Abstract
The liver plays a vital role in hematopoiesis during mammalian prenatal development but its hematopoietic output declines during the perinatal period. Nonetheless, hepatic hematopoiesis is believed to persist into adulthood. We sought to model human adult-liver hematopoiesis by transplantation of fetal and neonatal hematopoietic stem cells (HSCs) into adult immunodeficient mice. Livers were found to be engrafted with human cells consisting primarily of monocytes and B-cells with lesser contributions by erythrocytes, T-cells, NK-cells and mast-cells. A resident population of CD117++CD203c+ mast cells was also documented in human midgestation liver, indicating that these cells comprise part of the liver's resident immune cell repertoire throughout human ontogeny. The murine liver was shown to support human multilineage hematopoiesis up to 321 days after transplant. Evidence of murine hepatic hematopoiesis was also found in common mouse strains as old as 2 years. Human HSC engraftment of the murine liver was demonstrated by detection of high proliferative-potential colony-forming cells in clonal cultures, observation of CD38−CD34++ and CD133+CD34++ cells by flow cytometry, and hematopoietic reconstitution of secondary transplant recipients of chimeric liver cells. Additionally, chimeric mice with both hematopoietic and endothelial reconstitution were generated by intrasplenic injection of immunodeficient mice with liver specific expression of the urokinase-type plasminogen activator (uPA) transgene. In conclusion, the murine liver is shown to be a hematopoietic organ throughout adult life that can also support human hematopoiesis in severely immunodeficient strains. Further humanization of the murine liver can be achieved in mice harboring an uPA transgene, which support engraftment of non-hematopoietic cells types. Thus, offering a model system to study the interaction of diverse human liver cell types that regulate hematopoiesis and immune function in the liver.
Highlights
The liver is the primary site of hematopoiesis during the latter half of human embryonic development through midgestation [1,2]
Mature human blood cells are found in the murine liver To determine if the murine liver can support human hematopoiesis, we first sought to confirm that human cells found in the liver are not the result of trapped peripheral-blood cells
Mice transplanted with 2 different preparations of Human fetal bone marrow (hFBM) and 5 preparations of Lin2 light-density fetal liver (LDFL) all had human CD14+ monocytes and CD19+ B-cells present in their livers (Fig. 2B)
Summary
The liver is the primary site of hematopoiesis during the latter half of human embryonic development through midgestation [1,2]. At the start of the second trimester of gestation hematopoiesis begins in the bone marrow (BM), which eventually surpasses the liver as the primary site of hematopoiesis in the second half of gestation [8,9]. Liver hematopoiesis wanes early in human ontogeny, remnants of hematopoiesis are believed to persist into adulthood. In young-adult mice (6–8 weeks old) the presence of a resident population of hematopoietic cells has been demonstrated in the liver with the characteristics of HSCs and early progenitors [10]
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