UCLA scientists have managed to generate a large number of T cells of different subtypes and with different functions from just a single blood cell using a novel approach: lab-grown mouse thymus organoids. Their research furthers the understanding of how T cells arise, which is critical to their potential use in future therapies for certain diseases.
“You need T cells to be able to respond to vaccines, to fight viruses and to control cancerous changes in the body, so there’s a lot of interest in understanding how T cells are made,” says Gay Crooks, MBBS, co-director of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and Rebecca Smith Professor of Pathology and Laboratory Medicine. “This is a great system to help us study that basic biology.”
All T cells are formed from blood stem cells in the thymus. However, research into how blood stem cells differentiate into T cells has been stymied, because the cells rely on complex chemical signals from the thymus, a process that cannot be replicated easily in a lab dish or in isolated stem cells. After successfully creating lab-grown human thymus organoids — clusters of cells that mimic the thymus — in 2017, Dr. Crooks and her team adapted their work to also make mouse thymus organoids in the lab. This allows a different set of observations on T-cell formation than previously possible, since some types of experiments are possible in mice but not humans. “The main novelty with this mouse system is that we could start with one single stem cell,” says Amélie Montel-Hagen, PhD, associate project scientist in Dr. Crooks’ lab. “It’s amazing that from just one cell you can generate millions of diverse T cells.”
The researchers, who include UCLA MD/PhD candidate Victoria Sun, envision future experiments in which researchers remove or change genes thought to be important for generating T cells and use the thymus organoid to study the effect on mature T cells. While such experiments currently are possible inside genetically engineered mice, following the precise developmental paths of distinct groups of T cells is easier in an isolated laboratory system than in a living animal.
“For us to be healthy, the exquisite balance of immune cells and molecules in our bodies has to be just right,” says Dr. Crooks, who also is director of the Cancer and Stem Cell Biology Program at the UCLA Jonsson Comprehensive Cancer Center. “This will let us study how that balance is regulated.”
— Tiare Dunlap
“In Vitro Recapitulation of Murine Thymopoiesis from Single Hematopoietic Stem Cells,” Cell Reports, October 27, 2020