Researchers identify the protein that controls the self-renewal of blood stem cells

Blood cells - red blood cells, white blood cells and platelets - are all initially derived from hematopoietic stem cells (HSCs). During hematopoiesis, these multipotent stem cells then differentiate into several progenitors that will give the final blood cells. In many blood disorders, bone marrow disorders can significantly reduce the production of HSC. But recently, researchers have discovered a protein mechanism that allows HSCs to self-renew, opening the door to new therapeutic solutions.

UCLA scientists have discovered a link between a protein and the ability of human blood stem cells to self-renew. In a study published in the journal Nature , the team reports that the activation of the protein causes the automatic renewal of blood stem cells at least twelve times under laboratory conditions.

The multiplication of blood stem cells in conditions outside the human body could dramatically improve treatment options for blood cancers such as leukemia and for many inherited blood diseases. Blood stem cells, also known as hematopoietic stem cells, are found in the bone marrow where they are renewed and differentiated to create all types of blood cells.

Overcome rejection problems in bone marrow transplants

Bone marrow transplants have been used for decades to treat people suffering from certain diseases of the blood or immune system. However, they have significant limitations: it is not always possible to find a donor compatible with bone marrow, the immune system of the patient may reject foreign cells and the number of transplanted stem cells may not be sufficient to effectively treat disease.

In many blood diseases, bone marrow is reached, impacting the renewal of hematopoietic stem cells. Grafts are therefore performed, with risks of rejection generally high. Credits: Sophie Jacopin

When blood stem cells are removed from the bone marrow and placed in lab boxes, they quickly lose their ability to self-renew and they die or differentiate into other types of blood cells. Mikkola's goal of allowing the automatic renewal of blood stem cells under controlled laboratory conditions would open up many new possibilities for the treatment of many blood diseases, including the safer genetic engineering of blood stem cells. patients.

MLLT3: a gene involved in the renewal of blood stem cells

It could also allow scientists to produce blood stem cells from pluripotent stem cells, which can create any type of cell in the body. In the lab, researchers analyzed genes that go out when human blood stem cells lose their ability to self-renew, noting genes that are turned off when blood stem cells differentiate into specific blood cells, such as white or red blood cells.

They then placed the blood stem cells in lab boxes and observed which genes were inactivated. Using pluripotent stem cells, they made cells resembling blood stem cells that were unable to renew themselves and monitored which genes were not activated.

They found that the expression of a gene called MLLT3 was closely related to the potential for self-renewal of blood stem cells and that the protein generated by the MLLT3 gene gave the blood stem cells the necessary instructions to maintain its ability to self-renew. To do this, he collaborates with other regulatory proteins to ensure that important parts of the blood stem cell machinery remain operational during cell division.

A higher multiplication of HSCs thanks to the MLLT3 gene

The researchers wondered whether maintaining the level of MLLT3 protein in blood stem cells in lab boxes would be enough to improve their self-renewing abilities. Using a viral vector - a specially modified virus, capable of transmitting genetic information to the nucleus of a cell without causing disease - the team inserted an active gene MLLT3 into blood stem cells and observed that blood stem cells functional were able to multiply at least twelve times more.

The researchers found that activation of the MLLT3 (orange) gene allowed for greater turnover of hematopoietic stem cells. Credits: CurioCity

Other recent studies have identified small molecules - organic compounds often used to create pharmaceutical drugs - that help multiply stem cells from human blood in the laboratory. When Mikkola's team used these small molecules, she found that self-renewal of the blood stem cells generally improved, but that the cells could not maintain the appropriate MLLT3 levels and that they did not function properly. not as well when transplanted to mice.

Self-renewal of blood stem cells without side effects

Importantly, MLLT3 has allowed blood stem cells to self-renew at a reasonable pace; they have not acquired any dangerous characteristics such as excessive multiplication or mutation and the production of abnormal cells that can lead to leukemia.

The next steps for the researchers are to determine which proteins and which elements of the blood stem cell DNA influence the on-off switch for MLLT3, and how this can be controlled using the ingredients contained in the boxes. laboratory. With this information, they could eventually find ways to turn on and turn off MLLT3 without using a viral vector, which would be safer for use in a clinical setting.


MLLT3 governs human haematopoietic stem-cell self-renewal and engraftment

Vincenzo Calvanese, Andrew T. Nguyen, Hanna K. A. Mikkola

Nature (2019)


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