Faster Bone Regeneration With a Little Wnt

Nick Evans and his colleagues at the University of Southampton, UK have discovered that transient stimulation of the Wnt signaling pathway in bone marrow stem cells expands them and enhances their bone-making ability. This finding has led to an intense search for drugs that can stimulate the Wnt pathway in order to stimulate bone formation in wounded patients.

The Wnt pathway is a highly conserved pathway found in sponges, starfish, sharks, and people. Wnt signaling controls pattern formation during development, and the growth of stem cells during healing.

When it comes to healing, bone fractures represent a sizeable societal problem, particularly among the aged. While most fractures heal on their own, approximately 10 percent of all fractures take over six months to heal or never heal at all. In the worse cases, fracture patients can require several surgeries or might need amputation in desperate cases.

According the Evans, he and his research group are screening a wide range of chemicals to determine if they stimulate Wnt signaling. If such chemicals prove safe to use in laboratory animals, then they might become clinical tools to help stimulate bone formation and healing in patients with recalcitrant fractures.

Research from Evans’ group has shown that transient stimulation of the Wnt signaling pathway in isolated bone marrow cells increases the number of bone-making progenitor cells. However, if the Wnt pathway is activated for too long a time period, this regenerative effect is lost or even reversed. Hence the need to develop treatments that deliver small molecules that stimulate Wnt signaling in bone marrow cells for a specified period of time and in a targeted fashion.

Evans and his group have used nanoparticles loaded with Wnt proteins to do exactly that. The feasibility of this technology and its effectiveness requires further work, but the promise is there and the idea is more than a little intriguing.

A Molecular Switch that Causes Stem Cell Aging

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.

Crystal structure of XWnt8
Crystal structure of XWnt8

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).

Canonical Wnt signaling

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.

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.