الفهرس 
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Abstract
Introduction Liver is a very complex organ that performs numerous functions. So, maintaining a healthy liver is a crucial factor for the overall health. Liver diseases are major cause of morbidity and mortality which are rising globally. CCl4 is a potent hepatotoxin that is widely used in animal models for liver damage and fibrosis. Mesenchymal stem cells (MSCs) have immunomodulatory, anti-inflammatory, and anti-fibrotic effects. So, they can be used in treatment of liver diseases. Co-cultured MSCs with diseased liver tissue improve the homing capacity, survival rate and paracrine effects of MSCs, as well as the ability to enhance liver function. Aim of the work This work was carried out to compare the therapeutic effect of mesenchymal stem cells versus therapeutic effect of co-cultured mesenchymal stem cells with diseased liver tissue on carbon tetrachloride induced hepatotoxicity in adult male albino rats. Materials and methods This study was carried on 30 adult male albino rats that were divided into six equal groups as the following: 1-group I (Control group): was used to obtain the control liver and the bone marrow. 2-group II (Hepatotoxic group): received CCl4 intraperitoneally (i.p.) for induction of hepatotoxicity in a dose of 1ml ̸ kg once a week for 5 weeks. The diseased liver tissue specimens were taken for coculture. 3-group III (MSCs treated group): was injected with CCl4 i.p. as in group II, then injected with a single dose of (3x106) MSCs intravenous (i.v.) 24h after last dose of CCl4 injection, and liver specimens were obtained after 4 weeks of MSCs injection. 4-group IV (Co-cultured MSCs treated group): was injected with CCl4 i.p. as in group II, then injected with a single dose of (3x 106) cocultured MSCs with diseased liver tissue specimens i.v., 24h after last dose of CCl4 injection, and liver specimens were obtained after 4 weeks of co-culture suspension injection. 5-group V (Media treated group): was injected with CCl4 i.p. as in group II, then treated with 2ml of freshly prepared complete media i.v., and liver specimens were obtained after 4 weeks of media injection. 6-group VI (Recovery group): was injected with CCl4 i.p. as in group II, then left for self-recovery for 4 weeks. At the appropriate time, the animals were sacrificed, the blood samples were obtained for biochemical analysis, and the liver specimens were dissected and prepared for light and electron microscopic examination. Morphometric study and statistical analysis Six different non-overlapping randomly selected fields from each microscopic slide from each rat from each group were quantified for: A. Histological scoring in H&E stained sections. B. The mean area % of collagen fibers in Masson trichrome stained sections. Biochemical analysis of ALT and AST. ALT and AST were measured in blood samples of the experimental animals to assess liver functions. ❖ Results I-Light microscopic results: A) Hematoxylin & Eosin stain: group I (Control group): showed normal histological structure of the liver sections which consisted of indistinct hexagonal shape classic hepatic lobules, with central veins at the center of the lobules, and the portal tracts at the angles of the lobules. The portal tracts were formed of a branch of portal vein, a branch of hepatic artery, bile ductules, lymphatics, and few inflammatory cells. Liver was surrounded with connective tissue capsule. The hepatic lobule formed of hepatocytes arranged in anastomosing cords. The hepatocytes were polygonal in shape, most of them had acidophilic cytoplasm, and central rounded vesicular nuclei with prominent nucleoli, other hepatocytes were seen binucleated. group II (Hepatotoxic group): showed multiple histopathological changes as loss of hepatic architecture, with excess deposition of fibrous tissue between hepatic lobules. Also, there was increase in the thickness of the capsule with capsular deposition of fat cells. Moreover, the central veins were dilated, congested, and disrupted. In addition, Portal tracts showed dilated portal venule and bile ductular proliferation. Cellular infiltrations were peri-vascular, peri-portal, and interstitial. Most of hepatocytes were highly vacuolated, others had highly acidophilic cytoplasm. The highly acidophilic hepatocytes depicted either pyknosis or karyolysis. Some hepatocytes showed Mallory- Denk bodies or micro-steatosis or macro-steatosis. group III (MSCs treated group): showed restoration of normal histological structure to be more or less similar to control group. Few examined sections demonstrated mild dilatation and congestion of some blood sinusoids, mild dilated portal venule, bile ductular proliferation and localized inflammatory cellular infiltration. Few hepatocytes showed vacuolated cytoplasm, and others had fragmented nuclei. group IV (Co-cultured MSCs treated group): showed disappearance of histological alterations giving an image of the normal architecture of the control group. Cellular infiltration was still observed in few examined fields. group V (Media treated group) and group VI (Self recovery group): revealed pathological changes similar to that in CCl4 received group. B) Masson trichrome stain group I (Control group): showed thin strand of collagen fibers around central vein, and portal tract in addition to liver capsule. group II (Hepatotoxic group): showed thick collagen bundle peri-vascular, septal, and interstitial up to pseudo-lobulation and cirrhosis in all examined microscopic fields. group III (Stem cells treated group): showed thin collagen fibers close to control group. group IV (Co-culture treated group): showed thin collagen fibers similar to those of control group. group V (Media treated group) and group VI (Self recovery group): showed wide-spread deposition of thick collagen bundles.