, where the use of 'stem' often suggests differentiation capability, which is thought to be potentially misleading when it is generally accepted that not all stromal cell populations possess this stem-like ability.

The field of regenerative medicine is a fast-evolving one: clinical trial applications are rising exponentially due to the vast potential inherent in using 'MSCs' for therapy, but there is a clear need for better definitions of mesenchymal stromal cell subpopulations.