Identification of a molecular1 communications pathway that influences the mobilization of hematopoietic(造血的) (blood) stem cells could lead to targeted therapies for improving bone marrow2(骨髓) transplant success rates. In a bed-side to bench approach, researchers at Cincinnati Children's Hospital Medical Center report Sept. 26 in Nature Medicine that pharmacological(药理学的) inhibition of a signaling pathway triggered by Egfr (epidermal growth factor表皮生长因子 receptor) increased the mobilization of hematopoietic stem cells in mice. The finding provides a scientific basis for enhancing the effectiveness of autologous(自体的) bone marrow transplants, in which the recipient3 donates his or her own stem cells prior to the procedure.
"Up to 10 percent of bone marrow donors4 fail to mobilize sufficient numbers of stem cells, which impedes5(阻碍,妨碍) 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 investigator6 on the study. "Our findings reveal a new rationale(基本原理) 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 peripheral7(外围的,次要的) circulating blood is by targeting a signaling protein called granulocyte(粒细胞) colony stimulating8 factor, or G-CSF. G-CSF stimulates9 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 therapeutic10 targets that would boost stem cell mobilization. They work with specially11 bred mice (recombinant inbred天生的,近亲交配的 mice) in their research because much of the current knowledge about cellular12 and molecular regulation of G-CSF-induced stem cells comes from mouse studies. Because the G-CSF process that mobilizes hematopoietic stem and progenitor13(祖先,起源) cells is conserved14 through evolution between mice and humans, inbred mouse strains are valuable surrogates(代理) for studies that can be translated to people.
Working from their previously15 published research, the scientists were able track a region on chromosome16 11 in their mouse models that regulates G-CSF-induced mobilization of HSCs. Of 12 genes17 located in this region, testing pointed18 to Egfr, which is a protein involved in triggering molecular reactions that regulate cell growth, multiplication19 and migration20. 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 genetic21 manipulation and pharmacologic intervention22. 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."