Comparison of the different animal modeling and therapy methods of premature ovarian failure in animal model

HRT in the treatment of the POF animal model

AMH is a hormone secreted by granulosa cells in preantral follicles and small antral follicles of the ovary. Detection of AMH can determine the functional status of granulosa cells and number of follicles. It demonstrated that the recombinant AMH protein can increase primordial follicless, rescuing the fertility of a CTX-treated POF animal model. The protective mechanism of AMH on CTX-induced follicular loss may be related to autophagy [38].

Melatonin (N-acetyl-5-methoxytryptamine, honey), a hormone produced primarily by the pineal gland of the brain, can also be produced by peripheral reproductive tissue (the ovary, and the placenta). Many studies have shown that exogenous melatonin has protective effects on the nervous system, kidneys, lungs, testes, uterus, and ovaries [39, 40]. In ovarian tissues, as a free group purifier in follicles, melanin promotes egg maturation, embryo development, and luteinization of granuloma cells [41]. It is reported that intraperitoneal administration of melatonin (15 or 30 mg/kg) for 15 days can successfully rescue CIS-induced primordial follicle loss by inhibiting phosphorylation of PTEN/AKT/FOXO3a pathway components and preventing FOXO3a nuclear shuttling in primordial follicles [42]. Another study showed that melatonin (20 mg/kg/day) taken orally for 34 days can increase the number of primordial follicles and antral follicles, increase body and ovary weight, and enhance the level of AMH by attenuating the activation of SIRT1 signaling pathway [43].

As a member of the growth factor family, GH (a peptide hormone secreted by the anterior pituitary gland) plays a crucial role in regulating growth and development, the gonadal axis, metabolism, and the mental state. Using mouse recombinant mouse GH (rmGH) for CTX-induced POF can significantly reduced ovarian granulocyte injury and the number of atretic follicles, and significantly increased the number of mature oocytes. They confirmed that GH may promoted ovarian tissue repair and estrogen release by activating the Notch-1 signaling pathway in ovarian tissue [44]. Subsequently, it confirmed that GH possesses a protective effect on ovarian tissue in the CTX-induced POF rat model by directly or indirectly promoting the balance between oxidative stress and oxidative detoxification of cells [45].

Table 3 lists the recent research status of HRT in the POF animal model. Although the short-term effects of HRT on POF animal models are effective, the long-term effects on fertility remain unknown. Thus, HRT has been little studied in animal models of POF. However, clinically, the improvement of POF symptoms mostly depends on personalized hormone treatment, aiming to maximize efficacy and reduce the associated risks.

Table 3 Hormone replacement therapy (HRT) in the POF animal modelStem cells in the treatment of the POF animal modelStem cells from adult tissues in the treatment of the POF animal model

After using HRT for POF, the risk of cancer and cardiovascular disease is increased. Recently, stem cell therapy has become increasingly popular in POF studies. BMSCs are a member of the adult stem cell family with low immunogenicity and generally exist in the bone marrow microenvironment. BMSCs are isolated from bone marrow extract. Density gradient centrifugation is a common method of preparing BMSCs derived from bone marrow [47]. Under certain circumstances, BMSCs can renew and differentiate into different cells, such as bone, cartilage, and fat cells. Despite the low survival rate and limited differentiation potential of BMSCs after transplantation, cytokines secreted by the ovary can induce BMSCs to migrate to damaged tissues. In the ovarian microenvironment, BMSCs can inhibit inflammation, reduce OS, and regulate immunity to promote ovarian tissue repair by secreting cytokines (VEGF, HGF, IL-6) [48]. The specific mechanism of BMSCs in the treatment of POF has been fully described in this article [48]. However, the number of BMSCs is very limited, and the immunomodulatory properties of BMSCs vary among species. The aggressive procedure is painful for the patient and carries a risk of infection. In addition, their differentiation potential, number, and maximum lifespan significantly decrease with age. These factors greatly limit the clinical application of BMSCs.

ADMSCs have low immunogenicity and can secrete many important growth factors, cytokines, trophic factors, and regenerative factors. Compared with ADSCs from elderly donors, ADSCs from young donors showed a higher proliferation rate, and their differentiation ability still exists with age. Therefore, ADMSCs have advantages over BMSCs. ADSCs also maintain the potential to differentiate into cells of mesodermal origin. Their low immunogenicity makes them suitable for allogeneic transplantation and the treatment of drug-resistant immune diseases [49]. ADMSCs have the advantages of availability and repeatability in autologous cell repair and regeneration [50]. ADMSCs are usually derived from fat tissue during liposuction, lipoplasty, or isolated lipotomy procedures and are digested with collagenase, followed by centrifugation and washing [51]. ADMSCs from the inguinal subcutaneous fat of 6–8-week-old nondiabetic rats can be obtained. It also demonstrated that ADMSC transplantation can reduce the expression of Pannexin1 and Caspase3 molecules to play an anti-apoptotic role in the ovarian tissues of a POF animal model. ADSCs stopped growing at 11~12 subculture, and the number of ADSCs was lower than that of BMSCs. Mazini et al. compared the advantages and disadvantages of ADMSCs as well as the research status of their therapeutic application [52].

HuMenSCs can be isolated from menstrual blood. HuMenSCs are much easier to repair than other adult stem cells, possibly making them a potential clinical donor source. Gargett et al. first extracted HuMenSCs, which can differentiate into adipocytes, osteoblasts, and lung epithelial cells [53]. The therapeutic potential of HuMenSCs has been demonstrated in diabetes [54], myocardial infarction [55] and liver failure [56]. Human endometrial mesenchymal stem cells (ESCs) derived from menstrual blood have the characteristics of mesenchymal stem cells (MSCs). MSC surface markers (CD29, CD44, CD49f, CD90, CD105 and CD117) and ESC markers (Oct4 and SSEA3/4) were highly expressed on the HuMenSC surface [57]. It confirmed the differentiation of HuMenSCs into ovarian-like cells (especially GCs) by injecting HuMenSCs into CTX-induced POF rats through the tail vein [58]. However, the source of HuMenSCs in menstrual blood is limited, and there is a risk of infection.

BMSCs, ADMSCs and HuMenSCs are adult MSCs that have been extensively studied in POF animal models at present. Table 4 summarizes the research status and possible mechanisms of three types of stem cells and their exosomes in POF animal models. Its main advantages are low immunogenicity, strong homing ability and strong ability to split and self-renew. However, most of their extraction procedures are invasive and carry the risk of infection.

Table 4 The transplantation of stem cells from adult tissues in the POF animal modelStem cells from neonatal tissues in the treatment of the POF animal model

Compared with adult tissue stem cells, human–neonatal tissue stem cells have lower immunogenicity, fewer ethical issues, a lower risk of infection, and a painless and noninvasive harvesting process and are easy to expand in vitro. Neonatal tissues such as the umbilical cord, placenta, amniotic membrane, or chorionic membrane can be obtained directly after delivery, avoiding invasive procedures and ethical concerns [65]. Moreover, MSCs isolated from these neonatal tissues represent ontogenetic younger cells, at least as attractive candidates for tissue engineering and regenerative medicine. hUCMSCs are the most widely studied MSCs in human–neonatal tissue stem cells and are mainly extracted from different compartments of the human umbilical cord. Compared with BMSCs, hUCMSCs have extensive advantages. On the one hand, the extraction process is noninvasive, preventing the risk of infection. On the other hand, hUCMSCs show higher proliferation and differentiation activity and faster self-renewal. hUCMSCs maintained a stable doubling time (DT) until the 10th generation, and BMSCs showed notably increased DT after only the 6th generation. hUCMSCs have been widely investigated in clinical therapeutic phase I or II trials, such as spinal cord injury, Alzheimer’s disease, and liver failure [66]. In recent years, hUCMSCs have received much attention due to their enormous therapeutic potential in POF therapy. Several studies have shown that the injection of hUCMSCs (1 × 106/mL in 100 μL of PBS) through the tail vein can effectively improve the ovarian status. The method of extracting hUCMSCs from the human umbilical cord is fast, painless, and low immunity. However, there are more moral and ethical issues. The research progress of hUCMSCs in the POF animal model has been detailedly reviewed [4].

HESC-MSCs are cells isolated from an early embryo (before the gastrula stage) or primitive gonad. Compared with other sources of MSCs, hESC-MSCs,  they have a higher ability to proliferate and inhibit leukocyte growth [67]. HESC-MSCs show stronger anti-inflammatory properties than BMSCs [68]. HESC-MSCs can also overcome the obstacles encountered in harvesting MSCs from adult tissues, including the lack of appropriate donors, limited number of cells obtained in the acquisition process, limited ability to expand in vitro, and invasive nature of the procedure. HESC-MSCs have been shown to ameliorate chronic liver injury and autoimmune encephalitis. Bahrehbar et al. successfully extracted hESC-MSCs from the placenta and further confirmed that hESC-MSC transplantation was similar to BM-MSC transplantation, which can restore the structure and function of damaged ovarian tissue in CTX-induced POF mice and rescue fertility [69]. hESC-MSC transplantation has long been a controversial area. Proponents argue that it can help cure many intractable diseases because hESC-MSCs can differentiate into multifunctional APSCs, which most closely resemble human development. Opponents argue that hESC-MSC transplantation requires the destruction of embryos, which is anti-bioethical.

HPMSCs contain several stem cells based on placental anatomy: chorionic villi (CV-MSCs), amniotic membrane (AM-MSCs), chorionic plate (CP-MSCs), and umbilical cord Wharton Jelly (WJ-MSCs) [70]. Under the appropriate induction conditions, these placenta-derived MSCs can differentiate into various cell types. Compared with other stem cells from neonatal tissues, hESC-MSCs have the advantages of a convenient source, sufficient cell number, and easy isolation, culture, expansion, and purification, and they still possess the characteristics of stem cells after more than 30 generations. Transplantation of hESC-MSCs can restore the structure of damaged ovarian tissue and their function in CTX combined with BF-induced POF mice and rescue fertility. The possible mechanism is related to the promotion of follicle development, ovarian secretion, fertility, and ovarian cell survival through paracrine effects [69].

Human amniotic cells are divided into human amniotic epithelial cells (hAECs) and human amniotic mesenchymal stem cells (hAMSCs). Both cell types have the potential to differentiate into three layers of germ tissue. HAECs are a class of epithelial cells with stem cell characteristics that are not stem cells in nature because they cannot proliferate indefinitely. When hAECs were passaged to the fifth generation, the cells gradually became larger and older, and their proliferation ability was obviously weakened. However, hAMSCs could be transmitted to approximately the 30th generation without significant changes in cell morphology. hAMSCs had stronger differentiation and proliferation ability than hAECs. The biological characteristics of hAMSCs were superior to those of hAECs but were not superior in the expression of immune molecules. This effect may be because the cellular biological characteristics of hAMSCs, such as telomerase activity, expression level of pluripotent markers, cytokines, and collagen secretion, are superior to those of hAECs [71].

In addition to the above stem cells directly used in POF animal model therapy, other forms of stem cells have been investigated in POF treatment studies. Stem cell exosomes are a hot topic currently. Exosomes carry various microRNAs and proteins into target cells. Presently, exosomes from hUCMSCs and hAMSCs promote ovarian function by regulating the Hippo pathway and carry various microRNAs and proteins [72]. Collagen/hUCMSCs and Matrigel/hUCMSCs can also promote MSC adhesion and increase cell retention in the ovary [73]. In terms of the mode of administration in most animal studies, tail vein injections are the most widely used transplant method to deliver cells to recipients. However, most transplanted cells are trapped in the lungs and cannot reach the target organ. Hence, studies have designed sodium alginate-bioglass (SA-BG)-encapsulated hAECs to promote the adhesion properties, proliferative ability, migration, and homing ability of MSCs in the ovary [74]. Table 5 lists the transplantation of stem cells from neonatal tissues in the POF animal model.

Table 5 The transplantation of stem cells from neonatal tissues in the POF animal modelImmunological and gene therapy in POF animal model

In recent years, advances in immunology and genome medicine have improved our understanding of the pathogenesis of POF [94]. An increased number of B cells, CD4+ T cells, Th17 cells, and a decreased CD8+ T cells, Treg cells in POF patients have been reported [95]. Besides, the cytokines (IL-1α, IL-2, IL-6, IL-8, TNF-α, IFN-γ, IL-17 and IL-21) are upregulated [95, 96], and IL-10 is downregulated in POF patients [97]. Based on these advances, many related treatments such as thymopentin (TP-5), Ab4B19, and prednisone have gradually become research hotspots. Zhu et al. demonstrated that thymopentin (TP-5) significantly reduces the proportion of activated T cells (CD3+/CD8+) and M1/M2 macrophages, and the expression of inflammatory factors was decreased [37]. Co-administration of mouse zona pellucida 3 (mZP3) protein in combination with a DNA vaccine encoding the mZP3 gene can meliorate autoimmune ovarian disease through inducing Treg cells and anti-inflammatory cytokine production [98]. A clinical prospective study showed that short-term treatment with a prednisone can increase serum E2 levels and improves follicle growth [99]. However, the study requires a larger sample size.

Currently, most gene therapy research of POF is limited to the cellular and animal levels. These genes, including NEAT1/miR-654, miR-146a, miRNA-190a-5p, miR-146b-5p, miR-133b, and TRERNA1, are transferred into cells to ameliorate the POF symptoms by inhibiting apoptosis of ovarian granulosa cells (OGCs), stimulating estrogen synthesis, increasing the number of normal follicles, and decreasing the number of atretic follicle (Table 6) [100,101,102]. Gene therapy is still in experimental stage; it is not sure that whether the treatment will have a positive effect on patients.

Table 6 The immunological and gene therapy in the POF animal model

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