In and out: Benchmarking in vitro, in vivo, ex vivo, and xenografting approaches for an integrative brain disease modeling pipeline

• Published in: Stem cell reports Vol. 19; no. 6; pp. 767 - 795
• Main Authors: Pereira, Marlene F., Shyti, Reinald, Testa, Giuseppe
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.06.2024; Elsevier
• Subjects: Animals; Benchmarking; Brain; Brain Diseases; Disease Models, Animal; Heterografts; Humans; Review; Transplantation, Heterologous - methods
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2024.05.004

Human cellular models and their neuronal derivatives have afforded unprecedented advances in elucidating pathogenic mechanisms of neuropsychiatric diseases. Notwithstanding their indispensable contribution, animal models remain the benchmark in neurobiological research. In an attempt to harness the best of both worlds, researchers have increasingly relied on human/animal chimeras by xenografting human cells into the animal brain. Despite the unparalleled potential of xenografting approaches in the study of the human brain, literature resources that systematically examine their significance and advantages are surprisingly lacking. We fill this gap by providing a comprehensive account of brain diseases that were thus far subjected to all three modeling approaches (transgenic rodents, in vitro human lineages, human-animal xenografting) and provide a critical appraisal of the impact of xenografting approaches for advancing our understanding of those diseases and brain development. Next, we give our perspective on integrating xenografting modeling pipeline with recent cutting-edge technological advancements. For an associated discussion of this work, listen to the latest episode of The Stem Cell Report podcast at https://www.isscr.org/podcast/s3-e9, brought to you by the ISSCR. The rise of advanced human cellular systems, especially in 3D, alongside animal models and human-animal chimeras, is transforming our understanding of brain diseases through an expanded palette of options in need of critical benchmarking. Here Pereira, Shyti, and Testa provide a first systematic appraisal of the three approaches through a comparison of paradigmatic conditions affecting human neurobiology.