Erythropoietin modulation is associated with improved homing and engraftment after umbilical cord blood transplantation

Abstract

• EPO-EPOR signaling reduces UCB CD34 1 HSPC engraftment through inhibition of BM homing and enhancement of erythroid differentiation.• When used in clinical UCB transplantation, HBO therapy is safe and reduces EPO serum levels, potentially improving blood count recovery.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. 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 1 HSPC to BM. Such a systemic reduction of EPO in the host enhanced myeloid differentiation and improved BM homing of UCB CD34 1 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). (Blood. 2016;128(25):3000-3010)

Erythropoietin in umbilical cord blood transplantation: defining the role and implications

“…Our findings support a new role for EPO in UCB HSPC differentiation and BM homing, processes that dictate subsequent engraftment outcomes [9]. Approximately 20% of UCB HSPCs express EPOR [9]. Exposing UCB HSPCs to EPO reduced the percentage of UCB HSPCs migrating toward stromal derived factor-1 (SDF-1/CXCL12, a chemokine that mediates HSPC homing to the marrow [5]), an effect reversed by treating the cells with EPO-or EPOR-neutralizing antibodies or by depleting EPOR on HSPC.…”

“…Our findings support a new role for EPO in UCB HSPC differentiation and BM homing, processes that dictate subsequent engraftment outcomes [9]. Approximately 20% of UCB HSPCs express EPOR [9].…”

“…Exposing UCB HSPCs to EPO reduced the percentage of UCB HSPCs migrating toward stromal derived factor-1 (SDF-1/CXCL12, a chemokine that mediates HSPC homing to the marrow [5]), an effect reversed by treating the cells with EPO-or EPOR-neutralizing antibodies or by depleting EPOR on HSPC. We utilized hyperbaric oxygen (HBO) to lower EPO prior to HSPC infusion to study the effects of low EPO on HSPC homing [9] and engraftment in a murine UCB transplantation model [10], and this work was translated to study in human clinical UCB transplantation [9]. In our animal model, HBO significantly reduced EPO and resulted in improved early UCB HSPC BM homing to the marrow [9].…”

Stronger medical links for umbilical cord blood

“…He and his colleagues followed up with a phase 1 pilot study of 15 patients with cancer who received cord blood transplantation after undergoing chemotherapy and radiotherapy to kill off their own bone marrow. Dr. Aljitawi found that exposing them to hyperbaric conditions, using pure oxygen under higher atmospheric pressure, safely reduced their erythropoietin levels . For 48 control patients who received transplantations but no hyperbaric treatment, engraftment required an average of 20.5 days.…”

Long-Overdue Guidelines for the Cord Blood Banking Community

“…This includes the roles of glucocorticosteroids , inhibitors of histone deacetylase (HDAC) 5 , inhibitors of DPP4 in vitro and in vivo in patients using the FDA‐approved orally active DPP4‐inhibitor sitagliptin , combinations of a DPP4 inhibitor plus prostaglandin (PG)E , and short‐term exposure of cells to mild heat (39°C) exposure . Treatment of recipients undergoing CB HCT has also used hyperbaric chambers . All of the above‐described laboratory/clinical procedures, as well as those noted in my reviews , can be used alone to enhance preclinical/clinical CB HCT of human cells, but there is no reason that they cannot also be used in combination in sequence as noted in Figure , efforts currently ongoing in the laboratory, to see if such sequential combinations can more effectively enhance the efficacy of the CB cells for HCT than each single procedure.…”