In a bed-side to bench approach, researchers at Cincinnati Children's Hospital Medical Center report Sept. 26 in Nature Medicine that pharmacological inhibition of a signaling pathway triggered by Egfr (epidermal growth factor receptor) increased the mobilization of hematopoietic stem cells in mice. The finding provides a scientific basis for enhancing the effectiveness of autologous bone marrow transplants, in which the recipient donates his or her own stem cells prior to the procedure.
"Up to 10 percent of bone marrow donors fail to mobilize sufficient numbers of stem cells, which impedes autologous transplants and significantly delays transplant recovery time," said Hartmut Geiger, Ph.D., a researcher in the division of Experimental Hematology/Cancer Biology at Cincinnati Children's and senior investigator on the study. "Our findings reveal a new rationale for targeted pharmacological approaches to improve stem cell mobilization and transplantation outcomes."
Autologous bone marrow transplant is often used to restore a person's hematologic system after receiving radiation therapy for cancer treatment. Radiation exposure damages the system, which produces all of the body's blood cell types – including those vital to immune system function.
In clinical hematopoietic stem cell (HSC) transplants, the preferred source for mobilizing hematopoietic stem cells from bone marrow into peripheral circulating blood is by targeting a signaling protein called granulocyte colony stimulating factor, or G-CSF. G-CSF stimulates bone marrow so that it releases HSCs into circulating peripheral blood. Mobilization failures and delayed recovery rates suggest the need for a deeper molecular understanding of the mobilization process to further improve the treatment.
This prompted Dr. Geiger and his colleagues to search for therapeutic targets that would boost stem cell mobilization. They work with specially bred mice (recombinant inbred mice) in their research because much of the current knowledge about cellular and molecular regulation of G-CSF-induced stem cells comes from mouse studies. Because the G-CSF process that mobilizes hematopoietic stem and progenitor cells is conserved through evolution between mice and humans, inbred mouse strains are valuable surrogates for studies that can be translated to people.
Working from their previously published research, the scientists were able track a region on chromosome 11 in their mouse models that regulates G-CSF-induced mobilization of HSCs. Of 12 genes located in this region, testing pointed to Egfr, which is a protein involved in triggering molecular reactions that regulate cell growth, multiplication and migration. Mutations in Egfr have also been linked to cancer.
The researchers tested the G-CSF/Egfr pathway's influence on stem cell mobilization in several ways, including genetic manipulation and pharmacologic intervention. In one key experiment, involving mice undergoing bone marrow transplant, the researchers used an anti-cancer drug (Erlotinib) that blocks the Egfr pathway to enhance HSC mobilization. These mice experienced a 5-fold increase in stem cell mobilization.
"This suggests a possible application of these findings into the clinic," Dr, Geiger said. "Experiments are already planned to test whether this novel treatment for enhancing HSC mobilization might translate into novel therapies for patients."
First author on the study was Marnie A. Ryan, a research fellow of Dr. Geiger's laboratory team.
Funding support came from the National Institute of Health (NIH) through multiple grants and the Translational Research Initiative at Cincinnati Children's Hospital Medical Center.
Other institutions collaborating on the study include: the department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany; Institute of Molecular and Clinical Immunology, Otto von Guericke University, Magdeburg, Germany; department of Biological Sciences, Eastern Kentucky University, Richmond, Ky.; department of Internal Medicine, Markey Cancer Center, Division of Hematology/Oncology, University of Kentucky, Lexington, Ky., and the Hoxworth Blood Center, University of Cincinnati College of Medicine.
About Cincinnati Children's
Cincinnati Children's Hospital Medical Center is one of just eight children's hospitals named to the Honor Roll in U.S. News and World Report's 2010-11 Best Children's Hospitals. It is ranked #1 for digestive disorders and highly ranked for its expertise in pulmonology, cancer, neonatology, heart and heart surgery, neurology and neurosurgery, diabetes and endocrinology, orthopedics, kidney disorders and urology. Cincinnati Children's is one of the top two recipients of pediatric research grants from the National Institutes of Health. It is internationally recognized for quality and transformation work by Leapfrog, The Joint Commission, the Institute for Healthcare Improvement, the federal Agency for Healthcare Research and Quality, and by hospitals and health organizations it works with globally.
Novel mechanisms of action discovered for the skin cancer medication Imiquimod
21.10.2016 | Technische Universität München
Second research flight into zero gravity
21.10.2016 | Universität Zürich
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.
In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...
'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.
Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
21.10.2016 | Health and Medicine
21.10.2016 | Information Technology
21.10.2016 | Materials Sciences