Fetal Organoids Generated From Human Amniotic Fluid

A minimally invasive strategy for creating fetal organoids could facilitate precision medicine in the womb.

Moments after birth, a baby takes a first breath as the placenta, which has served as the fetus’ lungs during gestation, transfers responsibility to the baby's own organs. However, for patients born with congenital diaphragmatic hernia (CDH), a rare condition where the diaphragm fails to close, causing impaired lung development, entry into the world is more precarious. More severe cases of the disease lead to multiorgan damage, and approximately thirty percent of infants diagnosed with CDH never leave the hospital.

Diagnostic imaging and genetic screens help clinicians catch congenital fetal diseases in utero, but models for studying organ development and disease progression are limited. Over the last decade, organoids have become an increasingly popular platform for modeling organ function and disease. However, the generation of fetal organoids is complicated by ethical and legal restrictions on the harvesting of the human tissues needed to generate the mini-organs.

Now, reporting in Nature Medicine, researchers generated fetal organoids using cells derived from human amniotic and tracheal fluids. These mini-organs offer a minimally invasive approach for disease modeling during an active pregnancy and may eventually inform the development of personalized prenatal interventions.

Part 1

Scientists use patient cells to generate organoids that possess certain features and functions of the modeled organ while retaining the individual's genetic fingerprint. However, many of these platforms require lengthy dedifferentiation protocols to revert somatic cells into a state of pluripotency and then reprogram them to develop as another cell type. In contrast to organoids generated from pluripotent stem cells, primary organoids use tissue-specific stem cells or progenitor cells and therefore require minimal manipulation.3 While the organoid field is relatively advanced in terms of using adult tissues, researchers can only generate primary fetal organoids using tissue from terminated pregnancies. “This made it basically impossible to [generate organoids] compatible with the continuation of pregnancy, and therefore in a personalized medicine fashion”.
During gestation, the fetus floats in a protective pool of amniotic fluid.6 The yellowish liquid contains a concoction of nutrients and antibodies produced by the parent as well as less glamorous contributions from the fetus, including urine. It also includes fetal cells sloughed off during development, which doctors can extract and analyze for signs of disease.

“Those cells historically have been thought to be dead cells or cells that were shed from the lining of the amniotic fluid cavity.
Part 2

Most amniotic fluid cells are epithelial, but scientists knew very little about these cell populations. Everything changed when researchers started to look at the single cell level at what happened in the amniotic fluid.
used single-cell RNA sequencing to characterize the amniotic fluid of 12 patients and discovered subpopulations of epithelial cells that expressed markers typical of progenitors for the lung, kidney, and small intestine. The researchers cultured the tissue-specific progenitor cells, fed them a chemical cocktail to support growth, and watched as they proliferated, differentiated, and self-organized into 3D epithelial organoids. The mini-organs shared some transcriptomic and protein features found in their tissues of origin. For example, lung epithelial cells that developed and differentiated in culture had elevated expression of airway markers compared to their nondifferentiated counterparts. Similarly, kidney epithelial organoids expressed markers associated with renal tubules, which are integral components of the kidneys’ filtration system.

Although the amniotic fluid contained cells from other tissues, the researchers could not grow them into organoids, suggesting that they lack progenitor capabilities. Other research groups have successfully grown fetal organoids from somatic cells floating around the amniotic fluid, and the mini-organs generated using this approach are more complex.
reprogramming methods take up to 20 weeks to generate organoids. If the goal is to use organoids to inform prenatal interventions, timing is critical.
Part 3

Researchers re using these to study various diseases and find solutions to them.

More here: https://www.the-scientist.com/fetal-organoids-generated-from-human-...