title: Efficient generation of human T cells from a tissue-engineered thymic organoid.
abstract: Biocompatible inorganic matrices have been used to enhance bone repair by integrating with endogenous bone architecture. Hypothesizing that a three-dimensional framework might support reconstruction of other tissues as well, we assessed the capacity of a tantalum-coated carbon matrix to support reconstitution of functioning thymic tissue. We engineered a thymic organoid by seeding matrices with murine thymic stroma. Co-culture of human bone marrow-derived hematopoietic progenitor cells within this xenogeneic environment generated mature functional T cells within 14 days. The proportionate T-cell yield from this system was highly reproducible, generating over 70% CD3+ T cells from either AC133+ or CD34+ progenitor cells. Cultured T cells expressed a high level of T-cell receptor excision circles (TREC), demonstrating de novo T lymphopoiesis, and function of fully mature T cells. This system not only facilitates analysis of the T-lymphopoietic potential of progenitor cell populations; it also permits ex vivo genesis of T cells for possible applications in treatment of immunodeficiency.
authors.affiliation: AIDS Research Center and MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Poznansky
authors.forename: R H
authors.initials: RH
authors.lastname: Evans
authors.forename: R B
authors.initials: RB
authors.lastname: Foxall
authors.forename: I T
authors.initials: IT
authors.lastname: Olszak
authors.forename: A H
authors.initials: AH
authors.lastname: Piascik
authors.forename: K E
authors.initials: KE
authors.lastname: Hartman
authors.forename: C
authors.initials: C
authors.lastname: Brander
authors.forename: T H
authors.initials: TH
authors.lastname: Meyer
authors.forename: M J
authors.initials: MJ
authors.lastname: Pykett
authors.forename: K T
authors.initials: KT
authors.lastname: Chabner
authors.forename: S A
authors.initials: SA
authors.lastname: Kalams
authors.forename: M
authors.initials: M
authors.lastname: Rosenzweig
authors.forename: D T
authors.initials: DT
authors.lastname: Scadden
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD; D018952:Antigens, CD34 / Q000096:biosynthesis; D001187:Artificial Organs; D001854:Bone Marrow Cells / Q000166:cytology; D002244:Carbon / Q000378:metabolism; D020099:Coated Materials, Biocompatible; D018920:Coculture Techniques; D046508:Culture Techniques / Q000379:methods; D005434:Flow Cytometry; D006023:Glycoproteins / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D016130:Immunophenotyping; D051379:Mice; D008810:Mice, Inbred C57BL; D008855:Microscopy, Electron, Scanning; D009940:Organoids / Q000502:physiology* / Q000648:ultrastructure; D010455:Peptides / Q000378:metabolism; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D013997:Time Factors
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D018952:Antigens, CD34; D020099:Coated Materials, Biocompatible; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D002244:Carbon