Wnt-5A augments repopulating capacity and primitive hematopoietic development of human blood stem cells in vivo.
Human hematopoietic stem cells are defined by their ability to repopulate multiple hematopoietic lineages in the bone marrow of transplanted recipients and therefore are functionally distinct from hematopoietic progenitors detected in vitro. Although factors capable of regulating progenitors are well established, in vivo regulators of hematopoietic repopulating function are unknown. By using a member of the vertebrate Wnt family, Wnt-5A, the proliferation and differentiation of progenitors cocultured on stromal cells transduced with Wnt-5A or treated with Wnt-5A conditioned medium (CM) was unaffected. However, i.p. injection of Wnt-5A CM into mice engrafted with human repopulating cells increased multilineage reconstitution by >3-fold compared with controls. Furthermore, in vivo treatment of human repopulating cells with Wnt-5A CM produced a greater proportion of phenotypically primitive hematopoietic progeny that could be isolated and shown to possess enhanced progenitor function independent of continued Wnt-5A treatment. Our study demonstrates that Wnt-5A augments primitive hematopoietic development in vivo and represents an in vivo regulator of hematopoietic stem cell function in the human. Based on these findings, we suggest a potential role for activation of Wnt signaling in managing patients exhibiting poor hematopoietic recovery shortly after stem cell transplantation.
Murdoch
Barbara
B
Robarts Research Institute, Stem Cell Biology and Regenerative Medicine, 100 Perth Drive, London, ON, Canada N6A 5K8.
Chadwick
Kristin
K
Martin
Matthew
M
Shojaei
Farbod
F
Shah
Kavita V
KV
Gallacher
Lisa
L
Moon
Randall T
RT
Bhatia
Mickie
M
D000818:Animals; D002460:Cell Line; D002678:Chimera; D003114:Colony-Forming Units Assay; D006410:Hematopoiesis / Q000187:drug effects* / Q000502:physiology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D014183:Transplantation, Heterologous; D051153:Wnt Proteins; D000071818:Wnt-5a Protein
D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein