Despite extensive preclinical testing, cancer therapeutics can result in unanticipated toxicity to non-tumor tissue in patients. These toxicities may pass undetected in preclinical experiments due to modeling limitations involving poor biomimicry of 2-dimensional in vitro cell cultures and due to lack of interspecies translatability in in vivo studies. Instead, primary cells can be grown into miniature 3-dimensional structures that recapitulate morphological and functional aspects of native tissue, termed "organoids." Here, human bronchioalveolar organoids grown from primary alveolar epithelial cells were employed to model lung epithelium and investigate off-target toxicities associated with antibody-drug conjugates (ADCs). ADCs with three different linker-payload combinations (mafodotin, vedotin, and deruxtecan) were tested in bronchioalveolar organoids generated from human, rat, and nonhuman primate lung cells. Organoids demonstrated antibody uptake and changes in viability in response to ADC exposure that model in vivo drug sensitivity. RNA sequencing identified inflammatory activation in bronchioalveolar cells in response to deruxtecan. Future studies will explore specific cell populations involved in interstitial lung disease and incorporate immune cells to the culture.
Immunoconjugates , Organoids , Organoids/drug effects , Organoids/pathology , Animals , Immunoconjugates/toxicity , Humans , Rats , Drug Evaluation, Preclinical/methods , Macaca fascicularis , Cells, Cultured , Toxicity Tests/methods , Pulmonary Alveoli/drug effects , Pulmonary Alveoli/pathology , Alveolar Epithelial Cells/drug effects , Alveolar Epithelial Cells/pathology
Liver disease affects millions globally, and end-stage liver failure is only cured by organ transplant. Unfortunately, there is a growing shortage of donor organs as well as inequitable access to transplants across populations. Engineered liver tissue grafts that supplement or replace native organ function can address this challenge. While engineered liver tissues have been successfully engrafted previously, the extent to which these tissues express human liver metabolic genes and proteins remains unknown. Here, it is built engineered human liver tissues and characterized their engraftment, expansion, and metabolic phenotype at sequential stages post-implantation by RNA sequencing, histology, and host serology. Expression of metabolic genes is observed at weeks 1-2, followed by the cellular organization into hepatic cords by weeks 4-9.5. Furthermore, grafted engineered tissues exhibited progressive spatially restricted expression of critical functional proteins known to be zonated in the native human liver. This is the first report of engineered human liver tissue zonation after implantation in vivo, which can have important translational implications for this field.
End Stage Liver Disease , Liver Transplantation , Organ Transplantation , Humans , Tissue Engineering
Unraveling and replicating how cells communicate to regenerate organs remains one of the most compelling biological problems of our time. In this issue of Cell Stem Cell, Cordero-Espinoza et. al (2021) untangle how a subpopulation of liver mesenchymal cells residing adjacent to the bile ducts regulate biliary cell proliferation.
Bile Ducts, Intrahepatic , Touch , Bile Ducts , Cell Proliferation , Hepatocytes
