Animal Models of Normal and Leukemic Human Hematopoiesis

Abstract

Over the last 40 years the hematopoietic system has provided many of the important paradigms that guide our understanding of stem cell function. Much of our knowledge of the regulation of the hematopoietic system is derived from experiments in the mouse; these studies have involved identification of various classes of progenitor cells, growth factors that stimulate growth and differentiation, and molecular events that underlie the abnormalities that occur in diseases such as leukemia. This information has derived largely from the development of in vivo transplantation assays for normal stem cells and the ability to establish and grow leukemic cells in vitro and in vivo [1]. In contrast, our understanding of the biology of the human hematopoietic system has suffered relative to that in the mouse because of the lack of similar assays for normal stem cells and leukemic cells. Normal and leukemic human cells often appear to have complex growth factor requirements that are not easy to provide in short- or long-term cultures. Furthermore, the difficulties in growing primary human leukemic cells in culture suggest that there are selective processes that may result in alterations of the properties of such cells over time and the resultant cell Unes do not accurately reflect the original disease. In an attempt to develop in vivo animal models for human leukemic cells, a large body of literature has accumulated over the past 20 years on the growth of human tumor xenografts in immune-deficient nude mice [2]. However, the growth of human leukemic cells as an ascites or solid subcutaneous tumor in nude mice does not reflect the normal course of the disease in humans. In addition to leukemic cells, normal human hematopoietic cells have also been introduced into nude mice directly or in diffusion chambers. The transplantation of human bone marrow directly into mice generally yielded inconclusive results [3], while the implantation of diffusion chambers demonstrated the development of human progenitors for as long as 28 days in vivo although it was not possible to distinguish between persistence of progenitors and engraftment of stem cells [4].