Blood stem cells are rare cells in the bone marrow that produce the blood and immune cells needed throughout life, thus ensuring that the blood and immune system in the body are renewed. This is why they are also used in bone marrow transplantations and novel gene therapies for treating a range of blood disorders. However, during gene therapy the stem cells need to be processed in the laboratory prior to transplantation, which can cause them to lose some of their regenerative capacity and reduce the chance of the overall treatment being successful.
To improve the prospects of these therapies, researchers from the Institute for Regenerative Medicine (IREM) at the University of Zurich were looking for new signaling pathways that will improve the function of blood stem cells. To do this, they investigated how a protein called activated protein C (aPC) influences human blood stem cells. They compared the effect of aPC with that of thrombin – another protein that is involved in blood clotting and acts via the same cell receptor, known as protease-activated receptor 1 (PAR1). The work was a collaborative effort between UZH and the University of California, Santa Cruz (Dr. Marcel Rommel and Prof. Camilla Forsberg).
Same receptor, different effect
"Although both molecules activate the same receptor, PAR1, they produce very different outcomes," says first author Simon Pöllmann from the IREM. "We were able to demonstrate that aPC helps the blood stem cells to remain in a resting, protected state." In this state of rest known as quiescence, the cells treated with aPC divided less frequently, they were less likely to differentiate into specialized blood cells prematurely, and they retained their characteristics that are vital for stem cells to function over the long term. By contrast, thrombin resulted in greater differentiation of the cells, which can reduce their stem cell potential.
It was particularly important to note that treatment with aPC for just one hour improved the transplantability of human blood stem cells. This was shown in the animal model during transplantation into mice. "The treated cells produced more human blood cells and displayed a better capacity to sustain blood formation even after repeated transplantation," explains last author Ute Modlich, professor in IREM's Gene and Cell Therapy Division. In addition, the treatment with aPC protected the stem cells from being activated by inflammatory signals that would normally drive them out of their resting state.
Promising improvement for therapy
The results of the study therefore show that signal transmission via the activated protein C provides a promising strategy for preserving the quality and regenerative capacity of human blood stem cells. In the long term, the researchers believe this approach could help improve the success of stem cell transplantations and gene therapies, delivering a real benefit to patients with blood disorders.
