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Display of the human mucinome with defined O-glycans by gene engineered cells.

ABSTRACT: Mucins are a large family of heavily O-glycosylated proteins that cover all mucosal surfaces and constitute the major macromolecules in most body fluids. Mucins are primarily defined by their variable tandem repeat (TR) domains that are densely decorated with different O-glycan structures in distinct patterns, and these arguably convey much of the informational content of mucins. Here, we develop a cell-based platform for the display and production of human TR O-glycodomains (~200 amino acids) with tunable structures and patterns of O-glycans using membrane-bound and secreted reporters expressed in glycoengineered HEK293 cells. Availability of defined mucin TR O-glycodomains advances experimental studies into the versatile role of mucins at the interface with pathogenic microorganisms and the microbiome, and sparks new strategies for molecular dissection of specific roles of adhesins, glycoside hydrolases, glycopeptidases, viruses and other interactions with mucin TRs as highlighted by examples.

SUBMITTER: Nason R

PROVIDER: S-EPMC8249670 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Display of the human mucinome with defined O-glycans by gene engineered cells.

Nason Rebecca R Büll Christian C Konstantinidi Andriana A Sun Lingbo L Ye Zilu Z Halim Adnan A Du Wenjuan W Sørensen Daniel M DM Durbesson Fabien F Furukawa Sanae S Mandel Ulla U Joshi Hiren J HJ Dworkin Leo Alexander LA Hansen Lars L David Leonor L Iverson Tina M TM Bensing Barbara A BA Sullam Paul M PM Varki Ajit A Vries Erik de E de Haan Cornelis A M CAM Vincentelli Renaud R Henrissat Bernard B Vakhrushev Sergey Y SY Clausen Henrik H Narimatsu Yoshiki Y

Nature communications 20210701 1

Mucins are a large family of heavily O-glycosylated proteins that cover all mucosal surfaces and constitute the major macromolecules in most body fluids. Mucins are primarily defined by their variable tandem repeat (TR) domains that are densely decorated with different O-glycan structures in distinct patterns, and these arguably convey much of the informational content of mucins. Here, we develop a cell-based platform for the display and production of human TR O-glycodomains (~200 amino acids) w ...[more]

PMID: 34210959

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Project description:BackgroundSafety evaluations in preclinical studies are needed to confirm before translating a cell-based product into clinical application. We previously developed a serum-free, xeno-free, and chemically defined media (S&XFM-CD) for the derivation of clinical-grade umbilical cord-derived MSCs (UCMSCs), and demonstrated that intraperitoneal administration of UCMSCs in S&XFM-CD (UCMSCS&XFM-CD) exhibited better therapeutic effects than UCMSCs in serum-containing media (SCM, UCMSCSCM). However, a comprehensive investigation of the safety of intraperitoneal UCMSCS&XFM-CD treatment should be performed before clinical applications.MethodsIn this study, the toxicity, immunogenicity and biodistribution of intraperitoneally transplanted UCMSCS&XFM-CD were compared with UCMSCSCM in rats via general vital signs, blood routine, blood biochemistry, subsets of T cells, serum cytokines, pathology of vital organs, antibody production and the expression of human-specific gene. The tumorigenicity and tumor-promoting effect of UCMSCS&XFM-CD were compared with UCMSCSCM in nude mice.ResultsWe confirmed that intraperitoneally transplanted UCMSCS&XFM-CD or UCMSCSCM did not cause significant changes in body weight, temperature, systolic blood pressure, diastolic blood pressure, heart rate, blood routine, T lymphocyte subsets, and serum cytokines, and had no obvious histopathology change on experimental rats. UCMSCS&XFM-CD did not produce antibodies, while UCMSCSCM had very high chance of antibody production to bovine serum albumin (80%) and apolipoprotein B-100 (60%). Furthermore, intraperitoneally injected UCMSCS&XFM-CD were less likely to be blocked by the lungs and migrated more easily to the kidneys and colon tissue than UCMSCSCM. In addition, UCMSCS&XFM-CD or UCMSCSCM showed no obvious tumorigenic activity. Finally, UCMSCS&XFM-CD extended the time of tumor formation of KM12SM cells, and decreased tumor incidence than that of UCMSCSCM.ConclusionsTaken together, our data indicate that UCMSCS&XFM-CD display an improved safety performance and are encouraged to use in future clinical trials.

Dataset Information

Display of the human mucinome with defined O-glycans by gene engineered cells.

Publications

Display of the human mucinome with defined O-glycans by gene engineered cells.

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