Bone Marrow Transplantation Restores Follicular Maturation and Steroid Hormones Production in a Mouse Model for Primary Ovarian Failure

Mohsen Ghadami,Salama A Salama,Ayman Al-Hendy,Xinlei Chen,Billy R Ballard,M Ram Sairam,Ebtehal El-Demerdash,Anthony E Archibong,Awadh A Binhazim,Dong Zhang,Shree Ram Singh

doi:10.1371/journal.pone.0032462

Abstract

Recent studies suggest that bone marrow stem cells (BMSCs) are promising grafts to treat a variety of diseases, including reproductive dysfunction. Primary ovarian failure is characterized by amenorrhea and infertility in a normal karyotype female, with an elevated serum level of follicle-stimulating hormone (FSH) and a decrease level of estrogen caused by a mutation in FSH receptor (FSHR) gene. Currently, there is no effective treatment for this condition. The phenotype of FSHR (−/−) mouse, FORKO (follitropin receptor knockout), is a suitable model to study ovarian failure in humans. Female FORKO mice have elevated FSH, decreased estrogen levels, are sterile because of the absence of folliculogenesis, and display thin uteri and small nonfunctional ovaries. In this study, we determined the effects of BMSC transplantation on reproductive physiology in this animal model. Twenty four hours post BMSC transplantation, treated animals showed detectable estroidogeneic changes in daily vaginal smear. Significant increase in total body weight and reproductive organs was observed in treated animals. Hemotoxylin and eosin (H&E) evaluation of the ovaries demonstrated significant increase in both the maturation and the total number of the follicles in treated animals. The FSH dropped to 40–50% and estrogen increased 4–5.5 times in the serum of treated animals compared to controls. The FSHR mRNA was detected in the ovaries of treated animals. Our results show that intravenously injected BMSCs were able to reach the ovaries of FORKO mice, differentiate and express FHSR gene, make FSHR responsive to FSH, resume estrogen hormone production, and restore folliculogenesis.

Highlights

Hypergonadotropic hypogonadism accounts for up to 40% of women with primary amenorrhea [1]
Alleles, PCR amplification showed a normal allele band in (2/2) animals treated by bone marrow (BM) cells from (+/+) donors in all tested organs, including brain, lung, heart, liver, spleen, ovary, uterus, vagina and femur, while the control group of (2/2) recipients injected with (2/2) donor BM did not show this normal FSH receptor (FSHR) allele in any tested organs
We have shown here that cells extracted from the BM of normal syngeneic mice grafted to a preclinical FSHR knock-out mouse model (FORKO) stimulate follicular maturation to the antral stage, increase E2 production, decrease follicle-stimulating hormone (FSH) secretion, and express FSHR mRNA in the ovary

Summary

Introduction

Hypergonadotropic hypogonadism accounts for up to 40% of women with primary amenorrhea [1]. The term ‘‘resistant ovary syndrome’’ (ROS) is typically used to describe women with primary or secondary amenorrhea, elevated circulating endogenous FSH and luteinizing hormone (LH) levels, 46, XX karyotype, intact uterus and vagina, absence of concomitant autoimmune disease, and presence of numerous primordial follicles as evident in ovarian biopsy [3]. This condition is a common cause of primary ovarian failure [4] and is devastating for the patients who, besides being infertile, will usually face an accompanying wide range of physical and psychological problems. Selesniemi et al [16] showed that stem cell transplantation prevents age-related infertility in adult female mammals

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