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Clarification of stem cell migration – hope for more effective bone marrow transplants

Researchers from the University of Ulm, Germany, and the Cincinnati Children’s Hospital Medical Center, USA, have shown that pharmacological inhibition of a signalling pathway triggered by EGFR (epidermal growth factor receptor) increased the mobilisation of haematopoietic stem cells in mice.

The finding provides a scientific basis for enhancing the effectiveness of autologous bone marrow transplants. After eight years of research, the group of researchers has now reported their findings in the renowned journal “Nature Medicine”. The researchers Hartmut Geiger and Deidre Daria (MS) from Ulm University were involved in the international research project. Hartmut Geiger recalls the project as a “long, arduous though rewarding road” and sees it as an excellent example of how basic research results can be translated into targeted therapies for the benefit of patients.

Prof. Hartmut Geiger and Deidre Daria from the Department of Dermatology and Allergic Diseases at Ulm University Hospital © University of Ulm

Bone marrow transplant is often used to restore a person's haematologic system after they have undergone chemotherapy for cancer treatment. The patient is transplanted his or her own stem cells removed prior to the transplant or stem cells of a healthy donor. However, many bone marrow donors fail to mobilise sufficient numbers of stem cells, which delays recovery rates. G-CSF (granulocyte colony stimulating factor) stimulates bone marrow to release haematopoietic stem cells (HSC) into circulating peripheral blood. These vital cells can then be recovered by way of haemodialysis. However, despite the administration of G-CSF, up to 10 per cent of bone marrow donors failed to mobilise sufficient numbers of stem cells. Delayed recovery and mobilisation failures suggested the need for a deeper understanding of the molecular processes of stem cell mobilisation and modulation in order to improve the treatment.

Breakthrough with EGF receptor

The researchers used recombinant inbred mice in their research to find out which gene region accounted for differences in G-CSF-induced HSC mobilisation. The administration of EGF (a protein located in the cell membrane) eventually led to an experimental breakthrough: “The activation of the EGF receptor leads to the inhibition of G-CSF-induced stem cell migration,” explains Hartmut Geiger. The pharmacological intervention of EGFR-induced signalling enhanced HSC migration. The researchers used an anti-cancer drug (Erlotinib) that blocks the EGFR pathway to enhance HSC mobilisation in mice, and the mice subsequently experienced a five-fold increase in stem cell mobilisation.

Because the G-CSF process has been conserved during evolution by both mice and humans, results obtained with inbred mouse strains can be translated to people. The researchers are therefore hoping that their findings can be applied in the clinic. However, tests with human stem cells will be carried out on mice, before studies involving patients are initiated.

Other institutions collaborating in 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., USA; Department of Internal Medicine, Markey Cancer Center, Division of Hematology/Oncology, University of Kentucky, Lexington, Ky., USA and the Hoxworth Blood Center, University of Cincinnati College of Medicine, USA.

Basic research is now bearing fruit

The biochemist and stem cell researcher Hartmut Geiger has been a professor in the life sciences research centre of the “Molecular and Cellular Ageing – from mechanisms of action to clinical perspectives” research group at the University Hospital of Ulm since 2008. Geiger, who is mainly interested in haematopoietic stem cells, previously spent nine years in the USA: after three years as postdoctoral researcher at one of the world’s leading stem cell laboratories in Lexington/Kentucky he became assistant professor at the Cincinnati Children’s Hospital in the Medical Center of the Cincinnati Children's Research Foundation.

Marnie A Ryan, Kalpana J Nattamai, Ellen Xing, David Schleimer, Deidre Daria, Amitava Sengupta, Anja Köhler, Wei Liu, Matthias Gunzer, Michael Jansen, Nancy Ratner, Timothy D Le Cras, Amanda Waterstrat, Gary Van Zant, Jose A Cancelas, Yi Zheng & Hartmut Geiger: Pharmacological inhibition of EGFR signaling enhances G-CSF-induced hematopoietic stem cell mobilization, Nature Medicine (2010) doi:10.1038/nm.2217

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