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 Table of Contents  
Year : 2021  |  Volume : 5  |  Issue : 4  |  Page : 237-246

Insights into stem cell therapy for premature ovarian insufficiency

1 Department of Gynecology, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011; Department of Integrative Medicine and Neurobiology, Institute of Integrative Medicine of Fudan University, Institute of Brain Science, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
2 Department of Integrative Medicine and Neurobiology, Institute of Integrative Medicine of Fudan University, Institute of Brain Science, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China

Date of Submission25-Mar-2021
Date of Decision30-Sep-2021
Date of Acceptance27-Oct-2021
Date of Web Publication30-Dec-2021

Correspondence Address:
Cong-Jian Xu
Department of Gynecology, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011
Yi Feng
Department of Integrative Medicine and Neurobiology, Institute of Integrative Medicine of Fudan University, Institute of Brain Science, School of Basic Medical Sciences, Fudan University, Shanghai 200032
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2096-2924.334379

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Hormone therapy, assisted reproductive technology, and regenerative medicine have been used to treat infertility due to premature ovarian insufficiency (POI), with limited success. It is timely to survey the field by outlining the controversies and promising prospects of evolving stem cell (SC) therapy for patients with POI. We first discuss several strategies of tissue-derived SC therapy and induced/engineered SC therapy and then enumerate mechanisms, including cellular regenerability induced in reproductive tissues and paracrine effects induced by various chemokines. Next, we evaluate the potential benefits of SC-based tissue engineering in reversing ovarian aging. Finally, we discuss the clinical feasibility of SC therapy and generalized regenerative medicine for the treatment of POI. In summary, SCs and SC-derived exosomes, induced pluripotent SCs, engineered SCs, and tissue engineering could start a new chapter for fertility rehabilitation in patients with POI. Uncovering the underlying molecular mechanisms and biological efficacy could be facilitated not only by animal experiments but also by security screening and clinical trials to validate SC-based therapy for POI.

Keywords: Premature ovarian failure; Premature ovarian insufficiency; Regenerative medicine; Stem cell; Tissue engineering

How to cite this article:
Pei ZL, Wang ZY, Lu WH, Zhang FF, Li X, Tong XY, Feng Y, Xu CJ. Insights into stem cell therapy for premature ovarian insufficiency. Reprod Dev Med 2021;5:237-46

How to cite this URL:
Pei ZL, Wang ZY, Lu WH, Zhang FF, Li X, Tong XY, Feng Y, Xu CJ. Insights into stem cell therapy for premature ovarian insufficiency. Reprod Dev Med [serial online] 2021 [cited 2022 Jun 30];5:237-46. Available from: https://www.repdevmed.org/text.asp?2021/5/4/237/334379

  Introduction Top

The average age for natural menopause in women is approximately 48–51 years.[1] Premature ovarian insufficiency (POI), also known as premature ovarian failure (POF), is defined as the cessation of menstruation due to loss of ovarian function before the age of 40 years and affects approximately 1%–3% of women before 40,[2] 0.1% of women before 30,[3] and 0.01% of women before 20[4] years of age.

Women with POI are characterized by anovulation, estrogen deficiency, and primary or secondary amenorrhea. The diagnosis is mainly based on elevated levels of serum follicle-stimulating hormone (>40 IU/L, equal to the menopausal range).[3],[5] POI is divided into three clinical stages (occult, biochemical, and overt), whereas POF is better accounted for in the third stage.[6] This disorder is highly heterogeneous, with a broad spectrum of pathogenic causes, including genetic, autoimmune, metabolic (galactosemia), and iatrogenic (antitumor treatments).[2]

Currently, the management of POI includes hormone replacement therapy, oocyte cryopreservation, in vitro activation, and regenerative medicine.[1],[7] Although hormone replacement therapy remains the main therapy for POI, it is not effective in restoring ovarian function and may increase the risk of breast cancer, due to hormonal side effects. Recently, in vitro activation has emerged as a promising strategy for the treatment of patients with infertility due to POI; however, uncertainty remains with regard to the negative effects of Akt-stimulating drugs on oocytes.[8]

Cell, tissue, and organ restoration techniques have been developed to treat organ dysfunction; thus, an alternative therapeutic method called regenerative medicine has flourished, as shown in [Figure 1].[9],[10] Some of the key components of regenerative medicine are stem cells (SCs), which can be grouped into embryonic SCs and adult SCs based on their developmental stages. Among the latter, mesenchymal SCs (MSCs) have therapeutic potential for POI because of their low immunogenicity. There are several types of MSCs, including bone marrow stromal cells (BMSCs), adipose-derived MSCs (ADSCs), and peripheral blood mononuclear cells. Although increasing evidence has shown that SCs are effective in animal POI models,[11],[12],[13] the mechanisms underlying the efficacy of SCs in POI management remain to be elucidated.
Figure 1: Stem cell-based therapy and tissue engineering approaches in regenerative medicine for management of premature ovarian insufficiency. Various novel treatment options have been tested for premature ovarian insufficiency. Preclinical studies and clinical trials have used various stem cell and progenitor cell populations to test their efficacy for therapeutic applications. In addition, stem cells can secrete some exosomes, which can perform paracrine-like functions by transferring microRNAs, enzymes, and some other bioactive molecules. Next-generation approaches are being explored, including in vitro implantation of reprogrammed engineered stem cells to optimize the phenotype. The regenerative capacity of engineered biomimetic reproductive tissues, such as follicles encapsulated in scaffolds, is still being evaluated.

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In this study, we investigated the SC-based and engineered tissue traits for treating ovarian dysfunction, the underlying intrinsic mechanism, and the latest preclinical and clinical progress on SC therapy. Our discussion illustrates that SC therapy provides potential therapeutic efficiency in reversing infertility induced by POI.

  Methods Top

A search for original articles on SC-based therapy related to POI published up to October 2020 was conducted using PubMed. Keyword combinations included “premature ovarian failure,” “premature ovarian insufficiency,” “stem cell,” “stem cell therapy,” “regenerative medicine,” and “engineering tissue.” We focused on research or investigations of the potential mechanism of SCs in POI management. Where appropriate, the reference list was also searched for further relevant reports. In total, 128 articles were identified and evaluated in this study. The confirmed articles were limited to full-text English papers.

  Results Top

Characteristics of stem cells

Tissue-derived stem cells

Bone marrow stromal cells

BMSCs are a type of multipotent adult SCs that can be found in the bone marrow microenvironment. Under certain conditions, these cells can differentiate into various cells, such as adipocytes, cartilage, and bone.[14]

BMSCs possess low immunogenicity due to minimal expression of major histocompatibility complex class II molecules and secretion of many anti-inflammatory factors.[15] Furthermore, BMSCs can serve as candidates for tissue repair because of their ability to migrate and home to injured sites.[16] They are actively involved in tissue damage repair by regulating the immune response and enhancing the function of related cells through various cytokine profiles.[17],[18]

Adipose-derived mesenchymal stem cells

ADSCs are another type of multipotent MSCs present within the adipose tissue.[19] These cells can be successfully isolated through collagenase digestion and centrifugal density gradient separation from the processed lipoaspirate, which is a less painful collection procedure than that of other sources such as BMSCs.[20]

The initial application of ADSCs in regenerative medicine has focused on their differentiation potential along the endodermal, ectodermal, and mesodermal lineages.[21] Moreover, their ability to exert paracrine effects on various cytokines, chemokines, and growth factors enables self-healing of damaged tissue.[22]

Menstrual blood-derived stromal cells (MenSCs); oogonial stem cells/female germline stem cells

Some SCs are uniquely derived from women, including menstrual blood-derived stromal cells (MenSCs) and oogonial SCs (OSCs). MenSCs have been employed in multiple studies because of their easy and noninvasive acquisition.[23],[24] Considering their differentiative capacity and plasticity, we propose that MenSCs can help devise new methods for infertility treatment.[25],[26],[27],[28] OSCs, also known as ovarian SCs or female germ SCs, possess the ability to assemble into mature follicles under suitable conditions.[29],[30],[31] Although controversies regarding whether they might be destroyed by chemotherapy exist, the hidden value of OSCs is still worth exploring.[32]

Human amnion-derived mesenchymal stem cells, umbilical cord mesenchymal stem cells, human placenta-derived mesenchymal stem cells

Several types of SCs can be isolated during the prenatal period. Maternal–fetal substances, including the amnion, umbilical cord, and placenta, are the sources of MSCs. Amniotic fluid SCs and human amniotic epithelial cells are often referred to as human amnion-derived MSCs (hAD-MSCs).[33],[34],[35] After a baby is delivered, umbilical cord MSCs retain very low immunogenicity; therefore, they are suitable for allogeneic therapy.[36] Among the MSCs derived from the umbilical cord, perivascular SCs (PSCs) derived from umbilical arteries show higher expression of the Notch ligand Jagged1 than PSCs derived from umbilical veins or Wharton's jelly-derived MSCs, which indicates their promising angiogenic potential.[37] Human placenta-derived MSCs (hPMSCs), also known as human chorionic plate-derived MSCs,[38],[39] are commonly used in reconstruction of ovarian function. hPMSCs have been demonstrated to secrete multiple cell factors, including granulocyte colony-stimulating factor, chemokine (C-C motif) ligand 5, and IL-6/-8/-10.[40]

Induced pluripotent stem cells

The first successful derivation of induced pluripotent SCs (iPSCs) occurred in 2006.[41] Researchers introduced four transcription factors, Oct4, Sox2, C-Myc, and Klf4, into somatic cells and obtained the iPSCs. Although probable risks of iPSCs, such as genetic and epigenetic abnormalities, and increased cancer risk due to overexpression of oncogenes, such as c-Myc,[42],[43],[44] have been reported, iPSCs still have enormous potential for ovarian function restoration.[45],[46]

Engineered stem cells

Gene editing technologies can be applied to produce SCs with advanced functions and specificity in comparison with their natural properties. These engineering approaches will help deepen the value and clinical applicability of next-generation SCs.[47]

The genetic modification of MSCs is achieved via the transfection of various vectors to optimize the phenotype. First, knocking out human leukocyte antigen genes can lower the immunogenicity of allogeneic SCs and provide a potential source of universal donor cells.[48] Second, targeted migration could be notably improved in modified MSCs.[49] Third, engineered MSCs are capable of overexpressing cytokines and growth factors to enhance tissue repair. For example, treatments may include transfection with microRNA (miR)-21 lentiviral vector, plasmids, or phospho-vascular endothelial growth factor (pVEGF) to overexpress some regulatory factors[50],[51] and heat shock pretreatment to enhance the vitality of MSCs.[52]

Stem cell-derived exosomes

A recent study showed that MSCs can secrete exosomes, which function as a cargo of multiple bioactive molecules, including enzymes, mRNAs, tRNAs, miRs, and heat shock proteins[53] [Figure 2]. Exosomes can directly influence cell-to-cell communication and signal transduction, thereby regulating the biological behavior of cells.[54] Exosomes may serve as an ideal nominator in acellular therapy because of their reduced risk of tumor formation or planting in ectopic tissues during MSC transplantation[55] and their wide range of sources and easy accessibility.[56] Studies have reported that MSC exosomes suppress chemotherapy-induced granulosa cell (GC) apoptosis in mouse models of POF by implanting functional miRNAs such as miR-644-5p and miR-10a.[57],[58],[59],[60],[61] Furthermore, some studies have pointed out that the appropriate packaging of secreted factors into synthetic microparticles can directly improve stability and recapitulate SC function.[62],[63] Further research is needed to elucidate the specific pathway by which SCs and exosomes interact with the ovary.
Figure 2: Schematic diagram of exosome-derived mesenchymal stem cells. Exosomes are nanovesicles, and their membrane is made up of ceramide, cholesterol, and phosphoglycerides. Exosomes contain multiple bioactive molecules, such as DNA, RNA, and HSPs. They also contain functional proteins, such as integrin, enzymes, cell attachment-related proteins, and cell recognition-related proteins, including annexin, tetraspanin, and flotillin. ICAM: Intercellular adhesion molecule; HSPs: Heat shock proteins; MHC: Major histocompatibility.

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Potential therapeutic effects

Preclinical studies on SC therapy are listed according to SC type [Supplementary Table 1]. Among the clinical studies mentioned in [Supplementary Table 2], most included patients with follicle-stimulating hormone levels >20 or 25 IU/l, under the age of 40 years, with a clinical POI diagnosis. We summarized next-generation SC-based therapies for POI [Supplementary Table 3], including treatment with iPSCs, engineered SCs, exosomes, and engineered tissues.

In summary, the numbers of secondary, primary, and primordial follicles increase and ovarian mass improves after SC transplantation. In addition, serum levels of estradiol and anti-Müllerian hormone increase, while follicle-stimulating hormone levels decrease in response to rising estradiol levels. These results indicate the restoration of ovary function. However, the mechanism underlying the progressive phenotype needs to be better elucidated.

Studies on therapeutic effects and molecular mechanisms

Differentiation properties of stem cells

SCs tend to migrate to damaged tissue sites,[64] which stimulate ovarian recovery. Multiple chemokine and growth factor receptors, such as the (C–C motif) ligand 5, vascular cell adhesion molecule-1, receptors of IL-8, hepatocyte growth factor (HGF), P-selectin, and matrix metalloproteinases (MMPs; MMP-2 and MMP-9), are involved in the homing of MSCs.[13],[65] In many studies, the ability of these cells to differentiate into other cell types, such as adipocytes, osteoblasts, neurons, and endotheliocytes, has been proven in vivo and in vitro.[66] However, further evidence is urgently needed to determine whether MSCs can differentiate into oocytes after migration. Another study revealed that ovarian-derived mesenchymal-like SCs possess high plasticity to differentiate into osteogenic and chondrogenic tissue as well as precursors of primordial germ cells.[67] Ovarian-derived SCs have been found in the ovarian surface epithelium in the ovaries of humans and other mammals, such as rabbits, mice, marmosets, and sheep.[68],[69],[70],[71],[72] However, a recent single-cell sequencing analysis did not support the existence of OSCs in the ovaries.[73] Therefore, it is notable that SCs of various cellular sizes, genetic signatures, and representative markers have been reported by other investigators using various approaches, and the precise identity of ovarian SCs remains elusive.

Paracrine effects of stem cells

It is widely recognized that the restorative effects of SCs rely more on paracrine activities than on pluripotent differentiation[74],[75] [Figure 3]. The paracrine activities of SCs refer to their capacity to secrete chemokines, growth factors, hormones, and other biochemical messengers to regulate adjacent cells.[28],[76],[77],[78] Paracrine signaling shapes the ovarian microenvironment by triggering angiogenesis, anti-inflammatory, immunoregulatory, antiapoptosis, and antifibrosis pathways.[13]
Figure 3: Paracrine mechanisms involved in stem cell-based therapies. (a) Apoptosis of GCs is inhibited by the activities of cytokines, microRNAs, transcriptional regulators, and genes. Cytokines include VEGF, HGF, FGF2, and IGF-1. (b) MMPs, TGF-β1, VEGF, bFGF, ADM, and ET-1 can protect ovaries from fibrosis. (c) Increasing secretion of VEGF, FGF2, HGF, angiogenin, TGF-β1, MMPs, IGF, and MCP1 promotes angiogenesis of targeted vessels. (d) Secreting HGF, TGF-β, and PGE2 regulates the ratio of T helper cell 17 and T regulatory immune cells. (e) Regulation of HO-1/-2 expression improves oxidative stress, leading to an increase in SOD1 and decrease in ROS levels. GCs: Granulosa cells; VEGF: Vascular endothelial growth factor; HGF: Hepatocyte growth factor; FGF-2: Fibroblast growth factor-2; IGF-1: Insulin-like growth factor-1; MMP: Matrix metalloproteinase; TGF-β: Transforming growth factor beta; bFGF: Basic fibroblast growth factor; ET-1: Endothelin-1; ADM: Adrenomedullin; LIF: Leukemia inhibitory factor; MCP-1: Monocyte chemoattractant protein-1; PGE-2: Phenyl glycidyl ether-2; SOD-1: Superoxide dismutase-1.

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Antiapoptotic effects

Follicles experience atresia when 10% of GCs undergo apoptosis.[79] Several studies have demonstrated the protective and regenerative effects of different MSCs in chemotherapeutic-induced ovarian toxicity, and the antiapoptotic mechanisms of SCs have been related to certain cytokines, exosomal miRNAs, transcriptional regulators, and target genes.[80],[81],[82],[83],[84],[85],[86],[87] Growth factors, including VEGF, HGF, fibroblast growth factor 2, and insulin-like growth factor-1, produced by MSCs may inhibit apoptosis in GCs.[13],[79] The involvement of many signaling pathways in antiapoptotic effects, including IRE1-alpha and nerve growth factor/TrkA, has been demonstrated.[87],[88] The overexpression of miR-144-5p and miR-21 in MSCs is relevant to the suppression of GC apoptosis by targeting phosphatase and tensin homolog.[50],[89] Moreover, miR-644-5p loaded by MSC exosomes has also been reported to suppress the apoptosis of GCs by targeting p53.[90],[91] ADSC-derived exosomes include miR-10a and miR-146a, both of which anchor on genes such as IRAK1, TRAF6, and BIM, which induce GC apoptosis.[59] The antiapoptotic activity of hAD-MSCs has also been demonstrated by the promotion of Bcl-2 and VEGF as well as inhibition of proto-oncogene (c-myc) mRNA and Bcl-2-associated X protein expression in chemotherapy-induced POI models.[28],[92],[93]

Antifibrotic effects

Ovarian fibrosis can be triggered by mechanical or cryogenic ovarian injury. Evidence has shown that multiple cytokines, such as MMPs, transforming growth factor (TGF)-β1, VEGF, and endothelin-1, are associated with POI-related fibrogenesis.[94] Notably, the level of TGF-β1 has been found to increase in patients with POI, which might be attributed to fibrogenesis due to accelerated follicular atresia.[94],[95] The antifibrotic effect is related to HGF, basic fibroblast growth factor, and adrenomedullin.[96] MSCs may influence the above-mentioned cytokines to inhibit fibroblast proliferation and extracellular matrix sedimentation. The intrinsic mechanism underlying the antifibrotic effects of SCs requires further clarification.

Angiogenesis effects

Importantly, MSCs generate a vast array of cytokines, part of which can boost neovascularization in various tissues. SCs promote angiogenesis and ovarian recovery via diverse bioactive factors, including VEGF, fibroblast growth factor 2, HGF, angiogenin, TGF-β1, MMPs, insulin-like growth factor, and monocyte chemoattractant protein 1.[45],[96],[97],[98],[99] HGF facilitates the growth of vascular area, and VEGF is a crucial angiogenic factor that has been shown to promote development, recruitment, and selection of dominant antral follicles, mainly by affecting the length, extent, and number of branching points of the targeted vessels.[100],[101] Interestingly, VEGF and HGF synergistically promote angiogenesis, leading to increased vascular diameters.[102],[103] Knockdown of membrane type 1 MMP results in reduced neovascularization.[104] Researchers have also observed increased expression of the proliferation marker Ki67 with MSC secretome management in the ovarian endothelial cells.[105]

Immunoregulatory and anti-inflammatory effects

Various types of SCs have been reported to regulate ovarian inflammation and immune system. In POI mice with PMSC transplantation, Th17/Tc17 and Th17/Treg cell ratios decrease via the PI3K/Akt signaling pathway after ovarian restoration;[106],[107] likewise, ADSC transplantation promotes Treg proliferation, and umbilical cord MSCs decrease Th1/Th2 cytokine levels and uNK cell expression.[108],[109] hAD-MSC transplantation can also reduce inflammatory reactions in the ovaries via the activities of tumor necrosis factor-alpha.[84] Although BMSCs are likely to regulate various types of immune system cells in vitro[110],[111] and in vivo[112] with the secretion of multiple molecules (HGF, TGF-β, prostaglandin E2),[113],[114] robust evidence of their role in POI is still needed.

Antioxidants effects

In the ovary, excessive accumulation of reactive oxygen species can induce infertility by reducing oocyte maturation and GC luteinization,[115],[116] which deteriorates oocyte quality and reproductive outcome.[117] However, reactive oxygen species levels can be significantly reversed in both hPMSC and ADSC transplantation mice with HO-1/2 expression, while levels of antioxidant biomarkers such as superoxide dismutase 1 and catalase are accordingly increased.[118],[119] Currently, the relationship between the antioxidant effects of BMSCs and ovarian function reservation in POI has not been reported.

Tissue engineering and regenerative medicine

Engineered biomimetic reproductive tissues are being manufactured to support germ cells and might eventually restore the reproductive capacity of patients with infertility.[120] The most promising development is the encapsulation of SCs/germ cells as well as tissues with three-dimensional (3D) culture hydrogels, allowing mimicking of microenvironments such as oocyte–somatic cell connections, which are lost in conventional 2D culture methods.[121],[122] Recent studies have attempted to adjust the size and construction of open micropores to achieve better nutrient diffusion and cell–cell interactions.[123],[124],[125]

To engineer these tissues, a composite system of cells, scaffolds, and bioactive compounds is taken for a tissue engineering triad.[126] Scaffolds are crucial because they provide surfaces for cell adhesion and proliferation.[1] Moreover, MSCs with bioactive scaffolds exert greater paracrine effects on cytokines than do MSCs alone in culture medium.[127],[128],[129] In this case, various materials, such as hydrogel encapsulation and decellularized extracellular matrix scaffolds, were tested and used in the scaffolds.[130],[131],[132]

However, the ovary is a heterogeneous organ, that is, quiescent and growing follicles must be in dynamic equilibrium to form an ovulatory cycle.[133] Hence, 3D printing can be applied to address all of these implant requirements for sophisticated biomimicry and personalization. Given the comprehensive recovery of ovarian function caused by tissue engineering, this novel technique can be a promising strategy to cure idiopathic and iatrogenic POI.[139],[140]

  Outlook Top

The area of SC therapy has greatly increased over the past 50–60 years. First-generation (primary, tissue-derived) SCs were used in laboratories and clinics decades ago, whereas second-generation cells (human embryonic stem cells (hESCs) and iPSCs) have been used in fundamental research in the past 5–10 years. Recently, functional oocyte derivation from iPSCs was achieved,[134] which brings new hope for women with insufficient ovarian reservation. Along with an SC engineering toolkit, engineered SCs can be used for novel therapeutic applications.

There are obvious advantages of SC therapy in patients with POI. First, compared with conventional approaches such as hormone replacement therapy and oocyte cryopreservation, SC therapy can better restore ovarian reserve, promote folliculogenesis, prevent GC apoptosis, and regulate the secretion of ovarian hormones. Second, SC therapy is potentially suitable for patients with POI caused by chemotherapy.[135] Although ethical concerns regarding embryonic SCs transplantation can be resolved by using MSCs as an alternative, there are several concerns that need to be addressed for therapeutic use. First, a major drawback of using SCs is access to high-quantity and -quality materials. The transplantation approach can be invasive and can potentially cause postoperative side effects such as immune responses. Second, the existence of variables between experimental models makes it difficult to standardize the efficacy of SCs. Third, as SC therapy is a cell-based therapy, its safety requires further evaluation because of the risks of forming tumors or ectopic tissue in vivo[55] and the inaccurate migration of MSCs in a systemic injection route.[136]

Of note, the field of organoid engineering promises to reform medicine with extensive applications of material, engineering, and clinical interest. The first 3D cultures of ovarian surface epithelium were constructed to demonstrate the relationship between chronic inflammation and ovarian cancer, demonstrating mechanical and therapeutic potentials of organoid engineering on reproductive systems.[137] Prospectively, as studies and technology progress, in vitro maturation of eggs via ovarian organoids would be a less invasive method in treating patients with infertility due to POI.

SCs and exosomes, including miRs, have positive effects on restoring ovarian function, including angiogenesis and hereditary stability. The application of human SC treatment in patients with infertility due to POI is still at a very early stage of preclinical trials and clinical research.[138] The efficacy and therapeutic mechanisms of SC and SC derivative therapy require specific observations and standardization.

Supplementary information is linked to the online version of the paper on the Reproductive and Developmental Medicine website.

Financial support and sponsorship

This work was supported partially by the by the National Natural Science Foundation of China (grant numbers 81973945 and 81673766 to YF, and grant number 81572555 to XL), the Shanghai Municipal Committee of Science and Technology (grant number 18411953800 to CJX), and the Development Project of Shanghai Peak Disciplines-Integrated Chinese and Western Medicine to YF.

Conflicts of interest

There are no conflicts of interest.

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