A study from the Cincinnati Children’s Hospital Medical Center, in collaboration with the University of Ulm in Germany has discovered a molecular switch that causes the aging of blood stem cells. This same work suggests a therapeutic strategy to delay stem cell aging.
Hematopoietic stem cells (HSCs) reside in the bone marrow and make all the red and white blood cells that populate the bloodstream. Proper HSC function is absolutely vital to the ongoing production of different types of blood cells that allow the immune system to fight infections and organs to receive adequate quantities of oxygen.
Hartmut Geiger from the Cincinnati Children’s Hospital Medical Center and the University of Ulm was the senior researcher on this project. Dr. Geiger said, “Although there is a large amount of data showing that blood stem cell function declines during aging, the molecular processes that cause this remain largely unknown. This prevents rational approaches to attenuate stem cell aging. This study puts us significantly closer to that goal through novel findings that show a distinct switch in a molecular pathway is very critical to the aging process.”
The pathway to which Dr. Geiger referred is the Wnt signaling pathway, which plays a foundational role in animal development, cell-cell communication, tissue generation, and is also involved in the pathology of various diseases.
Analysis of mouse models and cultured HSCs showed that under normal conditions, Wnt signaling in HSCs occurred through the so-called “canonical” Wnt signaling pathway. The canonical Wnt signaling pathway utilizes the typical components of Wnt signaling that were first identified in the fruit fly and then isolated and characterized in vertebrates (shown below).
However, Wnt proteins can also signaling through other, distinct signal transduction pathways, and these types of pathways are collectively known as “noncanonical” Wnt signaling pathway. In aging HSCs, a switch from canonical Wnt signaling to noncanonical Wnt signaling marked the onset of HSC aging. See below for one example of non-canonical Wnt signaling.
To test this observation, Geiger’s group overexpressed Wnt5 in HSCs (a Wnt protein known to induced signaling through noncanonical Wnt signaling pathways), and immediately, the HSCs began to show the signs of aging.
One of the targets of Wnt5 signaling is a protein called Cdc42, which influences the cytoskeleton of cells. Therefore, Geiger and his crew asked if Cdc42 was activated in those HSCs that overexpressed Wnt5. The answer to this question was a clear “yes.” Then they treated cultured HSCs with a molecule that inhibited Cdc42 activity. This treatment reversed the aging process in HSCs.
To test their hypothesis in a living animal, Geiger and others removed a copy of the Wnt5 gene from HSCs in laboratory mice. Mice that lacked functional Wnt5 protein in HSCs, showed rejuvenation of the aged HSCs. Mice that lacked both copies of the Wnt5 gene showed a delayed aging process in their HSCs.
Even though this study has definitely made an important contribution to understanding HSC aging, more work is needed before a therapeutic strategy is in place.