title: Megakaryocytes promote murine osteoblastic HSC niche expansion and stem cell engraftment after radioablative conditioning.
abstract: Successful hematopoietic stem cell (HSC) transplantation requires donor HSC engraftment within specialized bone marrow microenvironments known as HSC niches. We have previously reported a profound remodeling of the endosteal osteoblastic HSC niche after total body irradiation (TBI), defined as relocalization of surviving megakaryocytes to the niche site and marked expansion of endosteal osteoblasts. We now demonstrate that host megakaryocytes function critically in expansion of the endosteal niche after preparative radioablation and in the engraftment of donor HSC. We show that TBI-induced migration of megakaryocytes to the endosteal niche depends on thrombopoietin signaling through the c-MPL receptor on megakaryocytes, as well as CD41 integrin-mediated adhesion. Moreover, niche osteoblast proliferation post-TBI required megakaryocyte-secreted platelet-derived growth factor-BB. Furthermore, blockade of c-MPL-dependent megakaryocyte migration and function after TBI resulted in a significant decrease in donor HSC engraftment in primary and competitive secondary transplantation assays. Finally, we administered thrombopoietin to mice beginning 5 days before marrow radioablation and ending 24 hours before transplant to enhance megakaryocyte function post-TBI, and found that this strategy significantly enhanced donor HSC engraftment, providing a rationale for improving hematopoietic recovery and perhaps overall outcome after clinical HSC transplantation.
authors.affiliation: Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104. , USA.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Olson
authors.forename: Anna
authors.initials: A
authors.lastname: Caselli
authors.forename: Satoru
authors.initials: S
authors.lastname: Otsuru
authors.forename: Ted J
authors.initials: TJ
authors.lastname: Hofmann
authors.forename: Richard
authors.initials: R
authors.lastname: Williams
authors.forename: Paolo
authors.initials: P
authors.lastname: Paolucci
authors.forename: Massimo
authors.initials: M
authors.lastname: Dominici
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Horwitz
mesh_terms: D000818:Animals; D000077214:Becaplermin; D002465:Cell Movement / Q000502:physiology / Q000528:radiation effects; D049109:Cell Proliferation; D004730:Endothelium, Vascular; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000528:radiation effects; D008533:Megakaryocytes / Q000166:cytology* / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism / Q000528:radiation effects; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D053628:Receptors, Thrombopoietin / Q000502:physiology*; D015398:Signal Transduction; D055153:Stem Cell Niche / Q000502:physiology*; D013926:Thrombopoietin / Q000378:metabolism; D014916:Whole-Body Irradiation
chemical_list: C481270:Mpl protein, mouse; D020574:Proto-Oncogene Proteins c-sis; D053628:Receptors, Thrombopoietin; D000077214:Becaplermin; D013926:Thrombopoietin