Role of Hematopoietic Growth Factors on the ex Vivo Expansion of Primitive Cord Blood Stem Cells

Ex vivo expansion of hematopoietic cells has recently been suggested for clinical application.1.2 It has been demonstrated that hematopoietic compartments derived from human bone marrow (BM), mobilized peripheral blood (PB) or umbilical cord blood (CB) cells can be maintained and expanded in liquid culture or stroma coculture systems by the provision of combinations of growth factors.3–5 The potential benefits of such studies include accelerated engraftment, reduced risk of infection, smaller stem cell harvests, and improved effectiveness of genetically modified stem cells.1.2 Although controversies remain concerning what defined populations may or may not be useful for improving in vivo hematologic recovery, ex vivo expansion can only be considered successful when progeny receptor cells retain both pluripotent differentiation and self-renewal capacities of the original stem cells.4 In other words, are the various growth factor combinations able to amplify the late progenitor reservoir without exhausting the stem cell pool, in order to ensure long-term post-transplantation engraftment after a myeloablative conditioning regimen? Human culture systems employing Interleukin 3 (IL3) or Granulocyte-Colony Stimulating Factor (G-CSF) maintain at least some primitive cells;6–9 however, achieving a net expansion of early cells has proven elusive, although some laboratories have reported encouraging results.10–12 With the discovery of new growth factors, specific for early progenitor cells, investigators have re-examined the possibility of expanding stem cells in vitro. In particular, three cytokines discovered in the early 1990’s, c-kit ligand or Stem Cell Factor (KL), flt3 ligand (FL), and c-mpl ligand also termed Megakaryocyte Growth and Development Factor (MGDF) or Thrombopoietin (TPO), appear to have unique activities on primitive progenitor/stem cells.