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作者 Torabi, Alireza
書名 In utero stem cell transplantation: Induction of tolerance and generation of donor-derived hepatocytes
國際標準書號 9780542603204
book jacket
說明 164 p
附註 Source: Dissertation Abstracts International, Volume: 67-03, Section: B, page: 1241
Adviser: Esmail D. Zanjani
Thesis (Ph.D.)--University of Nevada, Reno, 2006
Our laboratory has shown that transplantation of hematopoietic stem cells (HSCs) into fetal sheep results in long-term multi-lineage hematopoietic chimerism. This demonstrated that tolerance can be induced during prenatal period by early injection of HSCs. We have also demonstrated that the optimal age for in utero transplantation in sheep, "window of opportunity", is between 55--65 days of gestation (term=145 days). However, the relationship between hematopoietic chimerism and tolerance has remained obscure. In the present study, distribution of CD4+CD25+ cells were analyzed in the fetal sheep lymphoid organs. These data showed the presence of CD4+CD25+ cells in the BM, spleen, and small intestine of the fetuses during early gestation. This population expressed CD45R in these organs. In the thymus, CD45R+ cells were only detected in the medulla, suggesting that they play a role in negative selection and tolerance induction. These data demonstrated that positive selection starts in the thymus of fetal sheep at day 45 of gestation; however, negative selection is delayed until day 65 of gestation. Taken together, these data confirm our previous observation regarding the "window of opportunity", and suggest that both central and peripheral mechanisms are involved in tolerance induction following in utero stem cell transplantation
We have previously shown that human hematopoietic stem cell preparations (HSCs) are able to engraft and transdifferentiate into human hepatocytes in the human/sheep xenograft model. In order to recover human hepatocytes from the liver of chimeric sheep transplanted with different type of human stem cells, livers were treated with collagenase to obtain a single cell suspension. Then, 3-5x105 cells/ml were cultured in optimized media designed to support the proliferation and maintenance of human and sheep hepatocytes. In this system, human (and sheep) hepatocytes were maintained/expanded for up to 3--4 months. These cells formed colonies in the culture, were able to produce human albumin, and were positive for CK18, CK19, OV-6, Thy-1, and alpha-fetoprotein. These results provide a unique non-injury large animal model, in which adult human stem cells generate robust numbers of functional human hepatocytes and suggest that this model could ultimately be used to generate donor-specific human hepatocytes for transplantation
School code: 0139
Host Item Dissertation Abstracts International 67-03B
主題 Biology, Cell
Alt Author University of Nevada, Reno
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