Scientists identify the 'missing piece' needed for self-renewal of blood stem cells

UCLA scientists have identified a protein that plays a critical role in regulating the self-renewal of human blood stem cells by helping them detect and interpret signals from their environment.

The study, published in Nature, brings researchers closer to developing methods to grow blood stem cells in a laboratory dish, which could make life-saving transplants of these cells more available and increase the safety of cell-based treatments blood strains, such as gene therapies.

Blood stem cells, also known as hematopoietic stem cells, have the ability to reproduce through a process called self-renewal and can differentiate to produce all blood and immune cells found in the body. For decades, transplants of these cells have been used as life-saving treatments for blood cancers such as leukemia and various other blood and immune disorders.

However, blood stem cell transplants have significant limitations. Finding a matching donor can be difficult, especially for people of non-European ancestry, and the number of stem cells available for transplantation may be too low to treat a person's disease safely.

These limitations persist because blood stem cells that have been removed from the body and placed in a laboratory dish quickly lose their ability to self-renew. After decades of research, scientists are close to solving this problem.

“We've figured out how to produce cells that look like blood stem cells and have all their characteristics, but when these cells are used in transplants, many of them still don't work; there’s something missing,” said Dr. Hanna Mikkola, lead author of the new study and a member of UCLA’s Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research.

To identify the missing piece that prevents these blood stem cell-like cells from being fully functional, Julia Aguade Gorgorio, first author and co-correspondent of the paper, analyzed sequencing data to identify genes that are inhibited when blood stem cells are placed in a laboratory. flat. One of these genes, MYCT1, which codes for a protein of the same name, was found to be essential for the self-renewal capacity of these cells.

They discovered that MYCT1 regulates a process called endocytosis, which plays a key role in how blood stem cells sense signals from their environment that tell them when to self-renew, when to differentiate, and when to shut down.

“When cells perceive a signal, they must internalize and process it; MYCT1 controls how quickly and efficiently blood stem cells perceive these signals,” said Aguade Gorgorio, deputy project scientist in the Mikkola lab. “Without this protein, signals from the cells’ environment change from whispers to screams and cells become stressed and dysregulated.”

Researchers compare MYCT1 to sensors in modern cars that monitor all nearby activity and selectively transmit the most crucial information to drivers at the right time, helping them make decisions such as when to turn or change lanes. completely safe. Without MYCT1, blood stem cells are like anxious drivers who, accustomed to relying on these sensors, suddenly find themselves lost without their help.

Next, the researchers used a viral vector to reintroduce MYCT1 to see if its presence could restore the self-renewal of blood stem cells in a laboratory dish. They found that restoring MYCT1 not only made blood stem cells less stressed and allowed them to self-renew in culture, but also allowed these enlarged cells to function efficiently after being transplanted into mouse models.

As a next step, the team will study why inactivation of the MYCT1 gene occurs, and then how to prevent this inactivation without the use of a viral vector, which would be safer for use in a clinical setting.

“If we can find a way to maintain MYCT1 expression in blood stem cells in culture and after transplantation, that will open the door to maximizing all of these other remarkable advances in the field,” said Mikkola, professor of biology. molecular, cellular, and developmental biology at UCLA College and a member of the UCLA Health Jonsson Comprehensive Cancer Center. “This would not only make blood stem cell transplants more accessible and effective, but also improve the safety and affordability of gene therapies using these cells. »

This work was supported by the National Institutes of Health, the Swiss National Science Foundation, the European Molecular Biology Organization, the UCLA Jonsson Cancer Center Foundation, the James B. Pendleton Charitable Trust, the McCarthy Family Foundation, the California Institute for Regenerative Medicine, the UCLA AIDS Institute, the Board of Governors Regenerative Medicine Institute at Cedars-Sinai Medical Center, the Royal Society, the Wellcome Trust, and the stem cell training program at the Broad Stem Cell Research Center at UCLA.