The study is expected to help in the search for therapeutic strategies to slow or reverse the aging process, and possibly rejuvenate these critically important stem cells (called hematopoietic stem cells, or HSCs), said scientists from Cincinnati Children's Hospital Medical Center and the University of Ulm in Germany who conducted study.
Published online Oct. 20, the study builds on earlier research from the same scientific team, who in 2012 reported they could make aging HSCs from laboratory mice functionally younger.
Properly functioning HSCs – which form in the bone marrow – are vital to the ongoing production of different types of blood cells that allow the immune system to fight infections. The cells are also important for the regeneration of other important cells in the body.
"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," said Hartmut Geiger, PhD, senior investigator and a scientist at Cincinnati Children's and the University of Ulm. "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 is called the Wnt signaling pathway, a very important part of basic cell biology that regulates communications and interactions between cells in animals and people. Disruptions in the pathway have been linked to problems in tissue generation, development and a variety of diseases.
Analyzing mouse models and HSCs in laboratory cultures, the scientists observed in aging cells that a normal pattern of Wnt signaling (referred to in science as canonical) switched over to an atypical mode of activity (called non-canonical). They also noticed that the shift from canonical to non-canonical signaling was triggered by a dramatic increase in the expression of a protein in aged HSCs called Wnt5a.
When the researchers decided to test this observation by intentionally increasing the expression of Wnt5 in young HSCs, the cells began to exhibit aging characteristics.
Interestingly, the dramatic increase of Wnt5a in aged HSCs activated another protein called Cdc42, which turned out to be critical to stem cell aging. Cdc42 is the same protein the scientists targeted in their 2012 study. In that study, the authors showed that pharmacologically inhibiting Cdc42 reversed the aging process and rejuvenated HSCs to be functionally younger.
The researchers decided that for the current study, they would conduct experiments to see how blocking Wnt5a would affect HSC aging. To do so, they deleted Wnt5a from the HSCs of mice. They also bred mice to lack two functioning copies of the Wnt5a gene, which in essence blocked the protein's function in the HSCs of those animals. Deleting Wnt5 from cells functionally rejuvenated the HSCs. In mice bred to lack two functioning copies of the Wnt5a gene, the animals exhibited a delayed aging process in blood forming stem cells.
Although the study significantly expands what is known about the molecular causes of HSC aging, the authors emphasized more research is needed before knowing how the findings might become therapeutically relevant to people.
For one, researchers need to determine if increased Wnt5a expression is triggered from inside or outside of blood stem cells. Additionally, finding or developing a pharmacologic agent capable of blocking Wnt5a may be difficult because of how the protein functions.
Still, by tracking the causes of HSC aging back to an unexpected molecular switch in a fundamentally important pathway such as Wnt pathway, Geiger said researchers have pushed science much closer to understanding a critical part of getting older. Eventually, the scientists hope their work will lead to strategies for helping the elderly boost their immune systems, fight illnesses and enhance overall vitality.
Among the collaborators on the study was first author, Maria Carolina Florian, PhD, University of Ulm (Department of Dermatology and Allergic Diseases). Geiger is with the Division of Experimental Hematology/Cancer Biology at Cincinnati Children's and the Department of Dermatology and Allergic Diseases at the University of Ulm. Also collaborating were: Karin Dorr, Gina Marka, Bettina Ueberle, Virag Vas, Karin Scharffetter-Kochanek, Hans Armin Kestler (University of Ulm); Christina Eckl, Immanuel Andrä, Matthias Schiemann, Robert A. Oostendorp (Technische Universität Munchen, Germany); Yi Zheng, Kalpana J. Nattamai (Cincinnati Children's).
Work in the Geiger laboratory is supported by the Deutsche Forschungsgemeinschaft (KFO 142, GE2063/1, SFB1074), the German Federal Ministry of Education and Research, the Baden-Württemberg Foundation, National Institute of Health, (HL076604, DK077762, AG040118), the Edward P. Evans Foundation, the European Commission (FP7 Marie Curie Initial Training Network) and the Bausteinprogramm of the Department of Medicine, University of Ulm.
About Cincinnati Children's
Cincinnati Children's Hospital Medical Center ranks third in the nation among all Honor Roll hospitals in U.S. News and World Report's 2013 Best Children's Hospitals ranking. It is ranked #1 for cancer and in the top 10 for nine of 10 pediatric specialties. Cincinnati Children's, a non-profit organization, is one of the top three recipients of pediatric research grants from the National Institutes of Health, and a research and teaching affiliate of the University of Cincinnati College of Medicine. The medical center is internationally recognized for improving child health and transforming delivery of care through fully integrated, globally recognized research, education and innovation. Additional information can be found at http://www.cincinnatichildrens.org. Connect on the Cincinnati Children's blog, via Facebook and on Twitter.
Jim Feuer | EurekAlert!
Show me your leaves - Health check for urban trees
12.12.2017 | Gesellschaft für Ökologie e.V.
Liver Cancer: Lipid Synthesis Promotes Tumor Formation
12.12.2017 | Universität Basel
Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...
Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.
To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...
The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.
Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...
With innovative experiments, researchers at the Helmholtz-Zentrums Geesthacht and the Technical University Hamburg unravel why tiny metallic structures are extremely strong
Light-weight and simultaneously strong – porous metallic nanomaterials promise interesting applications as, for instance, for future aeroplanes with enhanced...
An interdisciplinary group of researchers interfaced individual bacteria with a computer to build a hybrid bio-digital circuit - Study published in Nature Communications
Scientists at the Institute of Science and Technology Austria (IST Austria) have managed to control the behavior of individual bacteria by connecting them to a...
11.12.2017 | Event News
08.12.2017 | Event News
07.12.2017 | Event News
12.12.2017 | Earth Sciences
12.12.2017 | Power and Electrical Engineering
12.12.2017 | Life Sciences