First Lung Organoid with Organ-Specific Blood Vessels

Advanced lab-grown tissues help show how special lung cells develop, shedding light on rare ACDMPV disease and suggesting potential ways to repair damage from viral infections such as COVID-19

CINCINNATI, June 30, 2025 /PRNewswire/ -- A team of experts at Cincinnati Children's reports another powerful step forward in organoid medicine: success at making human lung tissue that can produce its own blood vessels.

Their findings, published in the same month as a similar success involving liver organoids, reflect a new wave of advanced lab-grown tissues that can be used immediately in many research applications while moving ever closer to serving as living tissues that can directly repair damaged organs.

Details were posted online June 30, 2025, in the journal Cell.

"Prior to our study, the development of lung organoids with organotypic vasculature had not been achieved," says co-corresponding author Mingxia Gu, MD, PhD. "Notably, this method also could be applied to other organ systems such as intestine and colon."

Gu, now at UCLA, was a member of the Center for Stem Cell and Organoid Medicine (CuSTOM) and Division of Pulmonary Biology at Cincinnati Children's while this research was conducted. Co-first and co-corresponding author Yifei Miao, PhD, (now at the Chinese Academy of Sciences, Beijing) also was with Cincinnati Children's for this work. Co-corresponding author Minzhe Guo, PhD, remains with Cincinnati Children's along with several co-authors involved in this study.

Overcoming a major challenge

Researchers have been working for years to grow organoids -- sometimes called "organs in a dish."

Creating organoids involves converting mature human cells (such as blood or tissue cells) back into fetal-like stem cells that can be coaxed into growing a wide range of other tissue types. Unlike disconnected human cells kept alive in a dish, these are growing, developing mini-organs that form into seed-sized spheres that mimic the unique functions of full-sized organs.

Intestines that absorb and secrete. Stomachs that produce digestive acids. Hearts that pulse. Brain tissues with firing nerve cells and so on.

Cincinnati Children's has been a leader in organoid development since 2010 when experts here produced the world's first functional intestinal organoid grown from induced pluripotent stem cells (iPSCs).

More recently, the challenge has been learning how to grow organoid tissues that can connect with the rest of the body to integrate nerve connections, blood vessels, bile ducts, immune systems and more. During pregnancy, these differing tissue types naturally find each other as the fetus matures and becomes more complex. Organoid developers seek to re-produce these steps in the laboratory, which eventually may allow people to receive custom-grown tissues that could patch damage or boost disrupted functions.

Simpler forms of organoids have already begun transforming medical research, allowing many scientists to use living human tissue models to study disease while reducing current reliance on animal models to develop new medicines. But without the ability to make internal blood vessels, the tiny seeds lack the ability to grow into larger, more useful tissues.

How the team solved the vascular riddle

The new study thoroughly recounts the results of many experiments the team conducted to demonstrate success at inducing blood vessel formation. The work spanned four years and involved more than 20 people at Cincinnati Children's plus collaborations with experts at several other organizations.

"The challenge in vascularizing endodermal organs, particularly the lung, stems from different signaling requirements for lung epithelial versus vascular differentiation," says Miao. "Our success in this endeavor is attributable to our unique differentiation method."

In essence, the team grew iPSCs from multiple cell types then found the right moment to introduce them to each other. The resulting cell signals helped flip a developmental switch so that progenitor cells that could have become either blood vessels or the outer walls of the lung wound up becoming blood vessels. In achieving this vital step, the team:

• Produced lung organoids that include respiratory bronchial epithelial cells (RAS cells), a human cell type not previously reported in conventional lung organoid models.
• Pinned down the developmental moments when a rudimentary gut tube begins to send some cells to form the lungs while sending other cells to form the stomach and intestine. While the basic steps of this transformation have been studied in animals, it had not been possible to study this stage of development in humans without killing fetuses.
• Demonstrated that the rare disease ACDMPV occurs when cell signaling "crosstalk" gets disrupted during this early blood vessel formation stage. Within days of birth, infants born with Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV) struggle to breathe because their lungs' air sacs (alveoli) and blood vessels are malformed. Nearly all infants with this condition die within the first month of life, according to the National Organization for Rare Disorders.
• Revealed key functional information about the cells involved in gas exchange inside the human lung. Their learnings help explain the damage within tiny blood capillaries that occurs in the lungs in response to injuries. These new clues offer fresh ideas for developing ways to protect and potentially restore affected lung tissues.

What's Next?

Cincinnati Children's has filed patent applications related to the methods developed here to produce organoids with blood vessel formation capabilities and the CuSTOM team is moving to further develop this technology.

"We look forward to continuing to learn more about the fundamental biology involved in organ formation and applying those discoveries to improving outcomes across a wide range of difficult human diseases and conditions," says Aaron Zorn, PhD, co-director of CuSTOM and director of the Division of Developmental Biology.

In addition to publishing these findings in Cell, co-authors plan to present their work at the Keystone conference in Kyoto, Japan (iPSCs: Progress, Opportunities, and Challenges) in January 2026.

About the study

Cincinnati Children's co-equal first authors were Miao, Nicole Pek, BS, and Cheng Tan, MD.

Contributing co-authors from Cincinnati Children's were Cheng Jiang, MS, Zhiyun Yu, PhD, Kentaro Iwasawa, MD, PhD, Min Shi, MD, PhD, Daniel Kechele, PhD, Nambirajan Sundaram, PhD, Victor Pastrana-Gomez, MSTP student, Debora Sinner, PhD, Cheng-Lun Na, PhD, Keishi Kishimoto, PhD, Jason Tchieu, PhD, Jeffrey Whitsett, MD, Kyle McCracken, MD, PhD, Michael Helmrath, MD, James Wells, PhD, Takanori Takebe, MD, PhD, and Aaron Zorn, PhD.

Contributing co-authors included experts from Harvard Medical School, Icahn School of Medicine at Mount Sinai, Sophia Children's Hospital (The Netherlands), Boston University

This research also was supported by the Discover Together Biobank, the Bio-Imaging and Analysis Facility, and the Integrated Pathology Research Core at Cincinnati Children's and the University of Cincinnati Proteomics Laboratory.

Funding sources for this work included: the National Institutes of Health (R01HL166283, DK128799-01, N01-75N92020C00005 and R01HL095993); an Endowed Scholar Award from the Cincinnati Children's Research Foundation; the American Heart Association (1013861 and 906513); the Falk Transformational Awards Program; and the Brigham Research Institute.

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SOURCE Cincinnati Children's Hospital Medical Center