Immunological Mechanisms in Regenerative Medicine: A Lesson From the Human Placenta

A major goal in regenerative medicine is restoring damaged tissues through cell replacement or by activating endogenous repair pathways. Immune modulation is increasingly recognized as essential for creating a permissive environment for regeneration. Bioactive factors secreted by stem and stromal cells -either as soluble molecules or within extracellular vesicles (EVs)- can reshape immune responses, not just by reducing inflammation but by actively promoting pro-resolving, regenerative profiles. For nearly two decades, our research has focused on the therapeutic potential of human term placenta-derived cells, particularly mesenchymal stromal cells from the amniotic membrane (hAMSC). We have shown that hAMSC and their secretome (CM-hAMSC) exert potent immunomodulatory effects in vitro: suppressing T- and B-cell proliferation, downregulating proinflammatory Th1/Th17 phenotypes, enhancing regulatory T cells, and inhibiting naïve CD8 T cell polarization into memory subsets. They also reduce B-cell differentiation into antibody-secreting cells and steer monocytes away from dendritic cells and M1 macrophages toward anti-inflammatory M2 phenotypes. These effects have translated into therapeutic benefits in numerous preclinical models of inflammation-driven disease (including lung/liver fibrosis, sepsis, IBD, cardiac ischemia, autoimmune encephalomyelitis, rheumatoid arthritis, and traumatic brain injury) by tempering inflammation and promoting resolution. Ongoing studies aim to dissect the mechanisms driving these effects, especially whether they are mediated by soluble molecules, EVs, or both. A key area of interest is their ability to modulate the inflammasome pathway, a central driver of innate immunity linked to aging and degeneration. By regulating this pathway, placental factors may redirect chronic inflammation toward regeneration. Given inflammation’s dual role as trigger and barrier in many degenerative conditions, placental cells -especially those from the amniotic membrane- emerge as a powerful paradigm. This lecture will explore how their unique immunological properties can inspire innovative regenerative strategies.