title: Erythropoietin modulation is associated with improved homing and engraftment after umbilical cord blood transplantation.
abstract: Umbilical cord blood (UCB) engraftment is in part limited by graft cell dose, generally one log less than that of bone marrow (BM)/peripheral blood (PB) cell grafts. Strategies toward increasing hematopoietic stem/progenitor cell (HSPC) homing to BM have been assessed to improve UCB engraftment. Despite recent progress, a complete understanding of how HSPC homing and engraftment are regulated is still elusive. We provide evidence that blocking erythropoietin (EPO)-EPO receptor (R) signaling promotes homing to BM and early engraftment of UCB CD34+cells. A significant population of UCB CD34+HSPC expresses cell surface EPOR. Exposure of UCB CD34+HSPC to EPO inhibits their migration and enhances erythroid differentiation. This migratory inhibitory effect was reversed by depleting EPOR expression on HSPC. Moreover, systemic reduction in EPO levels by hyperbaric oxygen (HBO) used in a preclinical mouse model and in a pilot clinical trial promoted homing of transplanted UCB CD34+HSPC to BM. Such a systemic reduction of EPO in the host enhanced myeloid differentiation and improved BM homing of UCB CD34+cells, an effect that was overcome with exogenous EPO administration. Of clinical relevance, HBO therapy before human UCB transplantation was well-tolerated and resulted in transient reduction in EPO with encouraging engraftment rates and kinetics. Our studies indicate that systemic reduction of EPO levels in the host or blocking EPO-EPOR signaling may be an effective strategy to improve BM homing and engraftment after allogeneic UCB transplantation. This clinical trial was registered at www.ClinicalTrials.gov (#NCT02099266).
authors.affiliation: Division of Hematologic Malignancies and Cellular Therapy.|Hematology & Transplantation Translational Research Laboratory, and.|Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS.|Division of Hematology/Oncology and Bone Marrow Transplantation Program, University of Rochester Medical Center, Rochester, NY.
authors.forename: Omar S
authors.identifier: 0000-0001-8106-1152
authors.initials: OS
authors.lastname: Aljitawi
authors.affiliation: Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Soumen
authors.identifier: 0000-0002-4278-7329
authors.initials: S
authors.lastname: Paul
authors.affiliation: Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Avishek
authors.initials: A
authors.lastname: Ganguly
authors.affiliation: Division of Hematologic Malignancies and Cellular Therapy.|Hematology & Transplantation Translational Research Laboratory, and.
authors.forename: Tara L
authors.identifier: 0000-0002-0242-6449
authors.initials: TL
authors.lastname: Lin
authors.affiliation: Division of Hematologic Malignancies and Cellular Therapy.
authors.forename: Sid
authors.initials: S
authors.lastname: Ganguly
authors.affiliation: Department of Urology, University of Kansas Medical Center, Kansas City, KS.
authors.forename: George
authors.initials: G
authors.lastname: Vielhauer
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Maegan L
authors.initials: ML
authors.lastname: Capitano
authors.affiliation: Cardiovascular Research Institute.
authors.forename: Amy
authors.initials: A
authors.lastname: Cantilena
authors.affiliation: Division of Hematologic Malignancies and Cellular Therapy.|Hematology & Transplantation Translational Research Laboratory, and.|Division of Hematology/Oncology and Bone Marrow Transplantation Program, University of Rochester Medical Center, Rochester, NY.
authors.forename: Brea
authors.initials: B
authors.lastname: Lipe
authors.affiliation: Department of Biostatistics.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Mahnken
authors.affiliation: Division of Hematologic Malignancies and Cellular Therapy.|Hematology & Transplantation Translational Research Laboratory, and.
authors.forename: Amanda
authors.initials: A
authors.lastname: Wise
authors.affiliation: Division of Hematologic Malignancies and Cellular Therapy.|Hematology & Transplantation Translational Research Laboratory, and.
authors.forename: Abigale
authors.initials: A
authors.lastname: Berry
authors.affiliation: Division of Hematologic Malignancies and Cellular Therapy.
authors.forename: Anurag K
authors.identifier: 0000-0003-1114-9508
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Division of Hematologic Malignancies and Cellular Therapy.
authors.forename: Leyla
authors.initials: L
authors.lastname: Shune
authors.affiliation: Department of Radiation Oncology, and.
authors.forename: Christopher
authors.initials: C
authors.lastname: Lominska
authors.affiliation: Division of Hematologic Malignancies and Cellular Therapy.
authors.forename: Sunil
authors.initials: S
authors.lastname: Abhyankar
authors.affiliation: Department of Emergency Medicine, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Dennis
authors.initials: D
authors.lastname: Allin
authors.affiliation: Cleveland Cord Blood Center, Cleveland, OH; and.|Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH.
authors.forename: Mary
authors.initials: M
authors.lastname: Laughlin
authors.affiliation: Division of Hematologic Malignancies and Cellular Therapy.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: McGuirk
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Hal E
authors.initials: HE
authors.lastname: Broxmeyer
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology; D046528:Chimerism; D015331:Cohort Studies; D036101:Cord Blood Stem Cell Transplantation / Q000009:adverse effects; D004921:Erythropoietin / Q000378:metabolism*; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology; D006801:Humans; D006931:Hyperbaric Oxygenation; D008297:Male; D051379:Mice; D008875:Middle Aged; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism; D016019:Survival Analysis; D019172:Transplantation Conditioning; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018952:Antigens, CD34; D054377:Chemokine CXCL12; D017467:Receptors, Erythropoietin; D004921:Erythropoietin; D051997:ADP-ribosyl Cyclase 1