High mannose N-glycans promote migration of Bone-Marrow-Derived mesenchymal stromal cells

Vivian Alonso-Garcia, Cutter Chaboya, Qiongyu Li, Bryan Le, Timothy J. Congleton, Jose Florez, Victoria Tran, Gang Yu Liu, Wei Yao, Carlito B. Lebrilla, Fernando A Fierro

Research output: Contribution to journalArticlepeer-review

Abstract

For hundreds of indications, mesenchymal stromal cells (MSCs) have not achieved the expected therapeutic efficacy due to an inability of the cells to reach target tissues. We show that inducing high mannose N-glycans either chemically, using the mannosidase I inhibitor Kifunensine, or genetically, using an shRNA to silence the expression of mannosidase I A1 (MAN1A1), strongly increases the motility of MSCs. We show that treatment of MSCs with Kifunensine increases cell migration toward bone fracture sites after percutaneous injection, and toward lungs after intravenous injection. Mechanistically, high mannose N-glycans reduce the contact area of cells with its substrate. Silencing MAN1A1 also makes cells softer, suggesting that an increase of high mannose N-glycoforms may change the physical properties of the cell membrane. To determine if treatment with Kifunensine is feasible for future clinical studies, we used mass spectrometry to analyze the N-glycan profile of MSCs over time and demonstrate that the effect of Kifunensine is both transitory and at the expense of specific N-glycoforms, including fucosylations. Finally, we also investigated the effect of Kifunensine on cell proliferation, differentiation, and the secretion profile of MSCs. Our results support the notion of inducing high mannose N-glycans in MSCs in order to enhance their migration potential.

Original languageEnglish (US)
Article number7194
Pages (from-to)1-21
Number of pages21
JournalInternational journal of molecular sciences
Volume21
Issue number19
DOIs
StatePublished - Oct 1 2020

Keywords

  • Amino-linked glycans
  • Bone fracture
  • Kifunensine
  • MAN1A1
  • Mesenchymal stromal cells
  • Migration

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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