The broad, long-term objective of this project is to determine whether transplantation of endothelial progenitor cells (EPCs) can accelerate hematopoietic recovery in vivo. Dose intense radiation and chemotherapy as applied in the treatment of hematologic malignancies commonly result in prolonged cytopenias as a function of bone marrow (BM) suppression. In the setting of cord blood transplantation (CBT) in adults, delayed donor cell engraftment can result in profound and persistent neutropenia, thrombocytopenia and immune suppression leading to increased mortality risk. Since most transplant conditioning regimens involve the administration of myeloablative chemotherapy with or without radiotherapy, we hypothesize that a contributing factor to the delay in hematopoietic recovery post-CBT is the damage incurred by the bone marrow niche (endothelial cells, stromal cells). Since hematopoietic stem and progenitor cells depend upon the BM niche to provide regenerative and proliferative signals, we sought to determine whether therapies aimed at replacing BM niche function could translate into more rapid hematologic recovery in the setting of CB transplantation. Increasing evidence suggests that BM vascular endothelial cells provide proliferative and differentiative signals to hematopoietic stem and progenitor cells in vitro and in vivo. Therefore, we hypothesize that targeted replacement of vascular endothelial cell activity can accelerate hematopoietic recovery in vivo. In order to test this hypothesis in a highly clinically relevant model, we propose the following Specific Aims: 1) Determine whether transplantation of primary fetal blood EPCs can enhance hematopoietic recovery in a murine model of fetal blood transplantation, 2) Determine whether transplantation of human CB EPCs can enhance the homing and engraftment of human CB stem cells in immune deficient mice. Our Preliminary Results indicate that transplantation of primary EPCs alone significantly accelerates endogenous hematopoietic recovery in irradiated mice in both the autologous and allogeneic setting. This proposal provides a novel and potentially potent strategy to accelerate hematologic recovery in recipients of CB transplantation and, more broadly, provides the basis for therapies to replace endothelial cell activity in order to augment hematologic recovery following myelotoxic chemo- or radiotherapy.
Many patients with leukemia and lymphoma who undergo high dose chemotherapy and radiotherapy in the treatment of their disease will suffer prolonged suppression of their blood and immune systems, resulting in increased risk of infections, bleeding and hospitalization. Such prolonged depression of the blood and immune systems also commonly occurs in adult patients who undergo cord blood transplantation in the treatment of their disease. We propose that cellular therapy aimed at replacing the activity of vascular endothelial cells in the bone marrow will accelerate blood and immune system recovery in these patients and our preliminary results indicate this strategy is highly effective.
|Himburg, Heather A; Doan, Phuong L; Quarmyne, Mamle et al. (2017) Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms. Nat Med 23:91-99|
|Yan, Xiao; Himburg, Heather A; Pohl, Katherine et al. (2016) Deletion of the Imprinted Gene Grb10 Promotes Hematopoietic Stem Cell Self-Renewal and Regeneration. Cell Rep 17:1584-1594|
|Quarmyne, Mamle; Doan, Phuong L; Himburg, Heather A et al. (2015) Protein tyrosine phosphatase-? regulates hematopoietic stem cell-repopulating capacity. J Clin Invest 125:177-82|
|Himburg, Heather A; Yan, Xiao; Doan, Phuong L et al. (2014) Pleiotrophin mediates hematopoietic regeneration via activation of RAS. J Clin Invest 124:4753-8|
|Doan, Phuong L; Himburg, Heather A; Helms, Katherine et al. (2013) Epidermal growth factor regulates hematopoietic regeneration after radiation injury. Nat Med 19:295-304|
|Doan, Phuong L; Russell, J Lauren; Himburg, Heather A et al. (2013) Tie2(+) bone marrow endothelial cells regulate hematopoietic stem cell regeneration following radiation injury. Stem Cells 31:327-37|
|Himburg, Heather A; Harris, Jeffrey R; Ito, Takahiro et al. (2012) Pleiotrophin regulates the retention and self-renewal of hematopoietic stem cells in the bone marrow vascular niche. Cell Rep 2:964-75|
|Himburg, Heather A; Muramoto, Garrett G; Daher, Pamela et al. (2010) Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells. Nat Med 16:475-82|