Blood stem cells are used in bone marrow transplants and gene therapies to treat numerous blood disorders.
Image Credit: UZH
Scientific Frontline: Extended "At a Glance" Summary: Blood Stem Cell Transplantation and aPC Signaling
The Core Concept: Blood stem cells, which reside in the bone marrow and continually renew the body's blood and immune systems, can have their regenerative capabilities preserved and enhanced prior to transplantation by utilizing a specific protein signaling pathway.
Key Distinction/Mechanism: While both activated protein C (aPC) and the blood-clotting protein thrombin trigger the same cellular receptor (protease-activated receptor 1, or PAR1), they produce opposite effects; aPC maintains the stem cells in a protected, resting state known as quiescence, whereas thrombin promotes premature cellular differentiation that reduces stem cell potential.
Major Frameworks/Components:
- Hematopoietic Stem Cells: Rare bone marrow cells utilized in clinical transplants and gene therapies to treat blood disorders.
- Protease-Activated Receptor 1 (PAR1): The specific cellular receptor activated by both aPC and thrombin.
- Activated Protein C (aPC): A protein that preserves stem cell quiescence and prevents activation by inflammatory signals.
- Cellular Quiescence: A vital resting state that prevents stem cells from dividing too frequently or differentiating prematurely.
Branch of Science: Regenerative Medicine, Cellular Biology, Hematology
Future Application: A brief, one-hour laboratory treatment of stem cells with aPC prior to gene therapies or bone marrow transplants could significantly improve cell transplantability and long-term blood formation.
Why It Matters: Enhancing the regenerative capacity and engraftment success of transplanted blood stem cells provides a direct pathway to more effective treatments and higher success rates for patients suffering from severe blood disorders.
Gene therapies are used to treat many different blood disorders. However, blood stem cells often fail to achieve their full potential after transplantation. UZH researchers have now explored an alternative signaling pathway that could provide a remedy.
Blood stem cells are rare cells in the bone marrow that produce the blood and immune cells needed throughout life, ensuring that the body's blood and immune systems are renewed. For this reason, they are used in bone marrow transplants and novel gene therapies to treat a range of blood disorders. However, during gene therapy, stem cells must be processed in the laboratory prior to transplantation. This processing can cause them to lose some of their regenerative capacity, reducing the likelihood of a successful overall treatment.
To improve the prospects of these therapies, researchers from the Institute for Regenerative Medicine (IREM) at the University of Zurich sought new signaling pathways to enhance blood stem cell function. They investigated how a protein called activated protein C (aPC) influences human blood stem cells, comparing its effect with that of thrombin—another protein involved in blood clotting that acts via the same cell receptor, protease-activated receptor 1 (PAR1). This work was a collaborative effort between UZH and the University of California, Santa Cruz.
Same receptor, different effect
"Although both molecules activate the same receptor, PAR1, they produce very different outcomes," says first author Simon Pöllmann of the IREM. "We demonstrated that aPC helps blood stem cells remain in a resting, protected state." In this state of rest, known as quiescence, the aPC-treated cells divided less frequently, were less likely to differentiate into specialized blood cells prematurely, and retained the characteristics vital for long-term stem cell function. By contrast, thrombin caused greater cell differentiation, which can diminish stem cell potential.
Notably, treatment with aPC for just one hour improved the transplantability of human blood stem cells. This was demonstrated in an 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 senior author Ute Modlich, a professor in IREM's Gene and Cell Therapy Division. Furthermore, aPC treatment 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 study's results indicate that signal transmission via activated protein C provides a promising strategy for preserving the quality and regenerative capacity of human blood stem cells. Ultimately, the researchers believe this approach could improve the success rates of stem cell transplants and gene therapies, delivering substantial benefits to patients with blood disorders.
Published in journal: Embo Molecular Medicine
Title: Activated protein C promotes hematopoietic stem and progenitor cell quiescence and engraftment
Authors: Simon J Pöllmann, Marcel G E Rommel, Leal Oburoglu, Tanja Hirch, Fabiola Valdivia-Francia, Kah Mun Siow, Timon Menzi, Julia Ackva, Franziska Schenk, Matthias J Neeracher, Ataman Sendoel, Janine Reichenbach, E Camilla Forsberg, and Ute Modlich
Source/Credit: Universität Zürich
Edited by: Scientific Frontline
Reference Number: med100926_01