Exploring immune response toward transplanted human kidney tissues assembled from organoid building blocks
Thiago J. Borges,
Yoshikazu Ganchiku,
Jeffrey O. Aceves,
Ronald van Gaal,
Sebastien G.M. Uzel,
Ivy A. Rosales,
Jonathan E. Rubins,
Kenichi Kobayashi,
Ken Hiratsuka,
Murat Tekguc,
Guilherme T. Ribas,
Karina Lima,
Rodrigo B. Gassen,
Ryuji Morizane,
Jennifer A. Lewis,
Leonardo V. Riella
Affiliations
Thiago J. Borges
Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United states
Yoshikazu Ganchiku
Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United states
Jeffrey O. Aceves
Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, United states
Ronald van Gaal
Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, United states
Sebastien G.M. Uzel
Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, United states; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United states
Ivy A. Rosales
Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United states; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United states
Jonathan E. Rubins
Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, United states
Kenichi Kobayashi
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United states; Nephrology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United states
Ken Hiratsuka
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United states; Nephrology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United states
Murat Tekguc
Nephrology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United states; Harvard Stem Cell Institute (HSCI), Cambridge, MA, United states
Guilherme T. Ribas
Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United states
Karina Lima
Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United states
Rodrigo B. Gassen
Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United states
Ryuji Morizane
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United states; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United states; Nephrology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United states
Jennifer A. Lewis
Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, United states; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United states; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United states
Leonardo V. Riella
Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United states; Corresponding author
Summary: 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.
