Fms-related tyrosine kinase 3 expression discriminates hematopoietic stem cells subpopulations with differing engraftment-potential: Identifying the most potent combination

Yiming Huang, Mariusz Z. Ratajczak, Ryan Reca, Hong Xu, Michael Tanner, Francine Rezzoug, Lala Rukh Hussain, Isabelle Fugier-Vivier, Roberto Bolli, Suzanne T. Ildstad

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND. Fms-related tyrosine kinase 3 (Flt3)-ligand (FL) promotes the proliferation, differentiation, development, and mobilization of hematopoietic cells. We previously found that FL-mobilized hematopoietic stem cells (HSC) engraft efficiently, whereas FL-expanded bone marrow HSC do not. The function of FL-mobilized c-Kit Sca-1Lin (KSL) subpopulations has not been systematically evaluated. A precise definition of the repopulating ability is needed to define which HSC subpopulations are critical for long-term chimerism and tolerance induction. FL significantly mobilized c-Kit and c-Kit Sca-1Lin cells into peripheral blood (PB). Here, we evaluated the influence of Flt3 expression on long-term repopulating ability of HSC subpopulations. METHODS. c-Kit or c-Kit KSL cells were sorted from PB of FL-treated green fluorescent protein-positive donors. The function of these cells was evaluated using competitive reconstitution assays, colony-forming units spleen, and colony forming cell assays. The function of c-Kit CD34Flt3 KSL, c-Kit CD34Flt3 KSL, c-Kit CD34Flt3 KSL were investigated in an in vivo transplantation model. RESULTS. Only FL-mobilized PB c-Kit KSL cells exhibited high spleen colony-forming unit activity, generated high numbers of both lymphoid and myeloid colonies in vitro, and rescued ablated recipients. FL-mobilization expanded both c-Kit CD34Flt3 cells (short-term HSC) and c-Kit CD34Flt3 KSL cells (long-term HSC). There was a significant decrease in c-Kit CD34Flt3 KSL late multipotent progenitors in PB. A combination of c-Kit CD34Flt3 and c-Kit CD34Flt3 KSL cells offered the most effective rescue of ablated recipients. CONCLUSIONS. These data suggest that engraftment of purified HSC is influenced by both short- and long-term repopulating populations and that Flt3 expression may be useful for selecting the most critical HSC subpopulations for transplantation.

Original languageEnglish (US)
Pages (from-to)1175-1184
Number of pages10
JournalTransplantation
Volume85
Issue number8
DOIs
StatePublished - Apr 2008

Keywords

  • Flt3-ligand
  • Hematopoietic stem cells
  • Mobilization
  • Transplantation

ASJC Scopus subject areas

  • Transplantation

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