IL-8 dedifferentiates primary human luminal cells to multipotent stem cells

During aging, cellular plasticity and senescence play important roles in tissue regeneration and the pathogenesis of different diseases including cancer. We have recently shown that senescent breast luminal cells can activate their adjacent stromal fibroblasts. In the present report, we present clear evidence that these senescence-related active fibroblasts can dedifferentiate proliferating primary human luminal cells to multipotent stem cells in an IL-8-dependent manner. This was confirmed using recombinant IL-8, while the truncated protein was not active. This IL-8-related dedifferentiation of luminal cells was mediated through STAT3-dependent down-regulation of p16(INK4A) and miR-141. Importantly, these in vitro-generated mammary stem cells exhibited high molecular and cellular similarities with human mammary stem cells. They have also shown long-term mammary gland reconstituting ability, and capacity to produce milk post-delivery. Thereby, these IL-8-generated mammary stem cells could be of great value for autologous cell therapy procedures, and also for biomedical research as well as drug development.