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Publications of the Week

Dynamic Changes in Heparan Sulfate Nanostructure in Human Pluripotent Stem Cell Differentiation

By May 2, 2023No Comments

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This week we profile a recent publication in ACS Nano from Dr. Deena Al Mahbuba (pictured, second from left), Dr. Sayaka Masuko (second from right),  Shiwei Wang (far left), Deepsing Syangtan (far right), and others in Dr. Laura Kiessling’s lab at MIT.

Deena Al Mahbuba

Dr. Deena Al Mahbuba

Can you provide a brief overview of your lab’s current research focus?

The Kiessling Group uses chemical biology to elucidate the biological roles of carbohydrates, with a focus on learning new mechanistic concepts.

Understanding carbohydrate function is essential as all cells on earth have a carbohydrate coat called the glycocalyx.  The glycocalyx is poised to mediate or modulate diverse and critical biological and physiological events. The Kiessling Group at MIT is focused on understanding how carbohydrates are assembled, how they are recognized, and how they function. Using ideas and approaches that range from synthetic chemistry to molecular and cell biology, our research group is addressing the critical issues at this frontier.

What is the significance of the findings in this publication?

Glycans are ubiquitously present on all cell types since the emergence of life. However, they are significantly understudied compared to nucleic acids and proteins, particularly in complex biological processes such as stem cell differentiation. While previous analytical chemistry work has revealed the chemical composition and complexity of heparan sulfate (HS), a polysaccharide critical for human development, we have very limited understanding how its spatial organization impacts its function in physiological and disease processes. In this work, we presented an intriguing discovery that the function of heparan sulfate depends not only on its sulfation sequence as previously reported, but also on its localized organization. By imaging at super resolution with expansion microscopy, we found that the glycan’s spatial distribution and ultrastructure correlated with growth factor recruitment. Our observation that cell surface protrusion presents HS to engage growth factors was unexpected yet highlights another mechanism by which cells use glycosaminoglycans to regulate signaling that governs cell fate decisions.

What are the next steps for this research?

This study highlights the significance of proteoglycans in stem cell development as well as a new strategy of using expansion microscopy to visualize glycan ultrastructure and to understand structure-function relationships during multifaceted biological processes. Future developments at this frontier will enable us to visualize glycans at higher resolution, and to reveal molecular information of complex proteoglycans in situ. Overall, this work unveils how the ultrastructure of heparan sulfate is controlled to mediate signaling in human stem cells. This further leads us to consider the possibility that like other biomacromolecules the spatial organization of complex carbohydrates is meticulously orchestrated for the proper function of biological systems.

If you’d like to mention your funding sources, please list them.

This research project is supported by NIH, NSF graduate research fellowship, Open Philanthropy and Good Venture.

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