Production via good manufacturing practice of exofucosylated human mesenchymal stromal cells for clinical applications

Exofucosylation of Adipose Mesenchymal Stromal Cells Alters Their Secretome Profile

“…Mammalian MSCs characteristically express CD44, and stereospecific CD44 glycoengineering via fucosyltransferasemediated fucose modification of N-acetylglucosamine results in the transient generation of the tetrasaccharide sLe x (Sackstein et al, 2008;Abdi et al, 2015;Lopez-Lucas et al, 2018). Exofucosylation of CD44 on MSCs following treatment with either stereospecific fucosyltransferase-VI (FTVI) or -VII (FTVII) thereby creates the potent E-selectin ligand HCELL on MSC surface.…”

Cost-Effective, Safe, and Personalized Cell Therapy for Critical Limb Ischemia in Type 2 Diabetes Mellitus

“…Therefore, the desired therapeutic effect depends on many factors since the mechanism of action of an ATMP in tissue regeneration is likely to be multifaceted; ATMP potency can be determined by the ability of the injected cells to migrate, survive, integrate, differentiate, and produce functional paracrine mediator factor involved in “ cell-cell interactions .” As mentioned above, many diseases, including diabetes, affect the phenotypic and therapeutic properties of an ATMP, and in the search for safety and efficacy, the recipient tissue must respond favorably to the administered ATMP, which would result in the activation of endogenous regeneration mechanisms (111–114). Understanding the integration of exogenous mechanisms (injected ATMP) with the endogenous recipient (host) will play a decisive role in the future clinical use of adult stem cells (8, 97).…”

“…The lack of therapeutic efficacy of the generation (Generation 1) of unmodified, naïve, and wild type MSCs rated in clinical trials can be explained by the observation that, after their systemic infusion (intravenous), these cells become trapped in vascular filters (fundamentally liver and lung), with only a small percentage reaching the target tissues. Therefore, it is essential that we design strategies that favor their migration, nesting, and localization in the inflammatory and/or infectious focus to increase their effectiveness (Generation 2 MSCs) (111, 113).…”

“…Biodistribution and long-term follow-up of these cells in animal models have shown that only a few cells persist after long periods of transplantation. This phenomenon supports the idea that most of the effects of MSCs are probably based on a “ hit and run effect .” To increase the implantation of an ATMP in the injured tissue, Sackstein et al (113), developed a method to transiently modify the CD44 antigen present in the MSC cell membrane by enzymatic fucosylation, converting this molecule into HCELL glycoform and thus favoring the migration of MSCs to the inflamed tissues (111, 115, 116). This method, called glycosyltransferase-programmed stereosubstitution (GPS) to custom modify cell surface glycans without affecting cell viability, has been optimized for its clinical application using an alpha-1,3-fucosyltransferase preparation and enzymatic conditions specifically designed to treat live cells and formulated to preserve the cell viability and phenotype.…”

“…Therefore, this modification by fucosylation could improve the efficacy of the treatment with MSCs by increasing their migratory capacity to the inflamed tissues after systemic administration. More detailed knowledge of the mechanisms of biodistribution, migration and specific interaction of MSCs at the damaged loci may be beneficial to design new ATMP with increased safety and efficacy (111), and in this regard, our group has collaborated in a patent to classify these tentative responses for stem cells (WO2017032612).…”