Animal models have served as excellent models of many aspects of human biology and disease, but they cannot mimic every part of human physiology. Scientists have recently developed a new kind of researcg model called human organoids to try to address some of the gaps in research knowledge that have arisen because of the use of animal models. Organoids are simplified, miniaturized versions of human organs. They are created with human cells that are reprogrammed genetically, first to create induced pluripotent stem cells (iPSCs), and then again to develop the organoids of interest, which might be cerebral, lung, or another tissue type.
Researchers have used organoids to learn more about how SARS-CoV-2, the virus that causes COVID-19, can affect the human body.
In an April 2024 study published in Scientific Reports, researchers created vascular organoids from iPSCs. When these orgaoids were exposed to SARS-CoV-2, cells on the surface of the organoids died. The infection had triggered a programmed cell death pathway know as apoptosis. The infection also activated the inflammatory action of immune cells called macrophages.
The team also added hematopoietic cytokines to the organoids to create vascular immune organoids, This work showed that the viral infection could lead to the release of interferons. The study authors suggested that these organoids could help us understand how the virus causes cytokine release syndrome.
In an unrelated study reported in July 2024 in Proceedings of the National Academy of Sciences (PNAS), researchers collected cells from COVID-19 patients to create lung organoids. This work revealed that the virus is able to infect more cell types than we knew. This was true even when the investigators tested different variants of the SARS-CoV-2 virus.
"People used to say that SARS-CoV-2 only infects cells with certain receptors, especially those with the ACE2 receptor known to interact with the infamous SARS-CoV-2 spike protein," said Professor Evan Snyder, MD, PhD, director of the Center for Stem Cells and Regenerative Medicine at Sanford Burnham Prebys. "We demonstrated that when a direct entry point was unavailable, the virus just punches through the cell membrane instead."
Another July 2024 study reported in Cellular and Molecular Gastroenterology and Hepatology, scientists developed human intestinal tissue organoids referred to as enteroids. When the organoids were exposed to SARS-CoV-2, there was a familiar reaction in which proteins that transport other molecules across the membranes of cells began to change. This disrupts ion absorption and secretion, which can lead to diarrhea. But an unusual mechanism was also seen in which a calcium-activated chloride channel was also affected. This ion channel is not usually disrupted in infection, while the transport proteins typically are.
"The next big question is to determine what exactly allows the virus to live in the intestine and what allows the virus to live over a long period of time," said Mark Donowitz, MD, an Emeritus Professor at the Johns Hopkins University School of Medicine.
Sources: Sanford-Burnham Prebys, PNAS, Scientific Reports, Cellular and Molecular Gastroenterology and Hepatology