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Developmental Biology - Cell Signaling

Two Discoveries Boost Next-Generation Organoids

New research tunes into cell signaling that will help make organoids better at mimicing functions of the trachea, esophagus, stomach, liver, gallbladder, bile ducts and pancreas...

In back-to-back reports published Aug. 27, 2020, in Nature Communications, a team of scientists from Cincinnati Children's and Japan report discoveries that will be vital to a new wave of more-complex organoid development.

Their findings advance efforts to use human stem cells to grow organs from the fetal foregut including the trachea, esophagus, stomach, liver, gallbladder, bile ducts and pancreas.
"With single-cell analysis of mouse embryos, we defined the complex signaling networks controlling development of mesenchyme cells, which form the smooth muscle and fibroblast tissues that are essential for organ function. We then used this information from the mouse to differentiate the equivalent human tissue in the lab. This is important as up until now, all of the liver, lung, stomach and esophagus organoids that we make mostly lack these mesenchyme cell types."

Aaron M. Zorn PhD, Perinatal Institute Endowed Research Chair; Director, Center for Stem Cell and Organoid Medicine (CuSTOM); Associate Director, Division of Developmental Biology, Digestive Health Center; Professor, Department of Pediatrics; University of Cincinnati, College of Medicine, Cincinnati, Ohio, USA; & senior author.

The Center for Stem Cell & Organoid Medicine (CuSTOM) at Cincinnati Children's, has made groundbreaking advances in stomach, intestine, liver and esophageal organoid development. In 2019, the CuSTOM group launched a formal collaboration with RIKEN, Japan's largest comprehensive research institution, to pursue further organoid innovation.

The papers published in Nature Communications represent the first results of that collaboration.

Decoding Foregut Development Cell-by-Cell

In this study, scientists report detecting a set of signals within the foregut (a proto-organ in very early-stage embryos) that trigger how and when other organs form. Specifically, they found cell signals are driven by the genes Wnt and SHH, which travel between cells via the endoderm and mesoderm layers of very early embryos.

To define these signals, researchers Lu Han PhD, and Keishi Kishimoto PhD, collaborated with organoid experts James Wells PhD, and Takanori Takebe MD, to develop a high-resolution map of foregut development in mice. They detected an unexpected variety of cells sending a chorus of master signals that trigger formation of the various organs that branch out from the foregut.
This study is the first to pin down the dynamics at play in the embryonic mesoderm.

The action happens very early-between embryonic days 8.5 and 9.5 in mice, which roughly corresponds to days 17 to 23 in human gestation. During this brief window of development, groups of cells at certain spots along the simple foregut tube begin transforming into the sprouts of organs that become the trachea, esophagus, liver and pancreas.

By studying the molecular signaling activity during this period, at a cell-by-cell level, the researchers produced a roadmap that shows how and why the organs sprout where they do. They then used these signals to grow tissue from different organs from human pluripotent stem cells.
In September 2019, Takebe and colleagues reported the world's first success at growing a three-organoid system that included the liver, pancreas and biliary ducts. That breakthrough took five years to achieve and the organoids produced did not possess all the cell types needed for full-sized function.

The new road map will enable scientists to grow more complete interconnected organs says Zorn.

A Deep Dive Into Trachea Development

In a parallel paper also appearing in Nature Communications, the RIKEN and CuSTOM teams extended these studies with extensive experiments in mice to further define the mechanisms of trachea formation.

This study led by lung development expert Mitsuru Morimoto, PhD, in Japan used genetically modified mice to learn which cell signals were most important to trachea formation. When these signals fail, the developing embryo does not properly form the cartilage rings and smooth muscle tissues that the trachea needs to pipe air to the lungs.

Cincinnati Children's, which developed the first human esophagus organoid in 2018 has been working with the RIKEN team on this project as part of its involvement with the CLEAR Consortium (Congenital Esophageal and Airway Defect Research).
"This work helps explain what happens when birth defects like esophageal atresia, tracheoesophageal fistula, and tracheomalacia occur," Zorn says. "This work also opens the door to one day generating esophagus and trachea tissue for tissue replacement."

Implications for Tissue Engineering

The sheer complexity of the new signaling roadmap helps explain why it took so long to make the initial three-organoid breakthrough. For example, the map revealed five distinct populations of mesenchymal cells involved in liver formation alone.

Now, co-authors say the new roadmap will make the process faster, could expand the types of organs that can be grown together, and will allow researchers to grow sets of organoids engineered to mimic conditions that lead to birth defects or increased disease risk ± including some forms of cancer.
"One important outcome of our study is the use of a signaling roadmap to direct the development of stem cells into different organ cell types. This approach may have important applications for tissue engineering."

Takanori Takebe PhD, CuSTOM, Division of Gastroenterology, Cincinnati Children’s Hospital, Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio, USA.

Short term, such organoid systems can be used to test new medications with far less dependence on animal models, or to evaluate the harms caused by pollution, unhealthy diets, allergens, and so on. Longer term, once expects learn ways to grow organoids to significantly larger sizes, customized lab-grown tissues could be used to repair damaged organs and someday even replace failing ones.

Researchers layout in their paper protocols other scientists can use in making their own organoid systems. Detailed data also existes on their interactive website: Single cell transcriptomics of mouse foregut organogenesis.

Visceral organs, such as the lungs, stomach and liver, are derived from the fetal foregut through a series of inductive interactions between the definitive endoderm (DE) and the surrounding splanchnic mesoderm (SM). While DE patterning is fairly well studied, the paracrine signaling controlling SM regionalization and how this is coordinated with epithelial identity is obscure. Here, we use single cell transcriptomics to generate a high-resolution cell state map of the embryonic mouse foregut. This identifies a diversity of SM cell types that develop in close register with the organ-specific epithelium. We infer a spatiotemporal signaling network of endoderm-mesoderm interactions that orchestrate foregut organogenesis. We validate key predictions with mouse genetics, showing the importance of endoderm-derived signals in mesoderm patterning. Finally, leveraging these signaling interactions, we generate different SM subtypes from human pluripotent stem cells (hPSCs), which previously have been elusive. The single cell data can be explored at: https://research.cchmc.org/ZornLab-singlecell.

Lu Han, Praneet Chaturvedi, Keishi Kishimoto, Hiroyuki Koike, Talia Nasr, Kentaro Iwasawa, Kirsten Giesbrecht, Phillip C. Witcher, Alexandra Eicher, Lauren Haines, Yarim Lee, John M. Shannon, Mitsuru Morimoto, James M. Wells, Takanori Takebe and Aaron M. Zorn.

This work was supported by grant NICHD P01HD093363 to A.M.Z. and J.W.M. T.T. is a New York Stem Cell Foundation – Robertson Investigator. M.M. research is supported by a Japanese Grant-in-Aid for Scientific Research (B) (17H04185). K.K. is supported by a Memorial Foundation postdoctoral fellowship and a RIKEN-CuSTOM collaborative grant for Promotion of Joint International Research (A) (18KK0423). This project was supported in part by NIH P30 DK078392 (Integrative Morphology, Sequencing and Pluripotent Stem Cell and Organoid Cores) of the Digestive Disease Research Core Center in Cincinnati. We are grateful to Minzhe Guo, Yan Xu, and Nathan Salomonis for help with the pseudotime and trajectory analysis, to James Briggs and Caleb Weinreb from the Alon Klein lab for advice on SPRING and members of the Rahul Satija lab for help with Seurat. Drs. Rafi Kopan and Emily Miraldi provided critical discussions and advice.

Laboratory for Lung Development, RIKEN Center for Biosystems Dynamics Research (BDR), Kobe, 650-0047, Japan, Keishi Kishimoto and Mitsuru Morimoto

CuSTOM-RIKEN BDR Collaborative Laboratory, Cincinnati Children’s Hospital, Cincinnati, OH, USA

Keishi Kishimoto, Mitsuru Morimoto and Aaron M. Zorn

CuSTOM, Division of Gastroenterology, Cincinnati Children’s Hospital, Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH, 45229, USA
Hiroyuki Koike, Kentaro Iwasawa, Kirsten Giesbrecht and Takanori Takebe

Division of Pulmonary Biology, Cincinnati Children’s Hospital, Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH, 45229, USA
John M. Shannon

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While this mouse foregut was forming, single-cell RNA sequencing captured 3 points of change from early cell patterning to induction of specific cell lines. CREDIT Cincinnati Children's and RIKEN

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