Abstract
To determine whether transplanted amniotic membrane mesenchymal stem cells (AMSCs) ameliorated the premature senescent phenotype of Bmi-1-deficient mice, postnatal 2-day-old Bmi-1−/− mice were injected intraperitoneally with the second-passage AMSCs from amniotic membranes of β-galactosidase (β-gal) transgenic mice or wild-type (WT) mice labeled with DiI. Three reinjections were given, once every seven days. Phenotypes of 5-week-old β-gal+ AMSC-transplanted or 6-week-old DiI+ AMSC-transplanted Bmi-1−/− mice were compared with vehicle-transplanted Bmi-1−/− and WT mice. Vehicle-transplanted Bmi-1−/− mice displayed growth retardation and premature aging with decreased cell proliferation and increased cell apoptosis; a decreased ratio and dysmaturity of lymphocytic series; premature osteoporosis with reduced osteogenesis and increased adipogenesis; redox imbalance and DNA damage in multiple organs. Transplanted AMSCs carried Bmi-1 migrated into multiple organs, proliferated and differentiated into multiple tissue cells, promoted growth and delayed senescence in Bmi-1−/− transplant recipients. The dysmaturity of lymphocytic series were ameliorated, premature osteoporosis were rescued by promoting osteogenesis and inhibiting adipogenesis, the oxidative stress and DNA damage in multiple organs were inhibited by the AMSC transplantation in Bmi-1−/− mice. These findings indicate that AMSC transplantation ameliorated the premature senescent phenotype of Bmi-1-deficient mice and could be a novel therapy to delay aging and prevent aging-associated degenerative diseases.
Highlights
To assess if redox imbalance of multiple organs was ameliorated by Amniotic membrane mesenchymal stem cells (AMSCs) migrating and differentiating into the multiple tissue specific cells and expressing antioxidase in B lymphoma Mo-MLV insertion region 1 (Bmi-1)−/− mice, reactive oxygen species (ROS) and hydrogen peroxide (H2O2) levels, catalase (CAT) and total-superoxide dismutase (T-SOD) activities were examined in heart, liver, spleen, lung, kidney, bone marrow and thymus; superoxide dismutase 2 (SOD2) positive area was detected in skeletal muscle in vivo, and T-SOD and CAT activities were examined in AMSCs conditioned medium (CM) and Control CM in vitro
The results showed that the percentages of 8-OHdG-positive or γ -H2A.X-positive cells in bone marrow, spleen, lung and thymus were increased significantly in Bmi1−/− mice compared with wild-type mice, and were decreased dramatically in AMSC-transplanted Bmi1−/− mice compared with vehicle-treated Bmi-1−/− mice (Fig. 8E–H)
We demonstrated that Bmi-1 deficiency resulted in growth retardation and premature aging because of decreased proliferation and increased apoptosis, decreased ratios and dysmaturity of lymphocytic series, impaired skeletal growth and development and premature osteoporosis associated with decreased osteoblastic bone formation, increased adipocyte formation and up-regulated senescence-associated molecules, and increased oxidative stress and DNA damage of multiple organs
Summary
Genomic DNA of AMSCs contained Bmi-1 and the mRNA of AMSCs showed expression of embryonic stem cell markers including OCT-4, CXCR4 and Nanog (Fig. 1C–E) These results suggested that second-passage AMSCs from β -gal transgenic mice had good stem cell potential. AMSC transplantation prolonged the median survival from 39 days to 92 days, and increased body weight, and overall size of the body, thymus, spleen and kidney in Bmi-1−/− mice (Fig. 2A–D) These results demonstrated that AMSC transplantation ameliorated growth retardation and premature aging in Bmi-1−/− mice. Compared to vehicle-transplanted Bmi-1−/− mice, in AMSC-transplanted Bmi1−/− mice, the percentages of Ki67-positive thymocytes and renal cells were increased, the percentages of Caspase3-positive and TUNEL-positive thymocytes and renal cells were decreased significantly (Figure E–J) These results demonstrated that AMSC transplantation promoted cell proliferation and inhibited cell apoptosis in Bmi-1−/− mice. These results demonstrated that AMSC transplantation increased the ratio of lymphocytic series relative to total white blood cells in Bmi-1−/− mice
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