Glycome and Transcriptome Regulation of Vasculogenesis
Name
Sasisekharan_Glycome and.pdf
Size
2.8 MB
Format
Adobe PDF
Checksum (MD5)
3aa4d7e26d2e8e96312d752ab30038db
Author(s)
Eavarone, David A.
Kiziltepe, Tanyel
Sasisekharan, Ram
Sengupta, Shiladitya
Harfouche, Rania
Hentschel, Dirk M.
Piecewicz, Stephanie
Basu, Sudipta
Print, Cristin
Date Issued
October 2009
Journal
Circulation
Publisher
American Heart Association
Citation
Harfouche, R., D. M. Hentschel, S. Piecewicz, S. Basu, C. Print, D. Eavarone, T. Kiziltepe, R. Sasisekharan, and S. Sengupta. “Glycome and Transcriptome Regulation of Vasculogenesis.” Circulation 120, no. 19 (November 10, 2009): 1883–1892.
Version
Author's final manuscript
Abstract
Background— Therapeutic vasculogenesis is an emerging concept that can potentially be harnessed for the management of ischemic pathologies. The present study elucidates the potential coregulation of vasculogenesis by the heparan sulfate glycosaminoglycan–rich cell-surface glycome and the transcriptome.
Methods and Results— Differentiation of embryonic stem cells into endothelial cells in an in vitro embryoid body is paralleled by an amplification of heparan sulfate glycosaminoglycan sulfation, which correlates with the levels of the enzyme N-deacetylase/N-sulfotransferase 1 (NDST1). Small hairpin RNA–mediated knockdown of NDST1 or modification of heparan sulfate glycosaminoglycans in embryonic stem cells with heparinases or sodium chlorate inhibited differentiation of embryonic stem cells into endothelial cells. This was translated to an in vivo zebrafish embryo model, in which the genetic knockdown of NDST1 resulted in impaired vascularization characterized by a concentration-dependent decrease in intersegmental vessel lumen and a large tail-vessel configuration, which could be rescued by use of exogenous sulfated heparan sulfate glycosaminoglycans. To explore the cross talk between the glycome and the transcriptome during vasculogenesis, we identified by microarray and then validated wild-type and NDST1 knockdown–associated gene-expression patterns in zebrafish embryos. Temporal analysis at 3 developmental stages critical for vasculogenesis revealed a cascade of pathways that may mediate glycocalyx regulation of vasculogenesis. These pathways were intimately connected to cell signaling, cell survival, and cell fate determination. Specifically, we demonstrated that forkhead box O3A/5 proteins and insulin-like growth factor were key downstream signals in this process.
Conclusions— The present study for the first time implicates interplay between the glycome and the transcriptome during vasculogenesis, revealing the possibility of harnessing specific cellular glyco-microenvironments for therapeutic vascularization.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. School of Engineering
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1161/CIRCULATIONAHA.108.837724
