Abstract
Here we proposed a new concept that human spermatogonial stem cells (SSCs) can transdifferentiate into hepatocytes in vivo. We first established liver injury model of mice by carbon tetrachloride to provide proper environment for human SSC transplantation. Liver mesenchymal cells were isolated from mice and identified phenotypically. Human SSC line was recombined with liver mesenchymal cells, and they were transplanted under renal capsules of nude mice with liver injury. The grafts expressed hepatocyte hallmarks, including ALB, AAT, CK18, and CYP1A2, whereas germ cell and SSC markers VASA and GPR125 were undetected in these cells, implicating that human SSCs were converted to hepatocytes. Furthermore, Western blots revealed high levels of PCNA, AFP, and ALB, indicating that human SSCs-derived hepatocytes had strong proliferation potential and features of hepatocytes. In addition, ALB–, CK8–, and CYP1A2– positive cells were detected in liver tissues of recipient mice. Significantly, no obvious lesion or teratomas was observed in several important organs and tissues of recipient mice, reflecting that transplantation of human SSCs was safe and feasible. Collectively, we have for the first time demonstrated that human SSCs can be transdifferentiated to hepatocyte in vivo. This study provides a novel approach for curing liver diseases using human SSC transplantation.
Highlights
Human hepatocyte transplantation has been regarded as an alternative and effective treatment for acute- and end-stage liver failure and metabolic liver diseases [1,2,3]
We have demonstrated that human SSC line could be directly transdifferentiated to hepatocytes after transplantation with liver mesenchymal cells under renal capsule of mice with liver injury
This was the first report showing that human SSCs can be transdifferentiated to hepatocytes in vivo when placed in a proper microenvironment
Summary
Human hepatocyte transplantation has been regarded as an alternative and effective treatment for acute- and end-stage liver failure and metabolic liver diseases [1,2,3]. Transplantation of hepatocytes derived from ES cells and iPS cells could repair liver damage in animal models [15, 16]. Several key issues, e.g., ethic and safety issues associated with human ES cells and virus transduction and tumorigenesis related to human iPS cells [17], have not yet been solved for clinical applications of hepatocytes generated from human pluripotent cells. Adult stem cells derived from bone marrow can be converted into hepatocytes and improve liver injury [18, 19]. Subsets of stem cells from bone marrow lead to fibrogenesis within the liver in response to injury [20]. It is crucial to seek a readily available cell source from another stem cells and/or extra-hepatic tissues to provide human hepatocytes for cell therapy of liver diseases
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