This Research Topic is the second volume of the “Community Series in Safety, Efficacy and Mechanisms of Action of Mesenchymal Stem Cell Therapies”. Please see the first volume here.

Mesenchymal Stem Cell (MSC) therapies have been employed in more than 800 registered clinical studies across the globe, which makes them one of the most intensely pursued and promising cellular therapeutics. Meta-analysis of clinical trials with first-generation MSC products has demonstrated safety, although clinical efficacy still needs to be improved. Thus, efforts to improve potency evaluation and understanding of the mechanisms of action (MoA) are under way, to improve both the safety and efficacy of MSC therapies.

MSC modulation of the immune system for the treatment of a multitude of inflammatory conditions has driven the majority of translational applications of MSCs. Immune modulation by MSCs, however, is not mediated by a single MoA. Rather, MSCs have been shown to modulate different immune cells through soluble trophic factors, exosomes, and efferocytotic mechanisms. Despite being studied in isolation, an understanding of the interaction of these MoA in different experimental and in vivo contexts remains lacking. In addition, clarification on the role of host immune cells in responding to MSCs is needed to enable the identification of patients likely to respond to MSC-based therapies.

A great diversification in MSC products, treatment indications, and delivery methods has occurred over the past 10-15 years. Until 2008, MSCs and MSC-like investigational new drugs were almost exclusively comprised of bone marrow-derived MSCs, with an equal share of intravascular or local delivery. Today, more than half of the registered clinical MSC products are derived from adipose and perinatal tissues. This complicates any generalizations on product safety, efficacy and mechanism of action. While product diversification has overcome a number of problems apparent with the first-generation MSCs, such as limited starting material, painful harvesting technique, and potency issues, equivalence in safety and function cannot be assumed for MSCs harvested from alternative sources. Thus, it is currently not clear, whether the past experience on the safety of bone marrow MSCs can be extrapolated to MSC products derived from other tissue sources and how this interlinks with their therapeutic efficacy.

A better understanding of the underlying MoA of MSC therapeutics and standardized assessment of those MoA is paramount to improving their safety and efficacy. In this Research Topic, we welcome the submission of Reviews, Mini-Reviews and Original Research articles along with Methods, Protocols, Technology Report, Hypothesis and Theory, Perspective, Clinical Trial, Case Report, Classification, General Commentary, Opinion and Systematic Review articles that cover, but are not limited to, the following topics:

1. Safety and efficacy evaluation of MSC products derived from different tissue sources and optimal route or method of delivery (e.g. local vs. systemic delivery, or use of fresh vs. thawed cells)
2. MSC safety assessment: how to standardize the quantification of innate and adaptive immune responses towards MSC therapeutics, a clinical need for humanized model systems?
3. MSC potency assessment: how to reproducibly quantify intrinsic potency in tissue regeneration, and modulation of innate and adaptive immune responses by clinical grade MSC therapeutics?
4. MSC bioengineering towards improved safety and efficacy: novel strategies for modulation of MSC product properties, improved process design, and optimal clinical delivery
5. Novel signaling pathways, mediators, and biomarkers associated with MSC function: clinically relevant in vitro and in vivo environmental crosstalk of MSC therapeutics:
a. What data to feed into a combinatorial assay matrix to assess MSC potency?
b. Interaction of MSCs with the host environment / host cells, e.g. immunological crosstalk
c. Patient conditioning and pharmacological interference with MSC therapies and how to boost MSC performance in vivo

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