Tissue specific diversity of mesenchymal stem cells – Valuable insights through transcriptome analysis of extracellular vesicles

Mesenchymal stem cells (MSCs) represent a cell and/or a cell population of multi-potential stem/progenitor cells also referred to as multi-potential stromal cells, mesenchymal stromal cells and mesenchymal progenitor cells ^[1]. They were first isolated in the late 1980s and since then, over the course of 25 years, there have been thousands of clinical applications. From 2011 till 2018 there were 1043 MSC trials planned with a targeted enrolment of 47,548 patients. There are different sources of MSCs. Adult sources include bone marrow and the adipose tissue stromal vascular fraction. Young “adult” tissue sources include umbilical cord tissue and placenta ^[2]. For the various clinical applications, the MSCs from different tissue sources have been applied even for repair and regeneration of tissues that were not derived from the same germ layer or the source embryonic/pluripotent stem cells. When we examine whether the regenerative capabilities differ between the tissue sources of the MSCs, we find that gene expression varied according to the source of the original tissue. For example, genes associated with apoptosis and senescence were upregulated in MSCs obtained from adipose tissue; genes associated with heart morphogenesis and blood circulation were upregulated in those obtained from the chorion; and genes associated with the neurological system were upregulated from those obtained from the umbilical cord ^[3].

There was one commentary stating that MSCs may not be fit to be called stem cells, but rather tissue specific progenitor cells. In fact, microvesicles (MVs) from the MSCs have a similar potential of a paracrine effect leading to regeneration or repair rather than using the MSCs themselves. It states that MSCs contribute to regeneration or repair by paracrine effects only rather than differentiation or division. Though there are high expectations for MSCs in therapeutics, the results of most of the clinical trials on regenerative medicine applications have only established safety while the outcome in terms of efficacy is not spectacular ^[4]. However, one of the promising and relatively successful applications of MSCs is for Graft versus Host disease (GVHD), and the underlying mechanisms are multifactorial among which cell-secreted factors including extracellular vesicles (EVs) have been reported to play a major role ^[5]. In the current issue of JSRM, Terunuma et al ^[6] have placed their observations on the analysis of transcriptome of such mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) wherein dental pulp-derived MSCs showed distinct transcriptomic signatures of ability to give rise to neural cell lineages while adipose tissue-derived MSCs showed signatures of skeletal system development. They suggest that evaluating the transcriptome and defining the therapeutic applications of MSCs to each cell or tissue type will be of great potential for efficient outcomes. Thus, though MSCs are a very interesting cell type, several challenges and hurdles remain such as no precise characterization, cellular heterogeneity, and tissue- specific functional properties. In all of these challenges, transcriptomic techniques such as the one described by Terunuma et al will offer insights for enhancing their potential in therapeutic applications, either through cells or through cell-secreted products. Terunuma et al ^[6] have accomplished the evaluation of transcriptomes from different sources of MSCs. This approach may also be considered for studying the mechanisms behind MSCs efficacy for GVHD. If this analysis can be standardized, it may be considered a yardstick for evaluating the potential of other MSC applications as well.