Article Impact Level: HIGH Data Quality: STRONG Summary of Science, 388(6751), eadu9375. https://doi.org/10.1126/science.adu9375 Dr. Oscar J. Abilez et al.
Points
- A significant limitation in organoid research is the lack of an internal vascular system, which severely restricts organoid size, complexity, and long-term viability by preventing nutrient delivery.
- Researchers developed a new method by testing 34 chemical cocktails to induce human pluripotent stem cells to self-organize into organoids with their own de novo vascular networks.
- The resulting vascularized cardiac organoids contained 15 to 17 different cell types, closely mimicking the structural and functional complexity of a 6.5-week-old human embryonic heart.
- This versatile vascularization strategy was also successfully applied to create hepatic organoids and used to demonstrate how fentanyl exposure can alter vessel formation in a developmental model.
- This breakthrough creates more realistic biological models for studying early human development, screening for drug toxicities, and advancing the potential of organoids in future regenerative medicine applications.
Summary
Researchers addressed a key limitation of avascularity in organoid models, which restricts their growth to approximately 3 millimeters in diameter and limits physiological relevance. In a study by Abilez et al., a method was developed to generate vascularized organoids from human pluripotent stem cells (hPSCs). The team systematically evaluated 34 different growth factor and small molecule cocktails using micropatterned hPSCs with four fluorescent reporter systems. This approach allowed for the in-situ characterization of gastruloid, progenitor, and cardiovascular cell type formation to identify an optimal condition for generating a de novo vascular system within the organoids.
The optimal cocktail successfully induced the formation of cardiac vascularized organoids (cVOs) containing a branched, lumenized vascular network with vessels measuring 10 to 100 microns in diameter. Single-cell transcriptomic analysis revealed that these cVOs comprised 15 to 17 distinct cell types, closely recapitulating the complexity of a 6.5-postconception week human embryonic heart, which contains 16 cell types at Carnegie Stages 19 and 20. The mechanistic investigation confirmed that NOTCH and bone morphogenetic protein (BMP) signaling pathways were required for vascularization. BMP inhibition demonstrated a more significant negative impact than NOTCH inhibition on vessel formation.
The study demonstrated the broader utility of this protocol by successfully applying the same vascular-inducing cocktail to produce hepatic vascularized organoids (hVOs), suggesting a conserved developmental program for organ vascularization. As a proof-of-concept for toxicological studies, exposure of cVOs to fentanyl resulted in increased vessel formation. This technical advance provides a robust in vitro model for investigating early human organogenesis, corresponding to Carnegie Stages 9 and 10, and offers a platform for developmental biology studies, drug screening, and potential applications in regenerative medicine.
Link to the article: https://www.science.org/doi/10.1126/science.adu9375
References Abilez, O. J., Yang, H., Guan, Y., Shen, M., Yildirim, Z., Zhuge, Y., Venkateshappa, R., Zhao, S. R., Gomez, A. H., El-Mokahal, M., Dunkenberger, L., Ono, Y., Shibata, M., Nwokoye, P. N., Tian, L., Wilson, K. D., Lyall, E. H., Jia, F., Wo, H. T., … Wu, J. C. (2025). Gastruloids enable modeling of the earliest stages of human cardiac and hepatic vascularization. Science, 388(6751), eadu9375. https://doi.org/10.1126/science.adu9375
