Mesenchymal stromal cells (MSCs) have long intrigued regenerative-medicine researchers, but not because the cells themselves stick around. Instead, it is their secretome—the rich mix of soluble factors and extracellular vesicles (EVs) they release—that is increasingly viewed as the real therapeutic engine. In a new review, Rosa Maria Hernandez, PhD, professor of pharmaceutics at the University of the Basque Country in Spain, and colleagues argue that the field has reached a turning point: MSC secretomes should be developed not as biological curiosities, but as engineered, off-the-shelf biotherapeutic products.
“The therapeutic potential of the MSC secretome is no longer in doubt,” the authors write. “What remains uncertain is how to transform it into a standardized, scalable, and clinically approved biotherapeutic.” Their solution is a product-focused road map built on a simple but demanding principle: the process defines the product.
The review links early decisions—such as MSC tissue source and the preconditioning strategy—to downstream manufacturing, formulation, and regulatory outcomes. MSCs from bone marrow, umbilical cord, adipose tissue, dental pulp, or induced pluripotent stem cells all produce distinct secretomes, with measurable differences in immunomodulatory activity, angiogenesis, EV yield, and stability. “The choice of MSC tissue source is a critical determinant of secretome composition and potency,” Hernandez and colleagues emphasize, reinforcing that sourcing decisions cannot be divorced from clinical intent.
Preconditioning is another lever for potency. Hypoxia, for example, can enhance regenerative signaling, while inflammatory priming with cytokines such as IFN-γ and TNF-α boosts immunomodulatory factors. But the authors caution that these strategies demand tightly defined process windows to avoid unwanted effects, including pro-tumorigenic signaling.
Manufacturing scale-up is where promise often collides with reality. Static, two-dimensional cultures are inadequate for clinical dosing, pushing developers toward closed, GMP-compliant bioreactor systems. Each reactor type—stirred tank, hollow fiber, vertical wheel, or perfusion—shapes the final secretome differently, constraining downstream purification and formulation choices. “Bioreactors serve as the technological bridge between small-scale research and clinically relevant manufacturing,” the authors note, provided that upstream gains are matched by downstream processes that preserve bioactivity.
Perhaps the most urgent bottleneck is potency testing. Current functional assays are slow, variable, and poorly predictive of clinical outcomes. Omics-based signatures and multifactorial assays offer hope, but require validation and regulatory consensus.
Looking ahead, Hernandez and colleagues see convergence with artificial intelligence, smart delivery systems, and synthetic biology as key to the next generation of secretome products. By reframing MSC secretomes as designable, manufactured biologics rather than undefined extracts, they argue, the field can finally move from preclinical promise to clinical reality.
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