Soliciting strategies for developing cell-based reference materials to advance mesenchymal stromal cell research and clinical translation

Abstract

The mesenchymal stromal cell (MSC) field continues to rapidly progress with a number of clinical trials initiated and completed, with some reported successes in multiple clinical indications, and a growing number of companies established. The field, nevertheless, faces several challenges. Persistent issues include the definition of a MSC and comparability between MSC preparations. This is because of inherent cell heterogeneity, the absence of markers that are unique to MSCs, and the difficulty in precisely defining them by developmental origin. Differences in the properties of MSCs also depend on the site of tissue harvest, phenotypic and genotypic characteristics of the donor and the isolation, and storage and expansion methods used. These differences may be sufficient to ensure that attributes of the final MSC product could differ in potentially significant ways. Since there are currently no gold standards, we propose using a reference material to establish methods of comparability among MSC preparations. We suggest four possible "ruler scenarios" and a method for global distribution. We further suggest that critical to establishing a reference material is the need to define protocols for comparing cells. The main purpose of this article is to solicit input in establishing a consensus-based comparison. A comparative approach will be critical to all stages of translation to better clarify mechanisms of MSC actions, define an optimal cell manufacturing process, ensure best practice clinical investigations, extend the use of an MSC product for new indications, protect an MSC product from imitators, and develop uniform reimbursement policies. Importantly, a reference material may enable a consensus on a practical definition of MSCs.

FIG. 1.

Multiple modes of action attributed to MSCs include IBD, inflammatory bowel disease; RA, rheumatoid arthritis; GvHD, graft versus host disease; ARDs, acute respiratory distress syndrome; MI, myocardial infarction; OA, osteoarthritis; TBI, traumatic brain injury; CLI, critical limb ischemia; HSC, hematopoietic stem cells; MSC, mesenchymal stromal cell.

FIG. 2.

Sources of MSC and methods of isolation and differences in culture conditions and usual markers used. BM-MSCs, bone marrow MSCs; UCB-MSCs, umbilical cord blood MSCs; UCT-MSCs, umbilical cord tissue MSCs; AT-MSCs, adipose tissue MSCs; DP-MSCs, dental pulp MSCs; PMSCs, placental MSCs.

FIG. 3.

Flowchart on how one might use such a reference material. iPSCs, induced pluripotent stem cells; PACT, production assistance for cellular therapies; CCRM, Center for Commercialization of Regenerative Medicine; NIH, National Institutes of Health; TBD, to be determined.