Abstract
Many studies have suggested the significance of glycosyltransferase-mediated macromolecule glycosylation in the regulation of pluripotent states in human pluripotent stem cells (hPSCs). Here, we observed that the sialyltransferase ST6GAL1 was preferentially expressed in undifferentiated hPSCs compared to non-pluripotent cells. A lectin which preferentially recognizes α-2,6 sialylated galactosides showed strong binding reactivity with undifferentiated hPSCs and their glycoproteins, and did so to a much lesser extent with differentiated cells. In addition, downregulation of ST6GAL1 in undifferentiated hPSCs led to a decrease in POU5F1 (also known as OCT4) protein and significantly altered the expression of many genes that orchestrate cell morphogenesis during differentiation. The induction of cellular pluripotency in somatic cells was substantially impeded by the shRNA-mediated suppression of ST6GAL1, partially through interference with the expression of endogenous POU5F1 and SOX2. Targeting ST6GAL1 activity with a sialyltransferase inhibitor during cell reprogramming resulted in a dose-dependent reduction in the generation of human induced pluripotent stem cells (hiPSCs). Collectively, our data indicate that ST6GAL1 plays an important role in the regulation of pluripotency and differentiation in hPSCs, and the pluripotent state in human cells can be modulated using pharmacological tools to target sialyltransferase activity.
Highlights
Differentiated derivatives revealed that sialylation is a type of glycomodification that is typically altered when human pluripotent stem cells (hPSCs) lose their pluripotency[6,7]
These results suggested that ST6GAL1 may be functionally important in hPSCs, and that changes in ST6GAL1 expression may impact the regulation of pluripotency and cell differentiation
To begin to address the significance of ST6GAL1 expression in the regulation of pluripotent states in human cells, we analyzed ST6GAL1 mRNA and protein expression in multiple undifferentiated hPSC lines [including human embryonic stem cells and induced pluripotent stem cells], their differentiated derivatives, and somatic cells that were used for generating the hiPSCs
Summary
Differentiated derivatives revealed that sialylation is a type of glycomodification that is typically altered when hPSCs lose their pluripotency[6,7]. Using lectin microarrays and global gene expression profiling, we confirmed that there is a significant change in protein sialylation during differentiation in a large panel of hPSCs, and discovered the preferential expression of ST6GAL1 in undifferentiated hPSCs8,13. These results suggested that ST6GAL1 may be functionally important in hPSCs, and that changes in ST6GAL1 expression may impact the regulation of pluripotency and cell differentiation. Another recent study has provided an additional indication that the loss of terminal sialylation on the cell surface of hPSCs may lead to neuronal differentiation[14]. Systems biology tools were used to further dissect the signaling networks that are potentially modulated by ST6GAL1 in controlling the pluripotent state of hPSCs and cellular reprogramming
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