Maintains Embryonic Stem Cells Primed for Differentiation in a Heterogeneous State

Key Words. Differentiation • Embryonic stem cells • Heparin • Self-renewal Embryonic stem (ES) cells continuously decide whether to maintain pluripotency or differentiate. While exogenous leukemia inhibitory factor and BMP4 perpetuate a pluri-potent state, less is known about the factors initiating dif-ferentiation. We show that heparan sulfate (HS) proteoglycans are critical coreceptors for signals inducing ES cell differentiation. Genetic targeting of NDST1 and NDST2, two enzymes required for N-sulfation of proteo-glycans, blocked differentiation. This phenotype was res-cued by HS presented in trans or by soluble heparin. NaClO3, which reduces sulfation of proteoglycans, potently blocked differentiation of wild-type cells. Mecha-nistically, N-sulfation was identified to be critical for func