Unraveling the mysteries of blood: Gene that regulates self-renewal discovered

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They say working on the trauma unit isn’t for the faint of heart. But I think this also applies to being an immunologist. Because not only do you have to stand the sight of blood, you also have to understand it, and blood happens to host some very complicated conversations.

Each type of immune cell in our body is bombarded with signals from multiple other cells, continuously receiving mixed messages. Somehow, through the various cocktails of cytokines and growth factors, our immune system keeps a fine balance of pro-inflammatory and anti-inflammatory actions, and it knows to only become activated for as long as it takes to eliminate a foreign invader.

Given the complexity and often transient nature of many of these messages, you can imagine how difficult it is for immunologists to pinpoint key proteins that have very clearly defined roles. It’s like playing telephone at an Ozzy Osbourne concert and then trying to decipher the origin of what he says on stage. Completely impossible!

Well almost…

In the current issue of Nature Immunology, Dr. Norman Iscove’s group at Toronto’s University Health Network outlines a transcription factor that has a very clear message.

This message has to do with the fate of hematopoetic stem cells (HSCs) or blood stem cells. Different HSC populations have been identified as either “long term” (LT) or “intermediate term” HSCs. LT-HSCs, as the name implies, maintain their stem cell properties for longer and, as the less differentiated variant, they have the potential to replicate for a greater number of generations. However, when LT-HSCs are exposed to different cytokine milieus, they start to mature and lose some of that ability to self-renew, producing instead cells that are more specialized. Obviously, if you want to be able to grow up large quantities of HSCs in the lab, it would be ideal to prevent their switch from self-renewal to differentiation.

Herein lies the discovery by Dr. Iscove’s group. They have identified the transcription factor, GATA-3, as a regulator of HSC differentiation. Their experiments show that in LT-HSCs this protein quietly resides in the cellular cytoplasm, not affecting HSC fate. However, when LT-HSCs are exposed to the right environmental signals, GATA-3 moves to the nucleus of the cell where it affects gene transcription and promotes HSC differentiation.

Furthermore, through some very elegant animal studies, they show that inhibition of upstream mediators of this pathway (basically a modification of the processes that would tell the GATA-3 gene to become active) or deletion of the GATA-3 gene, can lead to prolongation of the LT-HSC phenotype. In other words, if you remove or keep the GATA-3 gene inactive, the LT-HSCs will continue producing more of the same type of cell. This is a good thing, when it comes to blood transplants.

As I’ve outlined in a previous blog, the motivation for being able to expand HSCs ex vivo is that there is a scarcity of HLA-matched HSCs, and patients require millions for transplantation. Given that proper engraftment can actually cure a number of leukemias, blood disorders, and potentially even promote tolerance to organ transplants, it is in the interest of everyone for the scientific community to learn as much as possible about how these cells converse with each other and what drives their ultimate fates.

This challenge has not been unmet by a number of Canadian scientists. From being the first to describe HSCs to now identifying several key regulators (GATA-3, HOXB4) important for long term HSC proliferation, they have made and continue to make significant contributions, which is clearly evidenced by Dr. Iscove’s recent article.

At this point I’m now dying to learn the rest of the story, i.e. how the various HSC regulators interact with each other and which points are most amenable to intervention. By piecing together the life cycle of an HSC, we can better understand how we so seamlessly deal with our everyday environmental stressors. And if we can even emulate a fraction of this, it will lead to a great achievement in transplantation science.

Research cited:
Frelin C., Herrington R., Janmohamed S., Barbara M., Tran G., Paige C.J., Benveniste P., Zuñiga-Pflücker J.C., Souabni A. & Busslinger M. & (2013). GATA-3 regulates the self-renewal of long-term hematopoietic stem cells, Nature Immunology, DOI: 10.1038/ni.2692
Weissman I.L. Translating Stem and Progenitor Cell Biology to the Clinic: Barriers and Opportunities, Science, 287 (5457) 1442-1446. DOI: 10.1126/science.287.5457.1442