# Engineering multi-organs in a dish

> **NIH NIH DP2** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $2,342,351

## Abstract

!
SUMMARY
Understanding the mechanisms governing organogenesis provides unique insight into strategies to engineer “in-
a-dish” mini-organ (aka organoid) systems from human stem cells, with the potential for studying developmental
disorders, drug screening, and therapeutic transplantation. We have thus capitalized on knowledge of
embryogenesis and have a history of innovation for engineering complex endodermal tissues from human
induced pluripotent stem cells (iPSCs), including gut, pancreatic and liver organoids with vascular and
macrophage components. Our vascularized human liver organoids, furthermore, were able to restore metabolic
function and maintain life of mice subjected to lethal acute liver failure. In this application, we will address the
next level challenge by proposing highly innovative 3-dimensional (3D) technologies of multi-organ engineered
from iPSC. In choosing a model system, we selected the hepato-biliary-pancreatic (HBP) system based on their
endoderm derivation, anatomical relatedness via interconnected ducts, and well-defined tissue subdomains.
The overall objective of the present proposal is to direct human iPSCs to generate balanced 3-D organogenesis
of the HBP system as a contiguous multi-organ system. In our human iPSC-differentiated HBP organogenesis
model, we discovered that, strikingly, the interaction between foregut-midgut enabled autonomous multi-organ,
i.e. HBP, patterning at the boundary and this critically required retinoic acid signals. Based on these exciting
preliminary data, we hypothesize that the boundary engagement of foregut-midgut interactions activates
multi-organ bud programming by localized retinoic acid signaling." Our approach will first leverage the
foregut-midgut boundary culture differentiated from human iPSCs to develop HBP organoid (HBPO) and will
determine the mechanisms by which retinoic acid establishes tissue boundaries and segregation of multi-organ
domains. Secondly, we will devise an efficient vascularization method for HBPO by our pioneering self-
condensation culturing methodology, wherein endothelial cells are incorporated into organoids to facilitate in vivo
engraftment. HBPO will be molecularly engineered to display dual organ subdomain reporter expression to
precisely map hepatobiliary domains. This will guide the development of surgical methods to direct the
anastomosis of extrahepatic biliary components into the recipient gut system. Finally, the metabolic maturation,
functionality, and persistence of this HBPO transplantable system will be challenged by testing therapeutic
efficacy to meet the metabolic needs of liver disease. Upon completion of the proposed studies, we will
demonstrate that the experimental multi-organ integrated model serves as a tractable, manipulatable and easily
accessible model for the study of human organogenesis and disease!in a way that cannot be accomplished by
direct human studies. In addition to serving as system to model human diseases, the prop...

## Key facts

- **NIH application ID:** 10002761
- **Project number:** 1DP2DK128799-01
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Takanori Takebe
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,342,351
- **Award type:** 1
- **Project period:** 2020-09-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10002761

## Citation

> US National Institutes of Health, RePORTER application 10002761, Engineering multi-organs in a dish (1DP2DK128799-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10002761. Licensed CC0.

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