Human hepatocytes in mice receiving pre-immune injection with human cord blood cells

ArticleinBiochemical and Biophysical Research Communications 326(1):66-73 · February 2005with12 Reads
DOI: 10.1016/j.bbrc.2004.10.204 · Source: PubMed
It is well established that certain subpopulations of human adult stem cells can generate hepatocyte-like cells when transplanted into adult immunosuppressed mice. In the present study, we wanted to explore whether xeno-transplantation of human cord blood CD34(+) (hCBCD34(+)) cells during pre-immune stages of development in immunocompetent mice might also lead to human-mouse liver chimerism. Freshly isolated hCBCD34(+) cells were xeno-transplanted into non-immunosuppressed mice by both intra-blastocyst and intra-fetal injections. One and four weeks after birth, immunostaining for different human-specific hepatocyte markers: human hepatocyte-specific antigen, human serum albumin, and human alpha-1-antitrypsin indicated the presence of human hepatocyte-like cells in the livers of transplanted animals. Detection of human albumin mRNA further corroborated the development of pre-immune human-mouse chimeras. The current report, besides providing new evidence of the potential of hCBCD34(+) cells to generate human hepatocyte-like cells, suggests novel strategies for generating immunocompetent mice harboring humanized liver.
    • "Some researchers have argued that stem cells derived from bone marrow or cord blood of human origin exhibit higher plasticity than the respective mouse or rat cells (Di Campli et al. 2004; Ishikawa et al. 2003; Kakinuma et al. 2003; Newsome et al. 2003; Tanabe et al. 2004; Turrini et al. 2005; Wang et al. 2003a). Indeed, several groups have detected high rates of human hepatocyte formation without signs of fusion in xenogenic murine transplantation models. "
    [Show abstract] [Hide abstract] ABSTRACT: The liver has adapted to the inflow of ingested toxins by the evolutionary development of unique regenerative properties and responds to injury or tissue loss by the rapid division of mature cells. Proliferation of the parenchymal cells, i.e. hepatocytes and epithelial cells of the bile duct, is regulated by numerous cytokine/growth-factor-mediated pathways and is synchronised with extracellular matrix degradation and restoration of the vasculature. Resident hepatic stem/progenitor cells have also been identified in small numbers in normal liver and implicated in liver tissue repair. Their putative role in the physiology, pathophysiology and therapy of the liver, however, is not yet precisely known. Hepatic stem/progenitor cells also known as "oval cells" in rodents have been implicated in liver tissue repair, at a time when the capacity for hepatocyte and bile duct replication is exhausted or experimentally inhibited (facultative stem/progenitor cell pool). Although much more has to be learned about the role of stem/progenitor cells in the physiology and pathophysiology of the liver, experimental analysis of the therapeutic value of these cells has been initiated. Transplantation of hepatic stem/progenitor cells or in vivo pharmacological activation of the pool of hepatic stem cells may provide novel modalities for the therapy of liver diseases. In addition, extrahepatic stem cells (e.g. bone marrow cells) are being investigated for their contribution to liver regeneration. Hepatic progenitor cells derived from embryonic stem cells are included in this review, which also discusses future perspectives of stem cell-based therapies for liver diseases.
    Full-text · Article · Feb 2008
    • "Besides their differentiation potential, USSCs can also be distinguished from MSC by their phenotype. But similar to adult and fetal MSCs, they are also nonimmunogeneic and even im- munosuppressive [25] . Some studies have shown that UCB may contain some hepatic progenitors. "
    [Show abstract] [Hide abstract] ABSTRACT: To study the condition and potentiality of human umbilical cord blood stem cells (HUCBSC) to differentiate into hepatocytes in vivo or in vitro. In a cell culture study of human umbilical cord blood stem cell (HUCBSC) differentiation, human umbilical cord blood mononuclear cells (HUCBMNC) were separated by density gradient centrifugation. Fibroblast growth factor (FGF) and hepatocyte growth factor (HGF) and the supernatant of fetal liver were added in the inducing groups. Only FGF was added in the control group. The expansion and differentiation of HUCBMNC in each group were observed. Human alpha fetoprotein (AFP) and albumin (ALB) were detected by immunohistochemistry. In the animal experiments, the survival SD rats with acute hepatic injury after carbon tetrachloride (CCL4) injection 48 h were randomly divided into three groups. The rats in group A were treated with human umbilical cord blood serum. The rats in group B were treated with HUCBMNC transplantation. The rats in group C were treated with HUCBMNC transplantation followed by intraperitoneal cyclophosphamide for 7 d. The rats were killed at different time points after the treatment and the liver tissue was histopathologically studied and human AFP and ALB detected by immunohistochemistry. The human X inactive-specific transcript gene fragment in the liver tissue was amplified by PCR to find human DNA. The results of cell culture showed that adherent cells were stained negative for AFP or ALB in control group. However, the adherent cells in the inducing groups stained positive for AFP or ALB. The result of animal experiment showed that no human AFP or ALB positive cells present in the liver tissue of group A (control group). However, many human AFP or ALB positive cells were scattered around sinus hepaticus and the central veins of hepatic lobules and in the portal area in group B and group C after one month. The fragment of human X chromagene could be detected in the liver tissue of groups B and C, but not in group A. Under certain conditions HUCBSC can differentiate into liver cells in vivo and in vitro.
    Article · Aug 2006
    • "CD34 + cells isolated from cord blood 3–5 · 10 5 for intra-fetal and 15–20 cells for intrablastocyst injection None Expression of human albumin, HepPar1 antigen, and human a1-antitrypsin (IHC, RT-PCR) 1 and 4 weeks after birth m [72] ulated a relatively large number of independent groups to study the fate of different types of human stem and precursor cells in livers of experimental animals (Table 2). Without doubt differentiation of human stem cells to genuine hepatocytes or even to liver tissue would be an enormous progress with high clinical relevance. "
    [Show abstract] [Hide abstract] ABSTRACT: In recent years the interest in liver cell therapy has been increasing continuously, since the demand for whole liver transplantations in human beings far outweighs the supply. From the clinical point of view, transplantation of hepatocytes or hepatocyte-like cells may represent an alternative to orthotopic liver transplants in acute liver failure, for the correction of genetic disorders resulting in metabolically deficient states, and for late stage liver disease such as cirrhosis. Although the concept of cell therapy for various diseases of the liver is widely accepted, the practical approach in humans often remains difficult. An international expert panel critically discussed the recent published data on clinical and experimental hepatocyte transplantation and the possible role of stem cells in liver tissue repair. This paper aims to summarise the present status of cell based therapies for liver diseases and to identify areas of future preclinical and clinical research.
    Full-text · Article · Aug 2006
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