期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 34, 页码 23465-23481出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.557447
关键词
Chondroitin Sulfate; Glycosaminoglycan; Hyaluronate; Inflammation; Mesenchymal Stem Cells (MSCs); Versican
资金
- National Institutes of Health from NEI [RO1 EY021768]
- Research to Prevent Blindness
- Ohio Lions Eye Research Foundation
- Hyaluronan Matrices in Vascular Pathologies - National Institutes of Health from NHLBI [P01 HL107147]
Background: Umbilical cord mesenchymal stem cells (UMSCs) have unique immunosuppressive properties. Results: UMSCs express a rich glycocalyx, which confers their ability to modulate both macrophages and T-regulatory cells and to lead to inflammatory cell death. Conclusion: UMSCs actively modulate inflammatory cells by suppressing the immune response and evading rejection. Significance: Engineering cells to express this rich glycocalyx could increase transplantation success. Umbilical cord mesenchymal stem cells (UMSCs) have unique immunosuppressive properties enabling them to evade host rejection and making them valuable tools for cell therapy. We previously showed that human UMSCs survive xenograft transplantation and successfully correct the corneal clouding defects associated with the mouse model for the congenital metabolic disorder mucopolysaccharidosis VII. However, the precise mechanism by which UMSCs suppress the immune system remains elusive. This study aimed to determine the key components involved in the ability of the UMSCs to modulate the inflammatory system and to identify the inflammatory cells that are regulated by the UMSCs. Our results show that human UMSCs transplanted into the mouse stroma 24 h after an alkali burn suppress the severe inflammatory response and enable the recovery of corneal transparency within 2 weeks. Furthermore, we demonstrated in vitro that UMSCs inhibit the adhesion and invasion of inflammatory cells and also the polarization of M1 macrophages. UMSCs also induced the maturation of T-regulatory cells and led to inflammatory cell death. Moreover, UMSCs exposed to inflammatory cells synthesize a rich extracellular glycocalyx composed of the chondroitin sulfate-proteoglycan versican bound to a heavy chain (HC)-modified hyaluronan (HA) matrix (HC-HA). This matrix also contains TNF-stimulated gene 6 (TSG6), the enzyme that transfers HCs to HA, and pentraxin-3, which further stabilizes the matrix. Our results, both in vivo and in vitro, show that this glycocalyx confers the ability for UMSCs to survive the host immune system and to regulate the inflammatory cells.
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