Under the microscope, a Botryllus colony looks like a bouquet of flowers, although in reality each “petal” is a separate organism with its own heart, gills, digestive system, brain and blood cells. The separate Botryllus organisms in the colony share a common blood supply, and even exchange cells. This blood sharing allows stem cells for sperm and eggs and stem cells for body tissues to be shared throughout the growing colony.

The researchers showed that there are close parallels between the blood systems in Botryllus and in mammals. They found that Botryllus has a sort of incubator of specialized cells, called a niche, that holds and supports blood stem cells and is a lot like the blood stem cell niche in mammalian bone marrow. They also found that Botryllus blood stem cells will find their own way from blood vessels to the niche, exactly as they do in mammals. And they found 327 genes involved in blood cell formation in Botryllus that are similar to genes involved in blood formation in mammals.

Previously, researchers in the Weissman lab showed that a single variant of a gene called BHF regulated whether separate Botryllus organisms would send out blood vessels from their own bodies and merge with adjacent individuals, or undergo an immune rejection, preventing blood cell exchanges.The new study identifies how BHF regulates whether organisms fuse together in the colony: If the protein produced by the gene is recognized as compatible by the other colony, it prevents the activation of a rejection process that is similar to the way that the human immune system’s natural killer cells attacks tissues that are not “self.”

An excellent model

The discovery of such strong parallels between the two systems offers researchers an excellent model for studying many biological phenomena in mammals, the researchers said. “Blood stem cells in mammals are hard to find and, when found, it’s very hard to follow what is going on in the blood stem cell niche,” Voskoboynik said. “Botryllus is a translucent organism, so we can easily spot the niche and visually follow the migration of each type of cell from one part of their body to the other.”

It’s also easy to observe how the cells in individual organisms interact when one mounts an immune attack against the other, or the two individuals fuse blood vessels. This could provide scientists with a better understanding of why an organism accepts or rejects foreign cells, knowledge that could give insights into organ transplant acceptance and rejection, Voskoboynik said.

“With its primitive but effective immune system, Botryllus may also give us insights into how we can boost our own immune responses to pathogens and cancer,” Voskoboynik said. “But in addition to any practical benefits this research may produce, we are delighted to explore this important guidepost on the path to understanding the evolution of vertebrates, and of their blood-forming and immune systems. Isn’t that what curiosity-driven science is supposed to do?”

Other Stanford authors are Garry Nolan, PhD, professor of microbiology and immunology; Aaron Newman, PhD, assistant professor of biomedical data science; Rahul Sinha, PhD, instructor at the Institute for Stem Cell Biology and Regenerative Medicine; former postdoctoral scholars Daniel Corey, MD, PhD, Norma Neff, PhD, and Jun Seita, PhD; former graduate students Jonathan Tsai, MD, PhD, Nathaniel Clarke, PhD, and Shih-Yu Chen, PhD; research funding associate Tal Raveh, PhD; research associates Karla Palmeri and Katherine Ishizu; and former research associates Jennifer Okamoto and Gary Mantalas.

The research was supported by the National Institutes of Health (grants R56AI089968, R01AG037968, RO1GM100315, 5T32AI07290 and T325T32AI07290), the Virginia and D.K. Ludwig Fund for Cancer Research, the Siebel Stem Cell Institute, the Stinehart Reed Foundation and the Human Frontier Science Program.

Stanford’s departments of Pathology, of Developmental Biology, of Bioengineering and of Applied Physics also supported the work.