| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 2094615 | Stem Cell Research | 2012 | 10 Pages |
Umbilical cord blood (UCB) transplantation has emerged as a promising therapy, but it is challenged by scarcity of stem cells. Eltrombopag is a non-peptide, thrombopoietin (TPO) receptor agonist, which selectively activates c-Mpl in humans and chimpanzees. We investigated eltrombopag's effects on human UCB hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) expansion, and its effects on hematopoiesis in vivo. Eltrombopag selectively augmented the expansion of human CD45+, CD34+, and CD41+ cells in bone marrow compartment without effects on mouse bone marrow cells in the NOD/SCID mice xenotransplant model. Consequently, eltrombopag increased peripheral human platelets and white blood cells. We further examined effects in the STAT and AKT signaling pathways in serum-free cultures. Eltrombopag expanded human CD34+ CD38−, CD34+, and CD41+ cells. Both eltrombopag and recombinant human TPO (rhTPO) induced phosphorylation of STAT5 of CD34+ CD41−, CD34− CD41+, and CD34− CD41− cells. rhTPO preferentially induced pSTAT3, pAKT, and more pSTAT5 in CD34− C41+ cells, while eltrombopag had no effects on pSTAT3. In conclusion, eltrombopag enhanced expansion of HSCs/HPCs of human UCB in vivo and in vitro, and promoted multi-lineage hematopoiesis through the expansion of bone marrow HSCs/HPCs of human UCB in vivo. Eltrombopag differed somewhat from rhTPO in the signal transduction pathways by favoring earlier HSC/HPC populations.
► Eltrombopag expanded HSC/HPC of human cord blood in bone marrow of NOD/SCID mice. ► Eltrombopag increased human platelets and WBCs in NOD/SCID mouse xenotransplants. ► Both eltrombopag and TPO expanded human cord blood HSC/HPC in serum-free cultures. ► Both eltrombopag and TPO activated STAT 5 pathway of HSC/HPC of human cord blood. ► In contrast to TPO, eltrombopag lacked activation of STAT3 and AKT of HSC/HPC.
