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Effects of VEGF + Mesenchymal Stem Cells and Platelet-Rich Plasma on Inbred Rat Ovarian Functions in Cyclophosphamide-Induced Premature Ovarian Insufficiency Model

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Abstract

Premature ovarian insufficiency (POI), a fertility disorder affecting women under 40 years of age, is characterized by early loss of ovarian function. This study was aimed to maintain ovarian function in POI animal models by mesenchymal stem cells (MSCs) transplantation with/without the supplementation of platelet-rich plasma (PRP). Adipose tissue-derived MSCs were isolated from inbred rats (Fisher-344), and constitutive expression of both VEGF and GFP were maintained by transfection with plasmids, pVEGF and pGFP-N. PRP was derived from the blood of healthy untreated rats. A total of 60 rats were divided into 5 groups of 12 rats in each. First group was kept as untreated-control (Control), and POI model was induced in Fisher-344 rats by cyclophosphamide in the next four groups. Second group was kept as sham-operated-control (Sham). MSC, PRP and MSC+ PRP-treated groups were transplanted following the validation of POI model in rats. After 2 months following the transplantation, anti-mullerian-hormone (AMH) and oestradiol (E2) blood levels were measured. Follicles were evaluated after hematoxylin-eosin staining, and the immunofluorescence staining and gene expression analyses were performed to show the ovarian regeneration. The follicular count was improved after MSC- and MSC + PRP-treatment to 63% of Control-group and significantly higher than that in Sham-group, but a significant increase was not observed in PRP-group. Higher AMH and E2 levels were measured in MSC + PRP than in Sham-group, and CXCL12, BMP-4, TGF-β and IGF-1 expressions were also increased. This study showed MSCs +/-PRP transplantation after POI supports recovery of the follicular count and function. For ovarian recovery, a single administration of PRP was found not sufficient. Although MSC treatment increased follicular regeneration, better results were obtained in the co-transplantation of MSCs and PRP. These results might be promising for follicular regeneration in POI patients.

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Abbreviations

AMH:

Anti-mullerian-hormone

AT-MSCs:

Adipose tissue-derived mesenchymal stem cells

bFGF:

Basic fibroblast growth factor

BMP-4:

Bone morphogenetic protein 4

CNTF:

Ciliary neurotropic factor

CXCL12:

C-X-C motif chemokine ligand 12

CYP19A:

Cytochrome P450 aromatase

R:

Pearson product-moment correlation coefficient

E2 :

Oestradiol

FBS:

Foetal bovine serum

G3PDH:

Glyceraldehyde 3-phosphate dehydrogenase

GDF9:

Growth Differentiation factor 9

GFP:

Green fluorescent protein

GV:

Germinal vesicle

H&E:

Hematoxylin and Eosin

IGF-1:

Insulin-like growth factor 1

IL-10:

Interleukin 10

IL1b:

Interleukin 1b

KGF:

Keratinocyte growth factor

KL:

Kit-ligand

LIF:

Leukemia inhibitory factor

MSCs:

Mesenchymal stem cells

OSCs:

Oogonial stem cells

p:

Probability

PCNA:

Proliferating cell nuclear antigen

POI:

Premature ovarian insufficiency

PRP:

Platelet-rich plasma

TGF-β:

Transforming growth factor beta 1

TRAIL:

TNF-related apoptosis-inducing ligand

VEGF:

Vascular endothelial growth factor

VSEL:

Very small embryonic-like stem cells

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Acknowledgements

We thank Experimental Medicine Research and Application Unit (DETAB) at Kocaeli University for their assistance in our experimental work. This work was supported by the Scientific and Research Council of Turkey (TUBITAK) [grant number 114S398].

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Authors and Affiliations

  1. School of Medicine, Department of Obstetrics and Gynecology, Reproductive Endocrinology and Infertility and Assisted Reproductive Technology (ART), Kocaeli University, Unit. Izmit, 41380, Kocaeli, Turkey

    Birol Vural

  2. Graduate School of Health Sciences, Department of Stem Cell, Center for Stem Cells and Gene Therapies Research and Practice, Kocaeli University, Izmit, 41380, Kocaeli, Turkey

    Gokhan Duruksu & Merve Gorguc

  3. Center for Stem Cells and Gene Therapies Research and Practice, Kocaeli University, Izmit, 41380, Kocaeli, Turkey

    Gokhan Duruksu

  4. Department of Obstetrics and Gynecology, University of Health Sciences- Haydarpasa Numune Training and Research Hospital, 34668, Istanbul, Turkey

    Fisun Vural

  5. Department of Histology and Embryology, Istinye University, 34460, Istanbul, Turkey

    Erdal Karaoz

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  1. Birol Vural
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Vural, B., Duruksu, G., Vural, F. et al. Effects of VEGF + Mesenchymal Stem Cells and Platelet-Rich Plasma on Inbred Rat Ovarian Functions in Cyclophosphamide-Induced Premature Ovarian Insufficiency Model . Stem Cell Rev and Rep 15, 558–573 (2019). https://doi.org/10.1007/s12015-019-09892-5

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