Roles of Heparan sulfate in mesendoderm differentiation of human embryonic stem cells

Abstract

Human embryonic stem cells (hESCs) are remarkable for their ability to self-renew indefinitely and differentiate into any cell type in the human body. The differentiation of hESCs is regulated by intrinsic and extrinsic signals in the stem cell niche. Heparan sulfate proteoglycans (HSPGs) are found on the membrane of all animal cells and have long been implicated in a wide range of cell-cell signaling and cell-matrix interactions. Multiple heparan sulfate (HS)-binding growth factors, such as Wnt, bone morphogenetic proteins (BMP), and fibroblast growth factor (FGF), critically regulate cell fate decisions of ES cells. Here, we showed that HS-deficient derived from hESCs have impaired ability to differentiate into Brachyury-positive mesendoderm (ME) cells. Exogenous addition of heparin partially rescued ME differentiation defect. Furthermore, examination of developmental signaling pathways revealed that HS ablation diminished FGF, Activin A and BMP signaling in differentiated cells. RNA-Seq revealed other biological processes affected by HS deficiency including neurogenesis, bone development and immune responses. Understanding the roles of HS in specific molecular mechanisms that regulate cell fates may provide insights into the complex molecular mechanisms underlying HS-associated human diseases and therefore facilitate the development of therapeutics.