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. 2016 Oct;12(4):2447-2454.
doi: 10.3892/etm.2016.3671. Epub 2016 Sep 6.

Mesenchymal stem cells with irreversibly arrested proliferation stimulate decidua development in rats

Alisa P Domnina  1 , Polina V Novikova  2 , Olga G Lyublinskaya  1 , Valeriy V Zenin  1 , Irina I Fridlyanskaya  1 , Vyacheslav M Mikhailov  1 , Nikolay N Nikolsky  1
Affiliations

Mesenchymal stem cells with irreversibly arrested proliferation stimulate decidua development in rats

Alisa P Domnina et al. Exp Ther Med. 2016 Oct.

Abstract

Stem cell transplantation, which is based on the application of mesenchymal stem/stromal cells (MSCs), is a rapidly developing approach to the regenerative therapy of various degenerative disorders characterized by brain and heart failure, as well as skin lesions. In comparison, the use of stem cell transplantations to treat infertility has received less attention. One of the causes of miscarriages and fetal growth delay is the loss of the decidual reaction of endometrial cells. The present study modeled decidualization processes in pseudopregnant rats. For cell transplantation experiments, the rats were transplanted with MSCs established from endometrial fragments in menstrual blood (eMSCs). These cells express common MSC markers, are multipotent and are able to differentiate into various tissue lineages. Cell therapy frequently requires substantial cell biomass, and cultivation of MSCs may be accompanied by significant changes to their properties, including malignant transformation. In order to minimize the potential for malignant transformation, the proliferation of eMSCs was irreversibly suppressed by irradiation and mitomycin C treatment. Transplantation of the rats with viable, non-proliferating eMSCs stimulated the development of all elements of decidual tissue. Conversely, transplantation of the rats with cells killed using 95% ethanol did not result in the development of decidual tissue. The present study demonstrated the potential for applying eMSCs to the cellular therapy of infertility associated with endometrial disorders characterized by decidualization insufficiency and implantation failure. In addition, the transplantation of viable but non-proliferating cells ensured that their oncogenic potential was limited.

Keywords: arrested proliferation; decidualization; mesenchymal stem cells of endometrium; pseudopregnancy.

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Figures

Figure 1.
Figure 1.
Endometrial mesenchymal stem cell (eMSC) properties. (A) Cell morphology. (B) Flow cytometry analysis of CD marker expression. All plots show relative expression of the surface markers (%). eMSCs differentiated into (C) adipocytes and (D) osteoblasts (magnification, ×400). Adipocytes and osteoblasts are characterized by accumulation of lipid droplets and calcium deposits, respectively. Lipid drops stained with Oil Red are located in the perinuclear area of the differentiated adipocytes. Сalcium deposits were stained with Alizarin Red. The frequency of adipogenic and osteogenic differentiation was 70–80 and 30%, respectively. (E) Nestin expression in native eMSCs (scale bar=25 µm). FITC, fluorescein isothiocyanate; PE, phycoerythrin; CD, cluster of differentiation; HLA-DR, human leukocyte antigen-DR.
Figure 2.
Figure 2.
Endometrial mesenchymal stem cells were exposed to 10 µg/ml Mit C for 1.5 h. (A) Cell viability was analyzed by flow cytometry with propidium iodide staining. (B) Proliferation was assessed by constructing growth curves, and (C) the cell cycle distribution was measured by flow cytometry at 24 and 72 h following treatment with Mit C, and 24 h after subculturing. Data are presented as the mean ± standard deviation (n=3). *P<0.05 vs. control. Mit C, mitomycin C.
Figure 3.
Figure 3.
Endometrial mesenchymal stem cells (eMSCs) were exposed to various doses (3, 6 or 10 Gy) of ionizing radiation (IR). (A) Cell viability was analyzed by flow cytometry with propidium iodide staining. (B) The proliferation of eMSCs irradiated with various doses of IR was assessed by growth curves, and (C) the cell cycle distribution was measured by flow cytometry at 24 and 72 h following irradiation, and 24 h after subculturing. Data are presented as the mean ± standard deviation (n=3). *P<0.05 vs. control.
Figure 4.
Figure 4.
Transplantation of irreversibly arrested endometrial mesenchymal stem cells (eMSCs) into the uterus of pseudopregnant rats promoted the decidualization process. (A and B) The uterus of pseudopregnant rats following inoculation with human eMSCs. (A) Viable eMSCs with arrested proliferation were inoculated into the left uterine horn (L), whereas PBS was injected into the right horn (R) (control). (B) eMSCs killed with 95% ethanol were injected into the left horn, and PBS was injected into the right horn. (C) The weights of decidual tissue in the uterine following injections of normal eMSCs, MitC-treated eMSCs, irradiated eMSCs (6 Gy), ethanol-fixed eMSCs (fixed cells) or PBS. *P<0.05 vs. PBS. (D and E) Histological sections of a pseudopregnant rat uterus following eMSC transplantation (hematoxylin and eosin staining; magnification, ×100). (D) Mesometrial part of the decidua consisting of large decidual cells. (E) Antimesometrial part of the decidua consisting of small decidual cells. MitC, mitomycin C; PBS, phosphate-buffered saline.
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