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Human induced pluripotent stem cells (hiPSCs) and organoids are particularly promising as they enable patient-specific modelling in the space environment. In this review, we examine the current literature on space-based hiPSC experimental models, highlighting their relevance to pediatric disorders with well-defined genetic backgrounds, namely mitochondrial diseases and congenital heart disorders. We summarize the evidence that spaceflight conditions alter mitochondrial function, cytoskeletal organization, oxidative stress, calcium handling, cellular maturation, and gene expression, and discuss how these responses may converge with metabolic disease-associated phenotypes. We highlight both adaptive and pathological responses reported in space-based hiPSC studies and identify key experimental and mechanistic gaps. Finally, we consider how advances in stem cell technologies and space-based biomedical research may enable the development of personalized, patient-specific disease models and therapeutics for rare pediatric diseases, ultimately accelerating translational discovery and clinical innovation.<\/jats:p>","DOI":"10.1093\/pcmedi\/pbag028","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:25:29Z","timestamp":1790594729000},"source":"Crossref","is-referenced-by-count":0,"title":["Human induced pluripotent stem cells and organoid models in space for investigating severe pediatric metabolic and congenital disorders"],"prefix":"10.1093","volume":"9","author":[{"given":"Sara","family":"Benedetti","sequence":"first","affiliation":[{"name":"Arrhythmia and Electrophysiology Centre, IRCCS Policlinico San Donato , San Donato Milanese, Milan 20097 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Psychiatric Research, Broad Institute of MIT and Harvard , Cambridge, MA 02142 ,","place":["United Sttes"]},{"name":"University of Pittsburgh McGowan Institute for Regenerative Medicine, Department of Surgery, , Pittsburgh, PA 15219 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher E","family":"Mason","sequence":"additional","affiliation":[{"name":"Center for Space Biomedicine, Trivedi Institute for Space and Global Biomedicine, University of Pittsburgh , Pittsburgh, PA 15219 ,","place":["United States"]},{"name":"The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine , New York, NY 10021 ,","place":["United States"]},{"name":"The WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine , New York, NY 10065 ,","place":["United States"]},{"name":"Weill Cornell Medicine Department of Physiology and Biophysics, , New York, NY 10065 ,","place":["United 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