Published on 06.03.2019
The tetratricopeptide repeat domain-7A (TTC7A) protein has a long history with the Imagine Institute, since in 2014, this protein was implicated in a rare and potentially fatal inherited pathology by Geneviève de Saint-Basile's Normal and Pathological Homeostasis of the Immune System team (Inserm, Imagine, Université de Paris), now co-led by Gaël Menasché and Fernando Sepulveda. The team showed that children with an alteration in the gene that produces the TTC7A protein are born with multiple atresias of the intestine, often associated with a profound immune deficiency.
Today, these researchers continue to study the functions of this protein. They have studied its role in the production of blood cells in an animal model. When the Ttc7a gene is altered, this results in greater resistance to stress in hematopoietic stem cells and a higher turnover of blood cells. This advantage comes at a price as the risk of developing hematological diseases is higher.
A subtle balance between homeostasis and pathology
At the heart of our body, in the bone marrow, are hematopoietic stem cells: they ensure the renewal of all blood cells: red blood cells, white blood cells, platelets.... "In response to a signal, a stem cell divides," Fernando Sepulveda reminds us. "It then gives birth to two cells: a new stem cell, to guarantee the continuity of the stock, and a more specialized cell. The latter will then continue its path by becoming more and more specialized with each division until it becomes a white blood cell or another blood cell.
The balance of this process is very fine and the slightest disturbance can have deleterious consequences for the body. This is exactly what the alteration of TTC7A does. "Our results show that the loss of TTC7A creates a kind of super stem cell that is more resistant to stress," says Fernando Sepulveda. "They then have a stronger capacity to repopulate the immune system and this over a long period of time. It's as if they start to proliferate excessively to compensate for the stress, but they don't know when to stop. But these enhanced self-renewal capabilities come at a cost," he says. The downside is that uncontrolled cell proliferation will cause a hematological syndrome. Altering TTC7A breaks the balance between blood cell production and stem cell maintenance, leading to a major risk throughout the body.
TTC7A functions are expanding
The team led by Fernando Sepulveda and Geneviève de Saint-Basile therefore describes Ttc7a as a regulator of hematopoietic stem cell self-renewal and stress response. Ttc7a guarantees the identity of these cells as stem cells. This is a new function for this gene which was already known as an essential player in the homeostasis of epithelial cells and the immune system.