Endogenous hematopoietic reconstitution induced by human umbilical cord blood cells in immunocompromised mice: Implications for adoptive therapy

Human umbilical cord blood (HUCB) cells show promising advantages over bone marrow (BM) cells for a variety of diseases that require transplantation. We observed that lethally irradiated SJL/J mice given a single injection of HUCB cells survive, whereas vehicle-injected mice do not. Because survival is not due to long-term engraftment of HUCB cells, we used this HUCB/mouse model to investigate additional therapeutic benefits of HUCB cells. We investigated the mechanism by which HUCB cells accelerated endogenous hematopoiesis in mice that received either lethal (9.5 Gy) or lower-dose (8.0 Gy) radiation and then were given a single injection of HUCB mononuclear cells. Compared to irradiated control mice, the lethally irradiated, HUCB-injected group showed significant increases in peripheral white blood cell counts, red blood cell indices, and granulocyte-macrophage colony-forming units (CFU-GM) by 3 weeks. In contrast, no significant differences in these parameters were observed between control and HUCB-injected mice that received the lower dose of irradiation. Moreover, regardless of the radiation dose, only HUCB-injected mice exhibited immune responses comparable to those of age-matched normal mice. The clinical relevance of these observations was determined in long-term, culture-initiating cell assays with human BM stem cells and irradiated (γ-) HUCB cells. CFU-GM colonies were detectable in cultures containing γ-HUCB cells by day 15, but were undetectable in cultures without γ-HUCB cells until day 40, suggesting a hematopoietic stimulatory role for HUCB cells. Overall, the results indicate that in addition to their use for transplantation, HUCB cells also may be used as an adjuvant therapy to enhance hematopoietic reconstitution and immunocompetence of the host. This hematopoiesis-enhancing effect represents a heretofore unrecognized function of HUCB cells.