Human cord blood-derived cells can differentiate into hepatocytes in the mouse liver with no evidence of cellular fusion

Newsome, Philip N.; Johannessen, Ingólfur; Boyle, Shelagh; Dalakas, Evangelos; McAulay, Karen A.; Samuel, Kay; Rae, Frances; Forrester, Lesley M.; Turner, Marc; Hayes, Peter; Harrison, David J.; Bickmore, Wendy A.; Plevris, John

doi:10.1016/s0016-5085(03)00401-3

Cited by 271 publications

(169 citation statements)

References 25 publications

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“…Studies utilizing human bone marrow-derived cells have produced similar results both in vitro and in animal studies (17,(23)(24)(25); however, the phenotype of the hepatocyte-like cells has not been adequately defined in most cases, and the demonstration of cellular fusion (26,27) posed a major limitation to the interpretation of animal transplantation studies. Human umbilical cord blood has also been suggested to be a reliable source of transplantable hepatic progenitor cells (15), and some limited attempts have been made to demonstrate that these cells can differentiate without cellular fusion (28). Both adult and fetal liver have long been considered to harbor hepatic progenitor cells because of anatomical homology, and several studies have now substantiated this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Side Population Cells Derived from Adult Human Liver Generate Hepatocyte-like Cells In Vitro

et al. 2005

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We sought to determine whether hepatic side population (SP) cells derived from adult human liver possess the potential of a novel candidate hepatic stem cell. Human cadaveric donor liver was subjected to collagenase perfusion and hepatocytes were separated from nonparenchymal cells by differential centrifugation. SP cells were isolated from the nonparenchymal portion after Hoechst 33342 staining. Since CD45 is a panleukocyte antigen, CD45-negative SP cells were separated from the vast majority of CD45-positive SP cells (90%), and hepatic growth medium was used to culture both groups. Both CD45-negative and CD45-positive hepatic SP cells generated colonies in the hepatic growth medium in 2-3 weeks. The colonies yielded large cells morphologically consistent with human hepatocytes, demonstrating granule-rich cytoplasm, dense, often double nuclei, and intracellular lipofuscin pigment. The cultured cells from both sources were positive for markers of human hepatocytes: HepPar, cytokeratin 8 (CK8), and human albumin. Reverse transcriptasepolymerase chain reaction (RT-PCR) performed on both groups demonstrated positivity for additional liver markers including human albumin, CK18, α-1 anti-trypsin, and the human cytochrome P450 enzyme CYP2B6. Double immunostaining (CD45 and HepPar) and RT-PCR confirmed that the hepatocyte-like cells derived from the CD45-negative SP cells acquired HepPar positivity but had no detectable CD45 antigen expression. In contrast, the cultured cells derived from the CD45-positive SP cells also acquired HepPar positivity, but only a minimal fraction expressed the CD45 antigen. We conclude that hepatic SP cells derived from the nonparenchymal portion of human liver are a potential source of human hepatocytes irrespective of their CD45 status, and further animal studies will be required to assess their regenerative potential. Keywordshuman; side population; stem cells; hepatic; CD45 SP cells are identified by flow cytometry because of their unique ability to efflux Hoechst 33342 dye and have been shown in animal studies to be highly enriched stem cells (1,2). While the true adult liver stem cell has not been characterized, human hepatic side population (SP) cells might contain certain cells that might have hepatic progenitor-like properties. The liver in a normal healthy adult maintains a balance between cell gain and cell loss. It is composed mainly of two epithelial cell types, hepatocytes and bile ductular cells, both of which have high regenerative capacity. After hepatic injury, a regenerative process repairs the liver and brings it back to its original mass within 10 days (3). This restoration of mild to moderate cell loss and "wear and tear" renewal is largely achieved by hepatocyte self-replication. A more severe liver injury activates the endogenous stem cell population; these are often termed "oval" cells and are much smaller than mature hepatocytes (4). These oval cells display a distinct phenotype and have been shown to be a bipotential progenitor of two types of cells found ...

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Section: Discussionmentioning

confidence: 99%

Side Population Cells Derived from Adult Human Liver Generate Hepatocyte-like Cells In Vitro

et al. 2005

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“…It is well known that CB-derived cells contribute to skeletal muscle (Gang et al, 2004;Brzoska et al, 2006), liver (Kakinuma et al, 2003;Newsome et al, 2003;Di Campli et al, 2004), neural tissue (Buzanska et al, 2002), and myocardium regeneration (Henning et al, 2004;Ma et al, 2005), and more importantly, recent multiorgan engraftment and differentiation has been achieved in goats after transplantation of human CB CD34 ϩ lin Ϫ cells (Zeng et al, 2006a). Furthermore, several groups of investigators described the presence of Oct-4 ϩ , Nanog ϩ , and SSEA-3/4 ϩ stem cells in human CB and umbilical cord matrix (Carlin et al, 2006).…”

Section: Oct-4 ؉ Stem Cells In Cord Bloodmentioning

confidence: 99%

Bone marrow‐derived very small embryonic‐like stem cells: Their developmental origin and biological significance

Kucia

Wan

Ratajczak

2007

Developmental Dynamics

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Data from our and other laboratories provide evidence that bone marrow (BM) contains a population of stem cells that expresses early developmental markers such as (1) stage-specific embryonic antigen (SSEA) and (2) transcription factors Oct-4 and Nanog. These are the markers characteristic for embryonic stem cells, epiblast stem cells, and primordial germ cells (PGC). The presence of these stem cells in adult BM supports the concept that this organ contains some population of pluripotent stem cells that is deposited in embryogenesis during early gastrulation. We hypothesize that these cells could be direct descendants of the germ lineage that, to pass genes on to the next generations, has to create soma and, thus, becomes a "mother lineage" for all somatic cell lineages present in the adult body. Germ potential is established after conception in totipotent zygotes and retained in blastomeres of morula, cells from the inner cell mass of blastocyst, epiblast, and population of PGC. We will present a concept that SSEA ؉ Oct-4 ؉ Nanog ؉ cells identified in BM could be descendants of epiblast cells as well as some rare migrating astray PGC. Developmental Dynamics 236:3309 -3320, 2007.

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“…The authors observed the expression of albumin and human hepatocyte-specific antigen after transplantation and concluded that the human cord blood cells differentiated into human parenchymal hepatic cells. Newsome et al 25 demonstrated the expression of the HepPar1 human hepatocyte-specific antigen and concluded that cells from human cord blood "become mature hepatocytes" in livers of NOD/SCID mice. Ishikawa et al 26 detected human albumin and the HepPar1 antigen in livers of immunodeficient mice, postulating that the engrafted cells from human cord blood "functioned as hepatocytes."…”

Section: Discussionmentioning

confidence: 99%

Fate of extrahepatic human stem and precursor cells after transplantation into mouse livers

et al. 2007

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Human cord blood-derived cells can differentiate into hepatocytes in the mouse liver with no evidence of cellular fusion

Cited by 271 publications

References 25 publications

Side Population Cells Derived from Adult Human Liver Generate Hepatocyte-like Cells In Vitro

Side Population Cells Derived from Adult Human Liver Generate Hepatocyte-like Cells In Vitro

Bone marrow‐derived very small embryonic‐like stem cells: Their developmental origin and biological significance

Fate of extrahepatic human stem and precursor cells after transplantation into mouse livers

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