1. Characterization of Human CD8+TCR− Facilitating Cells In Vitro and In Vivo in a NOD/SCID/IL2rγnull Mouse Model
- Author
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Yujie Wen, Esma S. Yolcu, Larry D. Bozulic, He Xu, Yiming Huang, Thomas Miller, Mary Jane Elliott, Mariusz Z. Ratajczak, Suzanne T. Ildstad, and Janina Ratajczak
- Subjects
Male ,0301 basic medicine ,CD8 Antigens ,Blotting, Western ,Receptors, Antigen, T-Cell ,Graft vs Host Disease ,Apoptosis ,chemical and pharmacologic phenomena ,Mice, SCID ,In Vitro Techniques ,Biology ,Real-Time Polymerase Chain Reaction ,Article ,Mice ,03 medical and health sciences ,Mice, Inbred NOD ,medicine ,Animals ,Humans ,Immunology and Allergy ,Pharmacology (medical) ,RNA, Messenger ,Progenitor cell ,Cells, Cultured ,Mice, Knockout ,Transplantation Chimera ,Transplantation ,Severe combined immunodeficiency ,Reverse Transcriptase Polymerase Chain Reaction ,T-cell receptor ,hemic and immune systems ,Hematopoietic Stem Cells ,medicine.disease ,Molecular biology ,Tissue Donors ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,Models, Animal ,lipids (amino acids, peptides, and proteins) ,Bone marrow ,Stem cell ,CD8 ,Interleukin Receptor Common gamma Subunit - Abstract
CD8(+)/TCR(-) facilitating cells (FCs) in mouse bone marrow (BM) significantly enhance engraftment of hematopoietic stem/progenitor cells (HSPCs). Human FC phenotype and mechanism of action remain to be defined. We report, for the first time, the phenotypic characterization of human FCs and correlation of phenotype with function. Approximately half of human FCs are CD8(+)/TCR(-)/CD56 negative (CD56(neg)); the remainder are CD8(+)/TCR(-)/CD56 bright (CD56(bright)). The CD56(neg) FC subpopulation significantly promotes homing of HSPCs to BM in nonobese diabetic/severe combined immunodeficiency/IL-2 receptor γ-chain knockout mouse recipients and enhances hematopoietic colony formation in vitro. The CD56(neg) FC subpopulation promotes rapid reconstitution of donor HSPCs without graft-versus-host disease (GVHD); recipients of CD56(bright) FCs plus HSPCs exhibit low donor chimerism early after transplantation, but the level of chimerism significantly increases with time. Recipients of HSPCs plus CD56(neg) or CD56(bright) FCs showed durable donor chimerism at significantly higher levels in BM. The majority of both FC subpopulations express CXCR4. Coculture of CD56(bright) FCs with HSPCs upregulates cathelicidin and β-defensin 2, factors that prime responsiveness of HSPCs to stromal cell-derived factor 1. Both FC subpopulations significantly upregulated mRNA expression of the HSPC growth factors and Flt3 ligand. These results indicate that human FCs exert a direct effect on HSPCs to enhance engraftment. Human FCs offer a potential regulatory cell-based therapy for enhancement of engraftment and prevention of GVHD.
- Published
- 2016