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Anti-aging Effect of Transplanted Amniotic Membrane Mesenchymal Stem Cells in a Premature Aging Model of Bmi-1 Deficiency.

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 ?-galactosidase (?-gal) transgenic mice or wild-type (WT) mice labeled with DiI. Three reinjections were given, once every seven days. Phenotypes of 5-week-old ?-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.

SUBMITTER: Xie C

PROVIDER: S-EPMC4570627 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Anti-aging Effect of Transplanted Amniotic Membrane Mesenchymal Stem Cells in a Premature Aging Model of Bmi-1 Deficiency.

Xie Chunfeng C Jin Jianliang J Lv Xianhui X Tao Jianguo J Wang Rong R Miao Dengshun D

Scientific reports 20150915

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-transpla ...[more]

PMID: 26370922

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Project description:BACKGROUND:Many adult women younger than 40?years old have premature ovarian failure (POF) and infertility. Previous studies confirmed that different tissue-derived stem cells could restore ovarian function and folliculogenesis in chemotherapy-induced POF mice. The aim of this study was to explore the therapeutic efficacy and underlying mechanisms of human amniotic mesenchymal stem cells (hAMSCs) transplantation for hydrogen peroxide-induced ovarian damage. METHODS:Bilateral ovaries of female mice were burned with 10% hydrogen peroxide to establish a POF model. After 24?h of treatment, hAMSCs and diethylstilbestrol were administered to POF mice by intraperitoneal injection and intragastric administration, respectively. After either 7 or 14?days, ovarian function was evaluated by the oestrus cycle, hormone levels, ovarian index, fertility rate, and ovarian morphology. The karyotype was identified in offspring by the G-banding technique. hAMSCs tracking, immunohistochemical staining, and real-time polymerase chain reaction (PCR) were used to assess the molecular mechanisms of injury and repair. RESULTS:The oestrus cycle was recovered after hAMSCs transplantation at 7 and 14?days. Oestrogen levels increased, while follicle-stimulating hormone levels decreased. The ovarian index, fertility rate, and population of follicles at different stages were significantly increased. The newborn mice had no obvious deformity and showed normal growth and development. The normal offspring mice were also fertile. The tracking of hAMSCs revealed that they colonized in the ovarian stroma. Immunohistochemical and PCR analyses indicated that changes in proteins and genes might affect mature follicle formation. CONCLUSIONS:These results suggested that hAMSCs transplantation can improve injured ovarian tissue structure and function in oxidatively damaged POF mice. Furthermore, the mechanisms of hAMSCs are related to promoting follicular development, granulosa cell proliferation, and secretion function by improving the local microenvironment of the ovary.

Project description:BackgroundMany reports have shown that various kinds of stem cells have the ability to recover premature ovarian aging (POA) function. Transplantation of human amniotic epithelial cells (hAECs) improves ovarian function damaged by chemotherapy in a mice model. Understanding of how to evaluate the distinct effects of adult stem cells in curing POA and how to choose stem cells in clinical application is lacking.MethodsTo build a different degrees of POA model, mice were administered different doses of cyclophosphamide: light dose (70 mg/kg, 2 weeks), medium dose (70 mg/kg, 1 week; 120 mg/kg, 1 week), and high dose (120 mg/kg, 2 weeks). Enzyme-linked immunosorbent assay detected serum levels of sex hormones, and hematoxylin and eosin staining allowed follicle counting and showed the ovarian tissue structure. DiIC18(5)-DS was employed to label human amniotic mesenchymal stem cells (hAMSCs) and hAECs for detecting the cellular retention time in ovaries by a live imaging system. Proliferation of human ovarian granule cells (ki67, AMH, FSHR, FOXL2, and CYP19A1) and immunological rejection of human peripheral blood mononuclear cells (CD4, CD11b, CD19, and CD56) were measured by flow cytometry (fluorescence-activated cell sorting (FACS)). Distinction of cellular biological characteristics between hAECs and hAMSCs was evaluated, such as collagen secretory level (collagen I, II, III, IV, and VI), telomerase activity, pluripotent markers tested by western blot, expression level of immune molecules (HLA-ABC and HLA-DR) analyzed by FACS, and cytokines (growth factors, chemotactic factors, apoptosis factors, and inflammatory factors) measured by a protein antibody array methodology.ResultsAfter hAMSCs and hAECs were transplanted into a different degrees of POA model, hAMSCs exerted better therapeutic activity on mouse ovarian function in the high-dose administration group, promoting the proliferation rate of ovarian granular cells from premature ovarian failure patients, but also provoking immune rejection. Meanwhile, our results showed that the biological characteristics of hAMSCs were superior to hAECs, but not to expression of immune molecules.ConclusionsThese results suggest that hAMSCs are a more effective cell type to improve ovarian function than hAECs. Meanwhile, this distinct effect is attributable to cellular biological characteristics of hAMSCs (telomerase activity, expression level of pluripotent markers, cytokine and collagen secretion) that are superior to hAECs, except for immunological rejection. Sufficient consideration of cell properties is warranted to move forward to more effective clinical therapy.

Project description:Although many reports show that various kinds of stem cells have the ability to recover function in premature ovarian aging, few studies have looked at stem cell treatment of natural ovarian aging (NOA). We designed this experimental study to investigate whether human amniotic mesenchymal stem cells (hAMSCs) retain the ability to restore ovarian function, and how hAMSCs work in this process.To build the NOA mouse model, the mice were fed for 12-14 months normally with young fertile female mice as the normal control group (3-5 months old). Hematoxylin and eosin staining permitted follicle counting and showed the ovarian tissue structure. An enzyme-linked immunosorbent assay was used to detect the serum levels of the sex hormones estradiol (E2), anti-mullerian hormone (AMH), and follicle-stimulating hormone (FSH). The proliferation rate and marker expression level of human ovarian granule cells (hGCs) (ki67, AMH, FSH receptor, FOXL2, and CYP19A1) were measured by flow cytometry (FACS). Cytokines (growth factors) were measured by a protein antibody array methodology. After hepatocyte growth factor (HGF) and epidermal growth factor (EGF) were co-cultured with hGCs, proliferation (ki67) and apoptosis (Annexin V) levels were analyzed by FACS. After HGF and EGF were injected into the ovaries of natural aging mice, the total follicle numbers and hormone levels were tested.After the hAMSCs were transplanted into the NOA mouse model, the hAMSCs exerted a therapeutic activity on mouse ovarian function by improving the follicle numbers over four stages. In addition, our results showed that hAMSCs significantly promoted the proliferation rate and marker expression level of ovarian granular cells that were from NOA patients. Meanwhile, we found that the secretion level of EGF and HGF from hAMSCs was higher than other growth factors. A growth factor combination (HGF with EGF) improved the proliferation rate and inhibited the apoptosis rate more powerfully after a co-culture with hGCs, and total follicle numbers and hormone levels were elevated to a normal level after the growth factor combination was injected into the ovaries of the NOA mouse model.These findings provide insight into the notion that hAMSCs play an integral role in resistance to NOA. Furthermore, our present study demonstrates that a growth factor combination derived from hAMSCs plays a central role in inhibiting ovarian aging. Therefore, we suggest that hAMSCs improve ovarian function in natural aging by secreting HGF and EGF.

Dataset Information

Anti-aging Effect of Transplanted Amniotic Membrane Mesenchymal Stem Cells in a Premature Aging Model of Bmi-1 Deficiency.

Publications

Anti-aging Effect of Transplanted Amniotic Membrane Mesenchymal Stem Cells in a Premature Aging Model of Bmi-1 Deficiency.

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