Bone marrow mesenchymal stem cells in premature ovarian failure: Mechanisms and prospects

Abstract

Premature ovarian failure (POF) is a common female reproductive disorder and characterized by menopause, increased gonadotropin levels and estrogen deficiency before the age of 40 years old. The etiologies and pathogenesis of POF are not fully clear. At present, hormone replacement therapy (HRT) is the main treatment options for POF. It helps to ameliorate perimenopausal symptoms and related health risks, but can't restore ovarian function and fertility fundamentally. With the development of regenerative medicine, bone marrow mesenchymal stem cells (BMSCs) have shown great potential for the recovery of ovarian function and fertility based on the advantages of abundant sources, high capacity for self-renewal and differentiation, low immunogenicity and less ethical considerations. This systematic review aims to summarize the possible therapeutic mechanisms of BMSCs for POF. A detailed search strategy of preclinical studies and clinical trials on BMSCs and POF was performed on PubMed, MEDLINE, Web of Science and Embase database. A total of 21 studies were included in this review. Although the standardization of BMSCs need more explorations, there is no doubt that BMSCs transplantation may represent a prospective therapy for POF. It is hope to provide a theoretical basis for further research and treatment for POF.

Keywords: bone marrow; mesenchymal stem cells; ovarian function; ovary; premature ovarian failure.

Figure 1

PRISMA flow diagram.

Figure 2

The possible mechanisms of bone marrow-derived mesenchymal stem cells (BMSCs) ameliorate premature ovarian failure (POF). BMSCs ameliorate ovarian function of POF through homing to injured ovary, paracrine effect, inducing angiogenesis, anti-apoptosis, anti-inflammatory, immunoregulation, autophagy regulation, antifibrosis, anti-oxidative stress and mitochondrial transfer.

Figure 3

The possible mechanisms of BMSCs homing to injured ovary. Tissue inflammation, hypoxia or injury may induce the high level of chemokines including stromal cell derived factor 1 (SDF1), hepatocyte growth factor (HGF), monocyte chemotactic protein-3 (MCP3). They are released into the bloodstream and promote BMSCs proliferation as well as express specific receptors such as CXC chemokine receptor 4 (CXCR4), cMET, CC chemokine receptor 1(CCR1). After binding with the ligand, BMSCs migrate to the injured tissue along the gradient of chemokines concentration. In addition, various adhesion molecules including CD44, p-selectin, vascular cell adhesion molecule 1 (VCAM1) participate in regulating the homing of BMSCs.

Figure 4

The possible mechanisms of BMSCs promote angiogenesis in POF. BMSCs help to promote angiogenesis through differentiating into endothelial cells (ECs), maintaining vascular stability, inhibiting ECs apoptosis and secreting angiogenic factors, including vascular endothelial growth factor (VEGF), stromal cell derived factor 1 (SDF1) and insulin-like growth factor 1 (IGF1) et. to promote ECs proliferation, as well as promoting ECs migration and tube formation via PI3K/Akt and GSK3β/βcatenin signal pathway. At the same time, the secrete factors reinforce the angiogenesis of BMSCs in turn.

Figure 5

The possible mechanisms of BMSCs in immunoregulation. BMSCs display immunomodulatory effect through paracrine effect and cell-cell contact. BMSCs secrete immunomodulatory related factors, including indoleamine 2,3 dioxygenase (IDO), nitric oxide (NO), prostaglandin E2 (PGE2), transforming growth factor-β (TGF-β), heme oxygenase 1 (HO1), hepatocyte growth factor (HGF), which participate in regulating the number or function of immune cells. BMSCs-derived tumor necrosis factor-stimulated gene-6 (TSG-6) promote the transform from pro-inflammatory macrophages (M1) to anti-inflammatory (M2) phenotype as well as inhibit the proliferation and inflammatory response of T cells. The paracrine effect is heightened after BMSCs- M1 contact, which enhance the expression of TSG-6. Moreover, CD200R on M1 bind with CD200 on BMSCs promote the transition of M1 to M2. At the same time, which contribute to promote the expression of CD200 on BMSCs.

Figure 6

The possible mechanisms of BMSCs in anti-apoptosis. BMSCs help to inhibit apoptosis through secreting vesicle containing microRNA-21(miR-210), which targeting to PDCD4 and PTEN, or secreting vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), insulin-like growth factor 1/2 (IGF1/2) or and regulating apoptosis related gene, including Bcl2, Bax, Caspase3, p53, as well as regulating genetic and epigenetic via TGFβ, Wnt/β-catenin, Hippo signal pathway.