الفهرس 
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Abstract
Leukemia is a progressive, malignant disease of the blood forming tissues, marked by high proliferation and increased num- ber of abnormal white blood cells and their precursors in the blood and bone marrow. The high proliferation of leukemic cells over the normal hematopoietic stem and progenitor cells is at- tributed to the disturbance of different signalling pathways, dif- ferentiation and cell survival programming, as a result of a num- ber of genetic and epigenetic defects. The etiology of leukemia is heterogeneous and complex, but it is widely accepted that both radiation and environmental pollutant play significant roles in the development of the disease.
The present study was planned to evaluate the potential effect of mesenchymal stem cells against leukemogenesis induced either by 7, 12 dimethyl benz[a] anthracence (DMBA) or gamma irradi- ation or both in rats.
Fifty juvenile male Wistar rats at the age of 27th day were divided into five groups, ten animals each as follows:
1. Control group (G1): rats of this group were served as con- trol.
2. DMBA group (G2): rats injected intravenousely with DMBA (35 mg/kg body weight) three times at biweeks in- terval.
3. DMBA+ MSCs (G3): rats injected intravenousely with DMBA (35 mg/kg body weight) three times at biweeks in- terval, then treated once with 3.5×106 MSCs intravenously.
4. Gamma irradiated group (G4): rats exposed to 1.5 Gy/
week for four weeks.
5. Gamma irradiated + MSCs group (G5): rats exposed to
1.5 Gy/ week for four weeks then treated with 3.5×106
MSCs intravenously.
At the end of the experimental period, all rats were sacrificed and the blood was collected via heart puncture. Part of the whole blood was collected in EDTA tubes for complete blood count. The other part was collected for the assessment of the bio- chemical parameters including liver functions (ALT & AST), kidney function (urea & creatinine). Both femurs were removed immediately. One was used for the preparation of bone marrow smears, and the other for flushing of bone marrow for the bio- chemical parameters estimations including oxidative stress (MDA and GSH), inflammatory markers (IL-6 & TGF-β) and molecular investigations (CXCR-4, Bax and Bcl-2) immunoblotting (PI3K, AKT, mTOR and PTEN). Additionaly, part of bone marrow,
lymph node and liver were rapidly excised for histopathological examinations.
The results exhibited that injection of DMBA or exposure to γ- radiation resulted in leukemogenesis and this was confirmed by the histopathological observations which showed changes in the blood and bone marrow architecture represented by hypocel- lularity and abnormal immature leucocytes.
Additionally, DMBA or γ-irradiation provoked oxidative stress in the bone marrow tissues which was indicated by the higher level of lipid peroxidation (MDA). This increase in MDA was associated with the depletion of glutathione (GSH) content. Treatment with mesenchymal stem cells (MSCs) decreased the MDA level and ameliorated the disturbances in GSH appeared in the bone marrow tissues.
Furthermore, there were impairment in both kidney and liver functions in the group injected with DMBA or exposed to γ- radiation. Treatment with MSCs ameliorated the biochemical dis- turbances and histological architecture in the liver parameters un- der investigation.
Moreovere, significant increases in the bone marrow in- flammatory markers were seen in rats injected with DMBA or ex- posed to γ-radiation, in contrast treatments with MSCs caused a significant decline. Additionally, either DMBA or γ- irradiation down regulated the expression of CXCR-4 gene while, MSCs
transplantation increased the homing efficacy of HSCs to bone marrow throughout up regulation of CXCR-4 expression.
The obtained results indicated that DMBA enhance prolif- eration while, exposure to radiation induces apoptosis. Mean- while, treatment with MSCs, modulate apoptosis/ proliferation of bone marrow. Furthermore, immunoblotting results (PI3K, AKT, mTOR and PTEN) confirmed the previous results through the icreased expression of (PI3K, AKT, mTOR) along with down regulation of PTEN expression in bone marrow of DMBA or γ- irradiated groups. Conversely, transplantation with MSCs modu- lated the PI3K /AKT/ mTOR/ PTEN signaling pathway.
In confirmation to these results, either DMBA or γ- irradiation demonstrated significant appearance of apoptotic and necrotic cells in bone marrow.
In conclusion, the findings of the present study revealed that MSC transplantation enhances and support hematopoiesis, repair bone marrow damage and improve the peripheral blood counts and other biochemical parameters. Interestingly, MSCs decrease the incidence of apoptosis /HSC exhaustion and senes- cence in bone marrow related to γ- irradiation. Meanwhile, they induce apoptosis alleviating the damage resulted from DMBA. Additionaly, MSCs modulate PI3K/AKT/ mTOR signaling. Fur- thermore, they increase mobilization of peripheral blood HSCs to re-establishing damaged bone marrow niche. These mechanisms
may contribute to the MSCs therapeutic potential in the treatment of leukemogenesis induced either by DMBA or γ- irradiation.
This shows the role of MSCs as a promising source for cell therapy in regenerative medicine due to to their potentials for trans-differentiation, immunomodulation, anti-inflammatory, in- hibitory effect on tumor proliferation and modulation of apoptosis