Immature human cord blood progenitors engraft and proliferate to high levels in severe combined immunodeficient mice

Abstract

Unseparated or Ficoll-Hypaque (Pharmacia, Piscataway, NJ)--fractionated human cord blood cells were transplanted into sublethally irradiated severe combined immunodeficient (SCID) mice. High levels of multilineage engraftment, including myeloid and lymphoid lineages, were obtained with 80% of the donor samples as assessed by DNA analysis, fluorescence-activated cell sorting (FACS), and morphology. In contrast to previous and concurrent studies with adult human bone marrow (BM), treatment with human cytokines was not required to establish high-level human cell engraftment, suggesting that neonatal cells either respond differently to the murine microenvironment or they provide their own cytokines in a paracrine fashion. Committed and multipotential myelo- erythroid progenitors were detected using in vitro colony assays and FACS analysis of the murine BM showed the presence of immature CD34+ cells. In addition, human hematopoiesis was maintained for at least 14 weeks providing further evidence that immature hematopoietic precursors had engrafted the murine BM. This in vivo model for human cord blood- derived hematopoiesis will be useful to gain new insights into the biology of neonatal hematopoietic cells and to evaluate their role in gene therapy. There is growing evidence that there are ontogeny-related changes in immature human hematopoietic cells, and therefore, the animal models we have developed for adult and neonatal human hematopoiesis provide useful tools to evaluate these changes in vivo.

Clinical and experimental uses of umbilical cord blood

“…This property is difficult to assess for human haemopoiesis, however several animal models have been developed that assess the capacity of human haemopoietic cells to engraft a xenogeneic host. In contrast to adult BM and mobilized PB, UCB cells engraft immunodeficient mice at relatively high levels with low cell numbers in the absence of exo­genous cytokine 21 …”

Biology of Human Umbilical Cord Blood‐Derived Hematopoietic Stem/Progenitor Cells

“…have reported stable human long‐term hematopoiesis in SCID mice transplanted with total or MNC from human UCB. Both myeloid and lymphoid cells of human origin were observed in the animal's tissues and human CFC, including multipotent, myeloid, and erythroid progenitors, were also detected by in vitro cultures [107]. These results indicate the engraftment of an early hematopoietic progenitor/stem cell.…”

Haematopoietic stem cells1

“…The primitive cells that initiated the graft were operationally defined as SCID repopulating cells (SRCs). Kinetic experiments showed that only 0.1% of the injected CFCs and LTC‐ICs were detectable in the murine BM 2 days post‐transplant and that there was a large expansion of these cells, as well as primitive CD34 + cells, over the next 4 weeks, implying their production from a more primitive cell32. Since this pioneering work, a number of research groups have confirmed these results33–35.…”