Exploring immune response toward transplanted human kidney tissues assembled from organoid building blocks
The increasing scarcity of organs and the significant morbidity linked to dialysis require the development of engineered kidney tissues from human-induced pluripotent stem cells. Integrative approaches that synergize scalable kidney organoid differentiation, tissue biomanufacturing, and comprehensive assessment of their immune response and host integration are essential to accomplish this. Here, we create engineered human kidney tissues composed of organoid building blocks (OBBs) and transplant them into mice reconstituted with allogeneic human immune cells. Tissue-infiltrating human immune cells are composed of effector T cells and innate cells. This immune infiltration leads to kidney tissue injury characterized by reduced microvasculature, enhanced kidney cell apoptosis, and an inflammatory gene signature comparable to kidney organ transplant rejection in humans. Upon treatment with the immunosuppressive agent rapamycin, the induced immune response is greatly suppressed. Our model is a translational platform to study engineered kidney tissue immunogenicity and develop therapeutic targets for kidney rejection.
Authors
- Ken Hiratsuka (ORCID: https://orcid.org/0000-0001-9218-5572)
- Thiago J. Borges (ORCID: https://orcid.org/0000-0002-6554-0169)
- Sebastien G. M. Uzel
- Ivy A. Rosales (ORCID: https://orcid.org/0000-0003-0621-3202)
- Karina Lima (ORCID: https://orcid.org/0000-0003-2478-1182)
- Jonathan E. Rubins (ORCID: https://orcid.org/0000-0001-6830-3110)
- Jennifer A. Lewis (ORCID: https://orcid.org/0000-0002-0280-2774)
- Rodrigo Benedetti Gassen (ORCID: https://orcid.org/0000-0003-0513-1555)
- Ryuji Morizane (ORCID: https://orcid.org/0000-0002-0377-5667)
- Yoshikazu Ganchiku (ORCID: https://orcid.org/0000-0001-7122-3066)
- Murat Tekgüç (ORCID: https://orcid.org/0000-0001-7570-5898)
- Ronald C. van Gaal (ORCID: https://orcid.org/0000-0002-4640-4612)
- Guilherme T. Ribas (ORCID: https://orcid.org/0000-0002-9752-4411)
- Jeffrey O. Aceves (ORCID: https://orcid.org/0009-0004-0757-9243)
- Kenichi Kobayashi (ORCID: https://orcid.org/0000-0002-6618-5664)
- Leonardo V. Riella (ORCID: https://orcid.org/0000-0002-7636-3196)
Institutions
- Harvard University (US)
- Massachusetts General Hospital (US)
- Inspire Institute (US)
- Center for Systems Biology (US)
- Harvard Stem Cell Institute (US)
Publication Details
- Journal
- iScience
- Published
- 2024-09-13
- DOI
- https://doi.org/10.1016/j.isci.2024.110957
- Citations
- 10
- Primary Topic
- Renal and related cancers
- Type
- article
- Field-Weighted Citation Impact
- 2.34
Funders
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- Wellcome Trust
- National Institute of Diabetes and Digestive and Kidney Diseases