TY - JOUR
T1 - Generation of functional thymic organoids from human pluripotent stem cells
AU - Ramos, Stephan A.
AU - Armitage, Lucas H.
AU - Morton, John J.
AU - Alzofon, Nathaniel
AU - Handler, Diana
AU - Kelly, Geoffrey
AU - Homann, Dirk
AU - Jimeno, Antonio
AU - Russ, Holger A.
N1 - Funding Information:
We acknowledge the organ donors and their families and Dr. James Jaggers, MD (Children’s Colorado Hospital), for providing access to patient samples. The Russ lab is or was supported by NIH / NIDDK grants R01DK12044 and P30DK116073 ; NIDDK/ HIRN RRID: SCR_014393 ; UC24 DK104162; the Culshaw Junior Investigator Award in Diabetes; the Children’s Diabetes Foundation ; and the Gate’s Grubstake Fund . The Jimeno lab is supported by National Institutes of Health grants R01CA149456, R01CA213102 , and P30-CA046934 (University of Colorado Cancer Center Support Grant) and the Daniel and Janet Mordecai Foundation . D.H. is supported by NIH/NIDDK P30DK020541, U01K123716, R01DK130425.
Funding Information:
We acknowledge the organ donors and their families and Dr. James Jaggers, MD (Children's Colorado Hospital), for providing access to patient samples. The Russ lab is or was supported by NIH/NIDDK grants R01DK12044 and P30DK116073; NIDDK/HIRN RRID: SCR_014393; UC24 DK104162; the Culshaw Junior Investigator Award in Diabetes; the Children's Diabetes Foundation; and the Gate's Grubstake Fund. The Jimeno lab is supported by National Institutes of Health grants R01CA149456, R01CA213102, and P30-CA046934 (University of Colorado Cancer Center Support Grant) and the Daniel and Janet Mordecai Foundation. D.H. is supported by NIH/NIDDK P30DK020541, U01K123716, R01DK130425., A.J. consults for SuviCa and owns stock options in SuviCa and Champions Oncology. H.A.R. was a SAB member at Sigilon Therapeutics and Prellis Biologics and consulted for Eli Lilly and Minutia. S.A.R. L.H.A. J.J.M. A.J. and H.A.R. filed patent applications based on this work.
Publisher Copyright:
© 2023 The Authors
PY - 2023/4/11
Y1 - 2023/4/11
N2 - The thymus is critical for the establishment of a functional and self-tolerant adaptive immune system but involutes with age, resulting in reduced naive T cell output. Generation of a functional human thymus from human pluripotent stem cells (hPSCs) is an attractive regenerative strategy. Direct differentiation of thymic epithelial progenitors (TEPs) from hPSCs has been demonstrated in vitro, but functional thymic epithelial cells (TECs) only form months after transplantation of TEPs in vivo. We show the generation of TECs in vitro in isogenic stem cell-derived thymic organoids (sTOs) consisting of TEPs, hematopoietic progenitor cells, and mesenchymal cells, differentiated from the same hPSC line. sTOs support T cell development, express key markers of negative selection, including the autoimmune regulator (AIRE) protein, and facilitate regulatory T cell development. sTOs provide the basis for functional patient-specific thymic organoid models, allowing for the study of human thymus function, T cell development, and transplant immunity.
AB - The thymus is critical for the establishment of a functional and self-tolerant adaptive immune system but involutes with age, resulting in reduced naive T cell output. Generation of a functional human thymus from human pluripotent stem cells (hPSCs) is an attractive regenerative strategy. Direct differentiation of thymic epithelial progenitors (TEPs) from hPSCs has been demonstrated in vitro, but functional thymic epithelial cells (TECs) only form months after transplantation of TEPs in vivo. We show the generation of TECs in vitro in isogenic stem cell-derived thymic organoids (sTOs) consisting of TEPs, hematopoietic progenitor cells, and mesenchymal cells, differentiated from the same hPSC line. sTOs support T cell development, express key markers of negative selection, including the autoimmune regulator (AIRE) protein, and facilitate regulatory T cell development. sTOs provide the basis for functional patient-specific thymic organoid models, allowing for the study of human thymus function, T cell development, and transplant immunity.
KW - cell therapy
KW - human T cell development
KW - human pluripotent stem cells
KW - positive and negative selection
KW - stem cell derived thymic organoids
KW - thymic epithelial cells
UR - http://www.scopus.com/inward/record.url?scp=85151525205&partnerID=8YFLogxK
U2 - 10.1016/j.stemcr.2023.02.013
DO - 10.1016/j.stemcr.2023.02.013
M3 - Article
C2 - 36963390
AN - SCOPUS:85151525205
SN - 2213-6711
VL - 18
SP - 829
EP - 840
JO - Stem Cell Reports
JF - Stem Cell Reports
IS - 4
ER -