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.
Sarah Millar and her team at the Perelman School of Medicine at the University of Pennsylvania have exploited a known property of hair follicle stem cells to restart hair growth in laboratory animals.
The Wnt signaling pathway is an important regulator of hair follicle proliferation, but does not seem to be required for hair follicle survival. Wnt signaling in cells culminated in the activation of a protein called beta-catenin, which goes to the nucleus of the cell and causes changes in gene expression.
Millar and her colleagues disrupted Wnt signaling in laboratory animals by expressed an inhibitor called Dkk1 in hair follicles. Dkk1 expression prevented hair growth, and when the hair follicles were examined, they still had their stem cell populations, but these stem cells were dormant. Removal of Dkk1 resumed Wnt/beta-catenin signaling, and restored hair growth.
Interestingly, Millar’s group found Wnt activity in non-hairy regions of the skin, such as palms, soles of feet, and so on. Therefore, in order for Wnt signaling to induce hair growth, it must occur within specific cell types.
This work also has additional applications: skin tumors often show over-active beta-catenin. Removing beta-catenin could prevent the growth of skin tumors, just as removing beta-catenin in the skin of these mice prevented proliferation of any hair follicles. However, agents that can activate beta-cateinin in hair follicles could reactivate dormant hair follicles and induce new hair growth.
Finding ways to safely reactivating the Wnt pathway in particular cells in the skin is a major focus of Millar’s research group. Such work may lead to treatments for male pattern baldness.
An improved method to produce heart muscle from embryonic stem cells or induced pluripotent stem cells could potentially fulfill the demand for heart disease treatments and models of testing new heart drugs. The challenging part of making heart muscle in the laboratory is the production of cells that are all the same. Otherwise their response to drugs or their transplantation into a damaged heart will be unpredictable and unreliable. Fortunately a new study published in the journal STEM CELLS Translational Medicine may provide a way to make large, homogeneous batches of heart muscle cells.
By mixing some small molecules and growth factors together, an international research team led by investigators at the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai developed a two-step system that induced embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) to efficiently differentiate into ventricular heart muscle cells. This protocol was not only highly efficient but also very reproducible. It also seemed to nicely recapitulate the developmental steps of normal heart development.
“These chemically induced, ventricular-like cardiomyocytes (termed ciVCMs) exhibited the expected cardiac electrophysiological and calcium handling properties as well as the appropriate heart rate responses,” said lead investigator Ioannis Karakikes, Ph.D., of the Stanford University School Of Medicine, Cardiovascular Institute. Other members of this research team consisted of scientists from the Icahn School of Medicine at Mount Sinai, New York, and the Stem Cell & Regenerative Medicine Consortium at the University of Hong Kong.
One of the unusual aspects of this research project was the integrated approach it took. This research group combined computational and experimental systems and by using these techniques, they showed that the use of particular small molecules modulated the Wnt pathway. Signals from the Wnt pathway pass from cell to cell and play a key role in determining whether cells differentiate into an atrial or ventricular muscle cell.
“The further clarification of the molecular mechanism(s) that underlie this kind of subtype specification is essential to improving our understanding of cardiovascular development. We may be able to regulate the commitment, proliferation and differentiation of pluripotent stem cells into heart muscle cells and then harness them for therapeutic purposes,” Dr. Karakikes said.
“Most cases of heart failure are related to a deficiency of heart muscle cells in the lower chambers of the heart,” said Anthony Atala, MD, editor of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine. “An efficient, cost-effective and reproducible system for generating ventricular cardiomyocytes would be a valuable resource for cell therapies as well as drug screening.”