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Much controversy surrounds the identity and origin of human hepatic stem and progenitor cells in part because of a lack of small animal models in which the developmental potential of isolated candidate cell populations can be functionally evaluated. We show here that adoptive transfer of CD34 +  cells from human fetal liver into sublethally irradiated NOD‐SCID Il2rg −/−  (NSG) mice leads to an efficient development of not only human hematopoietic cells but also human hepatocyte‐like cells in the liver of the recipient mice. Using this simple in vivo assay in combination with cell fractionation, we show that CD34 +  fetal liver cells can be separated into three distinct subpopulations: CD34 hi CD133 hi , CD34 lo CD133 lo , and CD34 hi CD133 neg . The CD34 hi CD133 hi  population contains hematopoietic stem/progenitor cells (HSPCs) as they give rise to T cells, B cells, NK cells, dendritic cells, and monocytes/macrophages in NSG mice and colony‐forming unit (CFU)‐GEMM cells in vitro. The CD34 lo CD133 lo  population does not give rise to hematopoietic cells, but reproducibly generates hepatocyte‐like cells in NSG mice and in vitro. The CD34 hi CD133 neg  population only gives rise to CFU‐GM and burst‐forming unit‐erythroid in vitro. Furthermore, we show that the CD34 lo CD133 lo  cells express hematopoietic, hepatic, and mesenchymal markers, including CD34, CD133, CD117, epithelial cell adhesion molecule, CD73, albumin, α‐fetal protein, and vimentin and transcriptionally are more closely related to HSPCs than to mature hepatocytes. These results show that CD34 lo CD133 lo  fetal liver cells possess the hepatic progenitor cell properties and that human hepatic and hematopoietic progenitor cells are distinct, although they may originate from the same precursors in the fetal liver. S TEM  C ells   2013;31:1160–1169

Human Fetal Hepatic Progenitor Cells Are Distinct from, but Closely Related to, Hematopoietic Stem/Progenitor Cells