title: Engineering the human thymic microenvironment to support thymopoiesis in vivo.
abstract: A system that allows manipulation of the human thymic microenvironment is needed both to elucidate the extrinsic mechanisms that control human thymopoiesis and to develop potential cell therapies for thymic insufficiency. In this report, we developed an implantable thymic microenvironment composed of two human thymic stroma populations critical for thymopoiesis; thymic epithelial cells (TECs) and thymic mesenchyme (TM). TECs and TM from postnatal human thymi were cultured in specific conditions, allowing cell expansion and manipulation of gene expression, before reaggregation into a functional thymic unit. Human CD34+ hematopoietic stem and progenitor cells (HSPC) differentiated into T cells in the aggregates in vitro and in vivo following inguinal implantation of aggregates in immune deficient mice. Cord blood HSPC previously engrafted into murine bone marrow (BM), migrated to implants, and differentiated into human T cells with a broad T cell receptor repertoire. Furthermore, lentiviral-mediated expression of vascular endothelial growth factor in TM enhanced implant size and function and significantly increased thymocyte production. These results demonstrate an in vivo system for the generation of T cells from human HSPC and represent the first model to allow manipulation of gene expression and cell composition in the microenvironment of the human thymus.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles (UCLA), California, USA.
authors.forename: Brile
authors.initials: B
authors.lastname: Chung
authors.forename: Amélie
authors.initials: A
authors.lastname: Montel-Hagen
authors.forename: Shundi
authors.initials: S
authors.lastname: Ge
authors.forename: Garrett
authors.initials: G
authors.lastname: Blumberg
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kim
authors.forename: Sam
authors.initials: S
authors.lastname: Klein
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Zhu
authors.forename: Chintan
authors.initials: C
authors.lastname: Parekh
authors.forename: Arumugam
authors.initials: A
authors.lastname: Balamurugan
authors.forename: Otto O
authors.initials: OO
authors.lastname: Yang
authors.forename: Gay M
authors.initials: GM
authors.lastname: Crooks
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D060833:Cellular Microenvironment / Q000502:physiology; D015870:Gene Expression; D006801:Humans; D038041:Lymphopoiesis / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013950:Thymus Gland / Q000166:cytology* / Q000187:drug effects; D023822:Tissue Engineering / Q000379:methods*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A
keywords: T-cell development; Thymic microenvironment; Thymus; Thymus transplantation; Tissue engineering; Vascular endothelial growth factor