A precision product framework for context-dependent mechanisms of MSC therapy.

Abstract

Despite decades of research, mesenchymal stem/stromal cell (MSC) therapy development has fallen short of expectations. Although regulatory convention prioritizes viability-centric metrics as proxies for potency, emerging evidence indicates that, in specific inflammatory contexts, efficacy is driven by apoptotic MSCs undergoing host efferocytosis. This paradox calls into question key assumptions underlying the "living-drug" paradigm. Here, I propose a "precision product" framework to resolve this dichotomy. By integrating conflicting data on cryopreservation, apoptosis, and metabolic activity, I discuss how paracrine signaling and apoptosis represent different phases of a functional continuum. Efficacy is not intrinsic to viability alone but depends on matching the product's state (secretory versus apoptotic) to the host's specific disease microenvironment. Ultimately, by abandoning reductionist "one-size-fits-all" manufacturing in favor of a precision product framework that embraces product heterogeneity and matches specific mechanisms of action to distinct disease microenvironments, the field can overcome current translational bottlenecks and more fully realize the therapeutic potential of MSC therapies.