MFGE‐8, a Corona Protein on Extracellular Vesicles, Mediates Self‐Renewal and Survival of Human Pluripotent Stem Cells

Extracellular vesicles (EVs) and secretory factors play crucial roles in intercellular communication, but the molecular mechanisms and dynamics governing their interplay in human pluripotent stem cells (hPSCs) are poorly understood. Here, we demonstrate that hPSC-secreted milk fat globule-EGF factor 8 (MFGE-8) is the principal corona protein at the periphery of EVs, playing an essential role in controlling hPSC stemness. MFGE-8 depletion reduced EV-mediated self-renewal and survival in hPSC cultures. MFGE-8 in the EV corona bound to integrin α_vβ₅ expressed in the peripheral zone of hPSC colonies. It activated cyclin D1 and dynamin-1 via the AKT/GSK3β axis, promoting the growth of hPSCs and facilitating the endocytosis of EVs. Internalization of EVs alleviated oxidative stress and cell death by transporting redox and stress response proteins that increased GSH levels. Our findings demonstrate the critical role of the extracellular association of MFGE-8 and EVs in modulating the self-renewal and survival of hPSCs.