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ORIGINAL RESEARCH ARTICLE

Expanded CD34⁺ Human Umbilical Cord Blood Cells Generate Multiple Lymphohematopoietic Lineages in NOD-scid IL2r^null Mice

Lisa J. Giassi^*, Todd Pearson^*, Leonard D. Shultz^,1, Joseph Laning, Kristin Biber, Morey Kraus, Bruce A. Woda, Madelyn R. Schmidt^||, Robert T. Woodland^||, Aldo A. Rossini^* and Dale L. Greiner^*

^* Division of Diabetes, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605; The Jackson Laboratory, Bar Harbor, Maine 04609; Viacell, Inc., Cambridge, Massachusetts 02142; Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01655; and ^|| Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, Massachusetts 01655

To whom requests for reprints should be addressed at ¹ The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609-1500. E-mail: lenny.shultz{at}jax.org

Umbilical cord blood (UCB) is increasingly being used for human hematopoietic stem cell (HSC) transplantation in children but often requires pooling multiple cords to obtain sufficient numbers for transplantation in adults. To overcome this limitation, we have used an ex vivo two-week culture system to expand the number of hematopoietic CD34⁺ cells in cord blood. To assess the in vivo function of these expanded CD34⁺ cells, cultured human UCB containing 1 x 10⁶ CD34⁺ cells were transplanted into conditioned NOD-scid IL2r^null mice. The expanded CD34⁺ cells displayed short- and long-term repopulating cell activity. The cultured human cells differentiated into myeloid, B-lymphoid, and erythroid lineages, but not T lymphocytes. Administration of human recombinant TNF to recipient mice immediately prior to transplantation promoted human thymocyte and T-cell development. These T cells proliferated vigorously in response to TCR cross-linking by anti-CD3 antibody. Engrafted TNF-treated mice generated antibodies in response to T-dependent and T-independent immunization, which was enhanced when mice were co-treated with the B cell cytokine BLyS. Ex vivo expanded CD34⁺ human UCB cells have the capacity to generate multiple hematopoietic lineages and a functional human immune system upon transplantation into TNF-treated NOD-scid IL2r^null mice.

Key Words: NOD-scid IL2r^null mice • SCID • umbilical cord blood • TNF • ex vivo expansion • human • immune response