Challenges in Clinical Development of Mesenchymal Stromal/Stem Cells: Concise Review

Abstract

Identified 50 years ago, mesenchymal stromal/stem cells (MSCs) immediately generated a substantial interest among the scientific community because of their differentiation plasticity and hematopoietic supportive function. Early investigations provided evidence of a relatively low engraftment rate and a transient benefit for challenging congenital and acquired diseases. The reasons for these poor therapeutic benefits forced the entire field to reconsider MSC mechanisms of action together with their ex vivo manipulation procedures. This phase resulted in advances in MSCs processing and the hypothesis that MSC-tissue supportive functions may be prevailing their differentiation plasticity, broadening the spectrum of MSCs therapeutic potential far beyond their lineage-restricted commitments. Consequently, an increasing number of studies have been conducted for a variety of clinical indications, revealing additional challenges and suggesting that MSCs are still lagging behind for a solid clinical translation. For this reason, our aim was to dissect the current challenges in the development of still promising cell types that, after more than half a century, still need to reach their maturity. Stem Cells Translational Medicine 2019;8:1135-1148.

Figure 1

Relationship between stemness and “stromalness.” Mesenchymal stromal/stem cell (MSC) stemness has been supported by a progressive accumulation of data regarding their proliferation and differentiation capacity since the late 1960s, reaching its peak around 2000. This feature then decreased slightly, leaving more room for another MSC feature, here defined as “stromalness,” based on tissue‐supportive functions (such as hematopoietic stem cell‐supportive function), which progressively increased involving the release of a variety of growth factors, chemokines, cytokines and, more recently, extracellular vesicles.

Figure 2

Mesenchymal stromal/stem cells (MSCs) heterogeneity. Representative photomicrograph showing the variety of cell sizes and shapes in bone marrow MSCs. There are tripolar‐shaped cells (yellow), long spindle‐shaped cells (orange), small round cells (red), short spindle‐shaped cells (blue), and flattened enlarged cells (black). Contrast Ph1 ×100 magnification, observer A1 (Zeiss).