title: Endothelium-targeted Delta-like 1 promotes hematopoietic stem cell expansion ex vivo and engraftment in hematopoietic tissues in vivo.
abstract: BACKGROUND
  Notch ligands enhance ex vivo expansion of hematopoietic stem cells (HSCs). But to use Notch ligands in HSC therapies of human diseases, efforts are required to improve ex vivo expansion efficiency and in vivo transplant engraftment.
  
  
  METHODS
  We designed and produced an endothelium-targeted soluble Notch ligand, the DSL domain of Delta-like 1 fused with a RGD motif (D1R), and examined the effects of this protein on HSCs ex vivo and in vivo.
  
  
  RESULTS
  D1R efficiently promoted ex vivo expansion of both mouse bone marrow (BM) and human umbilical cord blood HSCs. HSCs expanded with D1R up-regulated many of the stemness-related genes, and showed high BM engraftment efficacy with long-term repopulation capacity after transplantation. Moreover, in vivo administration of D1R increased the number of BM HSCs in mice, and facilitated BM recovery of mice after irradiation. Injection of D1R significantly improved HSC engraftment and myeloid recovery after BM transplantation in irradiated mice. D1R enhanced HSC engraftment not only in BM, but also in the liver and spleen after BM transplantation in mice. D1R induced the formation of compact cell clusters containing the transplanted HSCs in close contact with endothelial cells, reminiscent of HSC niches, in the liver and spleen.
  
  
  CONCLUSIONS
  D1R might be applied in improving both HSC expansion ex vivo and HSC engraftment in vivo in transplantation.
authors.affiliation: Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Deng-Mei
authors.initials: DM
authors.lastname: Tian
authors.forename: Liang
authors.initials: L
authors.lastname: Liang
authors.forename: Xing-Cheng
authors.initials: XC
authors.lastname: Zhao
authors.forename: Min-Hua
authors.initials: MH
authors.lastname: Zheng
authors.forename: Xiu-Li
authors.initials: XL
authors.lastname: Cao
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Qin
authors.forename: Chun-Mei
authors.initials: CM
authors.lastname: Wang
authors.forename: Ying-Min
authors.initials: YM
authors.lastname: Liang
authors.forename: Hua
authors.initials: H
authors.lastname: Han
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D004727:Endothelium / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins