Organoids Just Gained Their Missing Ingredient: Functional Blood Vessels

The Context: Organoids – 3D structures of human tissue derived from stem cells – are a critical tool for helping researchers study diseases like cancer and develop and test drugs. However, current organoid models do not contain functional blood vessels, limiting their ability to accurately model disease.

The Study: Scientists can now create organoids containing functional human blood vessels thanks to a new method published in Nature by a team of scientists led by founding member of NYSCF’s Medical Advisory Board Shahin Rafii, MD, of Weill Cornell Medicine and including NYSCF – Druckenmiller Fellows Ying Liu, PhD, and Jesus Gomez Salinero, PhD. 

The Importance: With the ability to generate organoids that contain functional blood vessels, our researchers can now better model cancer biology and identify effective therapies. Dr. Rafii is also collaborating with NYSCF Research Institute scientists to create vascularized ovarian cancer organoids.

Blood vessels in every organ, and tumor, are different. To regenerate a damaged organ or target a cancerous one, scientists must understand each organ’s unique vasculature. With Dr. Rafii’s new advancement, researchers can do this better than ever before.

“This advance allows us to generate a tissue-specific network of functional blood vessels to nourish and support a variety of model organs, or organoids, as well as the development of transplantable human pancreatic islets, which can be used for research studies and potentially for organ repair,” said senior author Shahin Rafii, MD, the Director of the Ansary Stem Cell Institute at Weill Cornell Medicine in a press release. “We can also now decipher how cancerous blood vessels acquire their abnormal features, permitting identification of new druggable targets for tumors.”

Building Better Organoids

The team’s work is based on a discovery made by Brisa Palikuqi, PhD, a former postdoc in Dr. Rafii’s lab. Dr. Palikuqi’s studies of lab-grown blood vessels identified a protein called ETV2 that could rejuvenate vascular endothelial cells (the building blocks of blood vessels) to a more malleable state, allowing scientists to grow them in a way that prompts integration into surrounding tissue.

“Adult endothelial cells don’t know how to make new blood vessels from scratch,” said Dr. Palikuqi, who is now a postdoctoral scholar at University of California, San Francisco. “Our idea was to use ETV2 to reset vascular endothelial cells (abbreviated as R-VECs) to a fetal state in which they can adaptively form new vessels based on signals from the surrounding tissue. Thus, they are re-educated to perform specialized vascular functions. We also identified a mixture of three natural tissue-molding ‘matrix’ proteins that helped R-VECs to form blood vessels in devices that carry fluids and blood. With this 3-D platform, which we call ‘Organ-On-VascularNet,’ we can use R-VECs to build tissue-specific blood vessels that may help regenerate organs.”

The team tested their R-VECs and found that the cells could self-assemble into functional networks of blood vessels in a dish, a feat that has not been possible until now. The vessels were also able to connect to vasculature in mice and remain functional for several months.

Implications for Diabetes, COVID-19, Cancer, and More

R-VEC vessels integrated into organoids have vast potential for understanding a variety of diseases, including cancer. Dr. Rafii is working with NYSCF Research Institute scientists to create vascularized ovarian cancer tumor organoids as part of our Women’s Reproductive Cancers Initiative. These organoids will recapitulate ovarian cancer better than ever before, allowing unique insights into what drives its progression and accelerating therapeutic development.

“With this technology, we can better understand exactly how ovarian cancer acts within the body, bringing us closer to personalized treatments for this incredibly individualized disease,” said Laura Andres-Martin, PhD, Research Investigator in Oncology at the NYSCF Research Institute.

The team is also already using R-VEC vessels to study COVID-19.

“We are utilizing the R-VEC vascular network to investigate how the SARS-CoV-2 virus wreaks havoc on small blood vessels within organs, setting the stage to formulate new therapeutics,” explained Robert Schwartz, MD, PhD, an Assistant Professor of Medicine in the Division of Gastroenterology at Weill Cornell.

The team also found that R-VECs could vascularize and support function of human islets (clusters of insulin-producing cells in the pancreas that are damaged by type 1 diabetes). Islet transplants are sometimes used as a therapy for type 1 diabetes, but the islets must be infused into the liver instead of a more accessible site such as the skin in order to ensure they receive adequate blood supply. 

“R-VECs’ capacity to vascularize human islets will lay the foundation to engineer long-lasting islets to potentially cure type I diabetes,” said co-author Joe Zhou, PhD, Professor of Regenerative Medicine in Medicine at Weill Cornell and a collaborator on the islet studies. “Such vascularized islets would be more accessible, could have a better survival rate and might be superior to what we have now in clinical use. They could also offer new avenues to test drugs aimed at stopping the autoimmune response.”

Exciting Implications for the Future

The team is excited about what their new method will enable for research into a variety of diseases.

“We see a new frontier in modern regenerative medicine as some of the major obstacles facing this field will now be challenged,” said Dr. Rafii. “With this work, we have learned how to capitalize on endothelial cells’ reparative functions and can begin to tackle a variety of unmet medical needs.”

Journal Article:

Adaptable haemodynamic endothelial cells for organogenesis and tumorigenesis
Brisa Palikuqi, Duc-Huy T. Nguyen, Ge Li, Ryan Schreiner, Alessandro F. Pellegata, Ying Liu, David Redmond, Fuqiang Geng, Yang Lin, Jesus M. Gómez-Salinero, Masataka Yokoyama, Paul Zumbo, Tuo Zhang, Balvir Kunar, Mavee Witherspoon, Teng Han, Alfonso M. Tedeschi, Federico Scottoni, Steven M. Lipkin, Lukas Dow, Olivier Elemento, Jenny Z. Xiang, Koji Shido, Jason R. Spence, Qiao J. Zhou, Robert E. Schwartz, Paolo De Coppi, Sina Y. Rabbany & Shahin Rafii. Nature. 2020. DOI: https://doi.org/10.1038/s41586-020-2712-z

Cover image: Ovarian cancer organoids derived from stem cells.

Image credit: Laura Andres-Martin