MYCT1 Protein Plays A Key Role in Human Hematopoietic Stem Cell Self-Renewal

In a new study, researchers from the University of California, Los Angeles discovered that a protein called MYCT1 plays a key role in regulating the self-renewal of human hematopoietic stem cells (HSCs) by helping them sense and interpret signals from their environment. This discovery brings scientists one step closer to developing a method to expand hematopoietic stem cells in laboratory dishes. This will make life-saving hematopoietic stem cell transplants more accessible and improve the safety of hematopoietic stem cell-based therapies, such as gene therapy. The relevant research results were recently published in the journal Nature, with the title of the paper "MYCT1 controls environmental sensing in human haematopoietic stem cells".

Hematopoietic stem cells are able to replicate themselves through a process of self-renewal and can differentiate into all blood and immune cells in the body. For decades, hematopoietic stem cell transplants have been used as a lifesaving treatment for blood cancers such as leukemia, as well as a variety of other blood and immune diseases. However, hematopoietic stem cell transplants have significant limitations. Finding a matching donor can be difficult, especially for people of non-European descent, and the number of hematopoietic stem cells available for transplantation may be too small to safely treat a patient's disease.

These limitations persist because hematopoietic stem cells extracted from the human body and placed in a laboratory dish quickly lose the ability to self-renew. After decades of research, scientists have come very close to solving this problem.

"We already know how to make cells that look like blood stem cells and have all of their characteristics," said Dr. Hanna Mikkola, co-corresponding author of the paper and a member of the Eli and Edith Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. "But when these cells are used for transplantation, many of them still don't work. Something is missing."

To find out what's missing that's preventing these blood stem cell-like cells from fully functioning, first author and co-corresponding author Julia Aguade Gorgorio analyzed sequencing data to identify genes that are silenced when blood stem cells are placed in a laboratory dish. One of these genes, MYCT1, is critical to the cells' ability to self-renew. They found that MYCT1 regulates a process called endocytosis, which plays a key role in how blood stem cells receive signals from their environment that tell them when to self-renew, when to differentiate, and when to be quiescent.

Figure 1. MYCT1 is located in endosomes and interacts with vesicle trafficking and receptor signalling machinery. (Aguadé-Gorgorió J, et al., 2024)

"When cells sense a signal, they must internalize it and process it," said Aguade Gorgorio, assistant project scientist in the Mikkola lab. "MYCT1 controls how quickly and efficiently blood stem cells sense these signals. Without this protein, signals from the cell's environment go from whispers to screams, and the cells become stressed and dysfunctional."

The authors liken MYCT1 to sensors in a modern car that monitor all nearby activity and selectively relay the most critical information to the driver when appropriate, helping them make decisions such as when to safely turn or change lanes. Without MYCT1, blood stem cells would be like drivers who have grown accustomed to relying on these sensors, only to suddenly find themselves without them.

Next, the authors used a viral vector to reintroduce MYCT1 to see if its presence could restore self-renewal in blood stem cells in a lab dish. They found that restoring MYCT1 not only reduced stress on blood stem cells, allowing them to self-renew in culture, but also enabled these expanded cells to function effectively after being transplanted into a mouse model. Next, the authors will investigate why MYCT1 gene silencing occurs and then study how to prevent it without using viral vectors, which would make it safer to use in a clinical setting.

"If we can find a way to maintain MYCT1 expression in hematopoietic stem cells in culture and after transplantation, it will open the door to maximize all the other remarkable advances in this field," Mikkola said. "Not only would this make hematopoietic stem cell transplants more convenient and more effective, it would also improve the safety and affordability of gene therapies using these cells."

Reference

Aguadé-Gorgorió J, et al. MYCT1 controls environmental sensing in human haematopoietic stem cells. Nature, 2024: 1-9.