الفهرس 
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Abstract
About a decade ago, many reports highlighted the broad developmental potential of bone marrow derived stem cells. This gave new hope for cell therapy using bone marrow cells, which has few ethical problems and has been applied to severe liver diseases. In the current study the role of regulatory T cells in homing of the transplanted bone marrow derived stem cells was evaluated. The ability of the transplanted bone marrow derived stem cells to regenerate liver function and structure in animal model of liver fibrosis was also assessed.
Bone marrow derived stem cells isolated from male rats were transferred into 52 female rats by the end of 8 weeks of CCl4 induced liver fibrosis. They were divided into two control groups (Negative and positive control groups) and three experimental groups that received bone marrow derived stem cells (MNSCs, HSCs and MSCs). Each group consisted of 13 female rats. Histopathological evidence of liver fibrosis was seen after 8 weeks of CCl4 induction confirmed with elevated concentration of PIIINP, in addition to considerable elevation of AST, ALT and GGT mean levels. The mean levels of albumin remained within the normal ranges.
By the end of 8 weeks after MSCs transplantation, Sry gene was detected in 100% of female rats. CD4 & IL2α/ CD25 were expressed in 85.7% of rats indicating the expansion of CD4 & IL2α/ CD25 by MSCs. Tregs regulate the immunomodulatory function of MSCs and played an important role in their homing. This group showed regression of liver fibrosis as indicated by marked decreased of PIIINP up to normal level after MSCs transplantation. This came in accordance with histopathological revealing improvement of hepatitis with complete restoration of hepatic architecture in most of animals. Liver enzymes ALT, AST and GGT started to decrease after MSCs administration in a time dependent fashion with good improvement compared to other groups.
GVHD is the most critical complication after hematopoietic stem cell transplantation compensated by expansion of Tregs cells. In the group received HSCs (Thy1.1+/ CD90.1), no expression of CD4 & IL2α/ CD25 was seen in 71.4% of animals after 8 weeks of HSCs transplantation. This may have explained the negative expression of Sry gene in 2 out of 13 female rats. Histopathological evaluation after 8 weeks of HSCs transplantation revealed good improvement of the necroinflammatory changes with reconstruction of liver structure in 57.1% of animals, rest of cases showed milder degrees of fibrosis (A1). The mean concentration of PIIINP decreased after 8 weeks HSCs transplantation, but still in a higher levels compared to the group received MSCs in the corresponding week of the study. The biochemical results of liver function tests showed insignificant decreased after HSCs administration compared to the CO+ group, but showed higher levels than MSCs group.
Transplantation of MNSCs has a cost and time benefit. In the current study MNSCs were transplanted to female rats, showed positive expression of Sry gene in 11 out of 13 animals. Most of animals showed positive expression of CD4 & IL2α/ CD25. More than half of the experimental animals showed good improvement of necroinflammatory changes with restoration of the hepatic architecture after8 weeks of MNSCs transplantation. The concentration of liver fibrotic marker PIIINP decreased after 8 weeks of transplantation but still in a higher level respectively compared to HSCs and MSCs groups. Also, ALT, AST and GGT remained within a higher concentration compared to HSCs and MSCs treated groups respectively. Insignificant difference of the mean levels of liver functions in all groups compared to control group was present.
Results obtained after 8 weeks of different types of stem cell transplantation showed good improvement compared to that obtained at 6 weeks. Insignificant difference of most results was reported. The difference of AST and ALT was significant after6 and 8 weeks of MSCs transplantation. Expression of CD4 and IL2α/ CD25 showed statistically significance relation after 6 and 8 weeks of HSCs transplantation. In groups treated with MSCs and MNSCs, the expression of CD4 and IL2α/ CD25 showed statistically significance relation after 6 weeks of transplantation.
In conclusion, bone marrow derived stem cells give a promise in improvement of hepatitis activity and reconstruction of hepatic architecture. Expansion of Tregs (CD4 & IL2α/ CD25) played an important role in homing of bone marrow derived stem cells, especially in MSCs received group. The group received MSCs showed the best improvement of general hepatic condition confirmed by decreased concentration of liver fibrotic marker, biochemical improvement of liver functions test results and restoration of hepatic architecture and regression of hepatitis activity. HSCs came in the second position. The role of Tregs cells in homing of HSCs and MNSCs need further investigations.