2013 Winner: A Novel Method to Mobilize Stem Cells for Transplantation in Cancer Therapies

Project Information
A Novel Method to Mobilize Stem Cells for Transplantation in Cancer Therapies
Engineering
BME 195: Senior Thesis Research; The Forsberg Laboratory
Patients with life-threatening cancers of the blood or bone marrow and no response to chemotherapy can receive hematopoietic stem cell (HSC) transplantations. A crucial procedure in transplantation therapy is mobilizing HSCs from the bone marrow niches to the peripheral blood of the cell donor for harvest. The common mobilization procedure using the granulocyte-colony stimulating factor (G-CSF) poses two challenges: the treatment requires four to six days and does not elicit a response in every donor. However, AMD3100, a small-molecule inhibitor of the Cxcr4 transmembrane receptor, has recently been shown to induce rapid mobilization within hours. In previous studies, our research group showed that two receptors—Cxcr4 and Robo4—cooperate to mediate homing of HSCs from the peripheral blood to the bone marrow. In this study, we demonstrate that Slit2, the putative ligand of the Robo4 surface receptor, in combination with AMD3100, more efficiently mobilizes HSCs and progenitors from the bone marrow and into the peripheral blood than does AMD3100 alone. In treatments with Slit2 in combination with AMD3100, marked increases in the numbers of multipotent progenitors (MPPs) and common myeloid progenitors (CMPs) in the peripheral blood indicate more efficient mobilization, whereas a marked increase in the number of HSCs in the peripheral blood confirms the roles of Cxcr4 and Robo4 in the homing of HSCs. We propose that co-mobilization by Slit2 and AMD3100 potentially provides a safer and more efficient alternative to common mobilization procedures in treatments for cancers of the blood and bone marrow.

Abstract in non-technical language:
Patients with life-threatening cancers of the blood or bone marrow and no response to chemotherapy can receive transplantations of hematopoietic stem cells (HSCs), which are the rescuing cells in bone marrow transplants. Residing in microenvironments in the bone marrow, HSCs give rise to all blood cells throughout life. A crucial procedure in HSC transplantations is their movement from these microenvironments in the bone marrow to the peripheral blood of the cell donor. These HSCs in the donor’s blood are then collected and transplanted into a patient (who can donate cells to oneself) who has undergone radiation and chemotherapy. Called cell mobilization, the common procedure uses a growth factor, called the granulocyte-colony stimulating factor (G-CSF). Treating donors with G-CSF poses two challenges: the treatment requires four to six days and does not elicit a response in every donor. However, AMD3100, a chemical compound that blocks the Cxcr4 receptor on the surface of an HSC, has recently been shown to induce rapid mobilization within hours. In previous studies, our research group showed that two receptors on the surfaces of cells—Cxcr4 and Robo4—cooperate to guide HSCs from the peripheral blood, back to their microenvironments in the bone marrow. Slit2 is a protein that is hypothesized to interact with the Robo4 receptor. In this study, we demonstrate that when combined with the AMD3100 molecule, Slit2 more efficiently mobilizes HSCs and other multipotent blood cells from the bone marrow to the peripheral blood than does AMD3100 alone. In treatments with Slit2 in combination with AMD3100, marked increases in the numbers of multipotent blood cells in the peripheral blood indicate more efficient cell mobilization, whereas a marked increase in the number of HSCs in the peripheral blood confirms previous findings about the roles of Cxcr4 and Robo4 in guiding HSCs to the bone marrow. We propose that co-mobilization by Slit2 and AMD3100 potentially provides a safer and more effective alternative to common mobilization procedures in treatments for cancers of the blood and bone marrow.
Students
  • Herman K Tsang (Eight)
Mentors