Researchers at UCLA have discovered a protein that is essential for controlling the self-renewal of human blood stem cells by enabling them to detect and process signals from the environment.
Their findings were published in the journal Nature.
This puts researchers one step closer to creating techniques for growing blood stem cells in a lab dish, which may boost the safety of blood stem cell-based medicines like gene therapies and increase the accessibility of life-saving transplants of these cells.
Hematopoietic stem cells, commonly referred to as blood stem cells, are able to divide into all of the body’s immune and blood cells as well as duplicate themselves in a process known as self-renewal. These cells have been transplanted for decades to treat leukaemia, other blood and immunological illnesses, and blood malignancies in hopes of preserving lives.
These restrictions stand because blood stem cells’ capacity to self-renew rapidly diminishes when they are taken out of the body and put in a lab dish. It has taken decades of investigation, but scientists are painfully close to finding a solution.
We’ve figured out how to produce cells that look just like blood stem cells and have all of their hallmarks, but when these cells are used in transplants, many of them still don’t work; there’s something missing,
Dr. Hanna Mikkola
The first and co-corresponding author of the research, Julia Aguade Gorgorio, used sequencing data analysis to discover genes that are silenced when blood stem cells are put in a lab dish. This allowed her to find the missing component that keeps these blood stem cell-like cells from being completely functioning. One such gene that stood out as being crucial to the ability of these cells to self-renew is MYCT1, which encodes a protein of the same name.
It was discovered that MYCT1 controls an activity known as endocytosis, which is essential for blood stem cells to absorb cues from their surroundings on when to differentiate when to self-renew, and when to remain silent.
When cells perceive a signal, they have to internalize it and process it; MYCT1 controls how fast and how efficiently blood stem cells perceive these signals,
Without this protein, the signals from the cells’ environment turn from whispers into screams and the cells become stressed out and dysregulated.
The researchers compare MYCT1 to the sensors in modern cars that monitor all nearby activity and selectively relay the most crucial information to drivers at the right time, aiding decisions like when to turn or change lanes safely. Without MYCT1, blood stem cells resemble anxious drivers who used to relying on these sensors, suddenly find themselves lost without their guidance.
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Next, the researchers reintroduced it via a viral vector to investigate if MYCT1’s presence might reinstate blood stem cell self-renewal in a lab dish. They discovered that MYCT1 restoration not only reduced stress on the blood stem cells and allowed them to proliferate in culture, but it also allowed the enlarged cells to perform well when grafted into mice models.
Subsequently, the group will look into the reasons for the MYCT1 gene’s silence and how to stop it without using a viral vector a safer approach in a clinical environment.
If we can find a way to maintain MYCT1 expression in blood stem cells in culture and after transplant, it will open the door to maximize all these other remarkable advances in the field,
This would not only make blood stem cell transplants more accessible and effective but also improve the safety and affordability of gene therapies that utilize these cells.
Dr. Hanna Mikkola
Source: University of California – Los Angeles Health Sciences News
Journal Reference: Calvanese, Vincenzo, et al. “MYCT1 Controls Environmental Sensing in Human Haematopoietic Stem Cells.” Nature, 2024, pp. 1-9, https://doi.org/10.1038/s41586-024-07478-x.
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