Mesenchymal stromal cell variables influencing clinical potency: the impact of viability, fitness, route of administration and host predisposition

Abstract

The International Society for Cell & Gene Therapy mesenchymal stromal cell (MSC) committee has been an interested observer of community interests in all matters related to MSC identity, mechanism of action, potency assessment and etymology, and it has regularly contributed to this conversation through a series of MSC pre-conferences and committee publications dealing with these matters. Arising from these reflections, the authors propose that an overlooked and potentially disruptive perspective is the impact of in vivo persistence on potency that is not predicted by surrogate cellular potency assays performed in vitro and how this translates to in vivo outcomes. Systemic delivery or extravascular implantation at sites removed from the affected organ system seems to be adequate in affecting clinical outcomes in many pre-clinical murine models of acute tissue injury and inflammatory pathology, including the recent European Medicines Agencyapproved use of MSCs in Crohn-related fistular disease. The authors further propose that MSC viability and metabolic fitness likely dominate as a potency quality attribute, especially in recipients poised for salutary benefits as defined by emerging predictive biomarkers of response.

Comparing the Therapeutic Potential of Stem Cells and their Secretory Products in Regenerative Medicine

“…It encompasses four mechanisms by which derivatives of MSCs can retain significant clinical efficacy, including apoptosis, autophagy, mitochondrial transfer, and extracellular vesicle production [57]. The bioactive parts of dead or dying MSCs can trigger immunomodulatory properties in the host without the concern over cell survival and the formation of large aggregates [58][59][60].…”

Safety and efficacy of autologous, adipose-derived mesenchymal stem cells in patients with rheumatoid arthritis: a phase I/IIa, open-label, non-randomized pilot trial

“…In response to inflammatory stimuli, live MSCs are capable of releasing an active secretome that consists of potent agents for immunomodulation, as opposed to dead or non-viable MSCs that fail to inhibit immune cell function [ 34 ]. MSC potency can be assessedlargely by cell viability, one of the most important cellular attributes influencing persistent therapeutic efficacy.…”

When Origin Matters: Properties of Mesenchymal Stromal Cells From Different Sources for Clinical Translation in Kidney Disease

“…However, controversy revolves around the use of banked products, with studies demonstrating reduced therapeutic potential, loss of functionality and increased susceptibility to trigger prothrombotic events (177)(178)(179)(180)(181), while others have showed minimal impairment of cell viability and fitness (182,183). In this context, clinical potency has been linked with the concept of metabolic fitness and product viability at the time of infusion (184,185) making it critical to develop manufacturing methods to rescue cryopreserved cells and restore cell functionality (186). Intriguingly, other studies have demonstrated that apoptotic or dead MSCs, and therefore less metabolically active, confer therapeutic benefits by enhancing the host innate immune response (187)(188)(189).…”

“…Determining novel predictive biomarkers of therapeutic potency is of utmost importance before clinical usage, and viability and metabolic fitness have been recently proposed as potency qualities (184). Metabolic status is affected after longterm in vitro expansion, and it can reflect differential stemness behavior (242,(247)(248)(249), as well as cell immune functionality (250).…”