Human embryonic stem (hES) cells are remarkable for their ability to self-renew indefinitely and differentiate into any cell type in the human body. The differentiation of hES cells is regulated by intrinsic and extrinsic signals in the stem cell niche. Heparan sulfate proteoglycans (HSPGs) are cell surface and extracellular polysaccharide-decorated proteins that have long been implicated in a wide range of cell-cell signaling and cell-matrix interactions. Multiple growth factors that bind heparan sulfate, such as Wnt, bone morphogenetic proteins (BMP), and fibroblast growth factor (FGF), critically regulate cell fate decisions of ES cells. Engineered hES cells that lack the enzyme EXT1, which is critical for heparan sulfate biosynthesis, exhibited impaired ability to differentiate into Brachyury(+) mesendoderm (ME) cells. Exogenous addition of heparin partially rescued mesendoderm differentiation defects. Furthermore, examination of developmental signaling pathways revealed that EXT1 ablation diminished FGF, Activin A/Nodal and BMP signaling in differentiated cells. RNA-Seq revealed other developmental signaling pathways affected by HS deficiency including VEGF, Notch, and Wnt signaling. Understanding the roles of HS in specific pathways that regulate cell fates will provide insights into the complex molecular mechanisms underlying HS-related human diseases and therefore facilitate the development of therapeutics.

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

256th National Meeting (2018)

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