Metabolic Glycoengineering: A Promising Strategy to Remodel Microenvironments for Regenerative Therapy

Abstract

Cell-based regenerative therapy utilizes the differentiation potential of stem cells to rejuvenate tissues. But the dynamic fate of stem cells is calling for precise control to optimize their therapeutic efficiency. Stem cell fate is regulated by specific conditions called “microenvironments.” Among the various factors in the microenvironment, the cell-surface glycan acts as a mediator of cell-matrix and cell-cell interactions and manipulates the behavior of cells. Herein, metabolic glycoengineering (MGE) is an easy but powerful technology for remodeling the structure of glycan. By presenting unnatural glycans on the surface, MGE provides us an opportunity to reshape the microenvironment and evoke desired cellular responses. In this review, we firstly focused on the determining role of glycans on cellular activity; then, we introduced how MGE influences glycosylation and subsequently affects cell fate; at last, we outlined the application of MGE in regenerative therapy, especially in the musculoskeletal system, and the future direction of MGE is discussed.

Glycan Modifications as Regulators of Stem Cell Fate

“…While genetic approaches to manipulate the expression of glycosyltransferase genes are available, their utility in glycan engineering has limitations due to the combinatorial nature of glycan biosynthesis and the functional redundancy of glycosyltransferase genes [101]. Additionally, genetic transfection using viral vectors may cause unpredictable risks, and irreversible gene modifications may raise safety concerns for clinical applications.…”

“…Metabolic glycoengineering (MGE) is another approach that is being exploited to control stem cell activities. Although MGE technique was introduced over three decades ago [114], it is currently finding renewed interest in modeling stem cell niches and controlling their fate [101]. The primary goal of MGE is to augment the expression of natural glycans and incorporate non-natural monosaccharides into cell surface glycoconjugates, such as ketone-, azide-, thiol-, or alkyne-modified glycans [115,116].…”

“…Furthermore, the modifications introduced by MGE are nonpermanent, enabling controlled reversibility. Bioorthogonal click chemistry and the wide array of sugar analogs available further contribute to the versatility of MGE by offering diverse options for membrane modification [101].…”

“…The sialic acid pathway was the first glycosylation pathway harnessed in MGE [118], and it remains the most frequently utilized pathway to date. The suitability of the sialic acid pathway for MGE lies in the notable substrate versatility of sialyltransferases [119], which enables the modified analogs to effectively intercept glycosylation pathways, resulting in chemically altered sialic [101]. Among human cells, N-Acetylneuraminic acid (Neu5Ac) is the most common form of sialic acid, while N-acetyl-D-mannosamine (ManNAc) serves as the physiological precursor of all sialic acids.…”

“…This breakthrough holds the potential to significantly improve neuronal regeneration. resulting in chemically altered sialic [101]. Among human cells, N-Acetylneuraminic acid (Neu5Ac) is the most common form of sialic acid, while N-acetyl-D-mannosamine (Man-NAc) serves as the physiological precursor of all sialic acids.…”