Editorial: Safety, Efficacy and Mechanisms of Action of Mesenchymal Stem Cell Therapies

Mesenchymal stromal/stem cell (MSC) therapies have been employed in more than 800 registered clinical studies across the globe (1) and there are now >55,000 publications readily available on MSCs (2). Their profound immunomodulatory and regenerative properties have made MSCs one of the most promising and intensely pursued cellular therapies (3). Although meta-analysis of clinical trials with first-generation MSC products has demonstrated safety (4), their clinical efficacy and understanding of the underlying mechanism of action (MoA) still needs to be improved [(1, 5–10); Caplan et al.]. A better understanding of the role of patient parameters and adjunct treatment protocols is key to yield an optimal short- and long-term therapeutic benefit. Indeed, different MSC products, as well as their dosing and delivery, may be tailored for specific clinical indications according to their individual needs (6, 8, 11). To optimize next-generation MSC therapies, efforts are now underway to improve product design and delivery to patients, safety and potency assessment pre- and post-treatment, and the understanding of the exact MoA. These important topics are covered within this article collection and in the following sections we will briefly put into context the 20 articles published within this Frontiers Research Topic: “Safety, Efficacy, and Mechanisms of Action of MSC Therapies”.


INTRODUCTION
Mesenchymal stromal/stem cell (MSC) therapies have been employed in more than 800 registered clinical studies across the globe (1) and there are now >55,000 publications readily available on MSCs (2). Their profound immunomodulatory and regenerative properties have made MSCs one of the most promising and intensely pursued cellular therapies (3). Although meta-analysis of clinical trials with first-generation MSC products has demonstrated safety (4), their clinical efficacy and understanding of the underlying mechanism of action (MoA) still needs to be improved [ (1,(5)(6)(7)(8)(9)(10); Caplan et al.]. A better understanding of the role of patient parameters and adjunct treatment protocols is key to yield an optimal short-and long-term therapeutic benefit. Indeed, different MSC products, as well as their dosing and delivery, may be tailored for specific clinical indications according to their individual needs (6,8,11). To optimize next-generation MSC therapies, efforts are now underway to improve product design and delivery to patients, safety and potency assessment pre-and post-treatment, and the understanding of the exact MoA. These important topics are covered within this article collection and in the following sections we will briefly put into context the 20 articles published within this Frontiers Research Topic: "Safety, Efficacy, and Mechanisms of Action of MSC Therapies".

DIVERSIFICATION IN MSC PRODUCTS AND DELIVERY
A great diversification in MSC products, treatment indications, and delivery methods has occurred over the past decade, raising many regulatory questions, and potentially entailing reevaluation of safety and efficacy for new products/applications [(1, 12); Caplan et al.]. Adjustments in manufacturing are manifold, e.g., cell expansion conditions, culture media composition, or cell priming (10). A key issue is the tissue source the MSCs are derived from, with clinical trials in the past 5 years utilizing MSCs from bone marrow (BM), adipose tissue (AT), and perinatal tissue (PT) at almost equal frequency (1).
Wilson et al. give a great overview on all aspects of MSC heterogeneity, from donor to tissue source, the role of cell isolation and in vitro expansion, and the regulatory considerations related to heterogeneous cell therapy. In line, Ankrum and coworkers, who recently reviewed the MSC manufacturing process for therapy (10), newly define isolation and culture conditions to better prepare MSCs for the challenging in vivo environments they encounter post transplantation in their title "Nature vs. Nurture" (Boland et al.).
In their review, Khan and Newsome provide an exemplary assessment on how the production process can shape the phenotype and functional properties of BM-derived multipotent adult progenitor cells (MAPC R , Athersys Inc, Cleveland Ohio) compared to various conventional BM-MSC products. Cryobiology: Fresh vs. Freeze-Thawed Therapeutic Cells Regarding cell-host immune interaction, it may also be crucial to differentiate between using fresh from culture-derived metabolically active cells, as compared to freeze-thawed cells readily derived from cryostorage, which may show a transient but reversible impairment of their metabolism and cellular integrity directly after thawing [ (15)(16)(17)(18)(19); Sierra Parraga et al.; Yuan et al.]. This is exemplified by a contribution from Sierra Parraga et al. who found altered activity of freeze-thawed compared to fresh MSCs in a model of normo-thermic machine perfusion to support transplant kidneys. Oja et al. shared their hands-on experience on how freezing steps in MSC manufacturing impact quality and cell functionality attributes, and how a short-term 24h culture recovery post thawing can restore the full functionality of the cells. In the past years, comparisons on the effect of fresh vs. freeze-thawed cellular therapeutics have gained greater interest in the cell therapy field as a whole, since this does not only seem to be of interest/relevance for MSC therapeutics, but also for other rapidly expanding fields such as bioengineered chimeric-antigen-receptor (CAR) T-cell therapies (19,20).

Modulating Cell-Host Interaction by Steering Therapeutic Cell Formulation
Not only the general mode of manufacturing, but also the final steps of clinical cell formulation/delivery (e.g., cell harvesting, freezing/recovery post cryobanking, or product formulation and mode of application) could be very decisive for therapeutic safety and efficacy outcome in clinical trials (1,8,10,19).
Early preclinical and clinical studies paid rather little attention to these aspects and information from publications is still scarce today. Fortunately, these aspects were discussed in great detail in the studies by Oja et al. and Sierra Parraga et al. Our own experience from early-stage trials indicated that freeze-thawed cells appear to be more prone to activate innate immune cascade systems thus being subject to faster clearance (21), which may influence their in vivo persistence (19). Furthermore, certain cell formulations (e.g., MSCs with low-dose heparin and human albumin instead of human blood type AB plasma) appear to give better clinical responses (22)(23)(24).
Thus, the composition of the final cell suspension including prior thawing and washing procedures, may be a key component for positively influencing cellular "pharmacodynamics" in vivo and should be studied with greater attention in order to optimize cellular therapeutics (1,19,20).