Animal Models for Human Hematopoiesis

Abstract

Despite seminal contributions provided by in vitro studies to the field of hematopoiesis, our present knowledge of mammalian lymphohemopoiesis and the mechanisms governing differentiation and self-renewal of hematopoietic stem cells has been derived in most part from elegant in vivo studies. The inability to apply such an approach to the examination of the human hematopoietic system is the primary reason why several aspects of human hematopoiesis including human stem cell biology are still poorly understood. To overcome the inability to probe human hematopoiesis in vivo, researchers have "humanized" animals via the transplantation of human hematopoietic progenitor cells and other tissues in an attempt to create human-animal chimera suitable for investigating human lymphohematopoiesis in vivo. To date, several of these "humanized" animal models have been developed. During their relatively short existence, human-animal models have contributed substantially to the field of experimental hematology. The development, peculiarities, shortcomings, and applications of these animal models as well as their potential use in exploring the field of human lymphohematopoiesis are the focus of this review.

Long-term repopulating ability of xenogeneic transplanted human fetal liver hematopoietic stem cells in sheep.

“…The human/sheep xenograft model is ideally suited to study the in vivo repopulating and self-renewal potential of these human HSC subsets. The rarity ofthe primitive HSC in human hematopoietic tissue frequently results in the isolation of relatively small numbers of highly characterized HSC subsets (42), which while adequate for in vitro studies may not be sufficient for the evaluation oftheir in vivo potential. The relatively small size of the preimmune sheep fetus ( 10 g at the time oftransplantation) and the availability of sites within the marrow ontogenetically primed to accept migrating HSC (including donor HSC) permit the assessment ofthe engraftment and proliferation potential of the relatively small cell inoculum.…”

Identification of hematopoietic stem/progenitor cells: strength and drawbacks of functional assays

“…At first, non-human primates could appear as more adapted than mice for identification of human stem cells given their size (allowing iterative samplings) and lifespan; however, the immunological barrier requires transplanting human cells in utero at a precise period when fetuses are immunologically tolerant. This strategy has been successfully pioneered by the group of E Zanjani (Srour et al, 1992;Zanjani et al, 1994), which convincingly showed the persistence of human cells several years after their transplant in sheep; and they have also highlighted important species-specific differences between mice versus large animal models for assessing stem cells in vivo. An alternative which has also been explored in monkeys is to work in an autologous transplant setting (Norol et al, 2002;Horn et al, 2003) and extrapolate the results to the human situation.…”

Comparative Medicine in the Twenty-First Century: Where are We Now and Where Do We Go from Here?

“…Despite the drug development failures mice undoubtedly have an important place in basic research, preclinical testing, and the development of translational research pathways. In order to facilitate translational research, the use of chimeric rodents and humanized mouse models has been proposed ( 7 , 8 ). Clearly, there are other obligations involved here since regulatory authorities require certain species to be used in toxicity as well as efficacy profiling.…”