Written by: Yang, Fujian Medical University
Expert review: Professor Li Jing, Affiliated Hospital of Jiangsu University
Recently, American and Indian scholars jointly published a review in the international journal Cells[1], which described the evidence of recent research on the treatment of infertility with different types of stem cells and current research, and concluded that mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs) are suitable candidates for clinical treatment of infertility.
01115% of couples worldwide are affected by infertility
Infertility is currently considered a global health problem, affecting about 15% of couples worldwide, which has a huge impact on the psychological and social health of couples, resulting in a decline in marital harmony and quality of life.
According to statistics[2], about 15% of couples worldwide (equivalent to 48.5 million couples) are affected by infertility; in the United States, about 9% of men aged 15 to 44 report infertility problems, compared with about 10% of women.
The causes of infertility may be related to men (30%), including varicocele, cryptorchidism, testicular cancer and azoospermia; women (30%), including premature ovarian failure and uterine disorders; or both (30%). These couples are deprived of the right to become parents, so there is an urgent need to develop effective treatments to fulfill their strong desire to conceive the next generation.
The picture is a common cause of infertility Picture from the literature[1]
At present, the conventional treatment of infertility is aimed at male factors, such as the ligation of varicocele spermatic veins, etc., and for female factors, such as the use of ovulation induction drugs and intrauterine artificial insemination. Assisted reproductive technology (ART) can also be used after conventional treatment fails, which can eventually enable 80% of infertile couples to find a solution. However, there are also a considerable number of couples who are unable to conceive after ART treatment, and ART is also unable to address infertility caused by gamete defects caused by genetic defects. As a result, scientists are seeking a less invasive and cost-effective treatment.
In recent years, stem cells have increasingly been studied as promising alternative therapies in the field of regenerative medicine. Stem cells can replenish damaged tissue and histiocytes that differentiate into multiple lineages through self-renewal properties, which is considered a new way to treat infertility. Extensive preclinical studies and clinical trials are underway to explore the safety and efficacy of stem cells as a promising treatment for restoring fertility.
02 Evidence of different types of stem cells for infertility
Stem cells are pluripotent cells that remain undifferentiated in embryonic and adult tissues and can self-renew and differentiate into specific tissue cells when needed, thereby restoring the function of damaged organ tissues. Currently, stem cells are showing new promise in various animal experiments and clinical studies to overcome problems associated with infertility.
Stem cells are divided into embryonic stem cells (ESC), adult stem cells (including mesenchymal stem cell MSCs), induced pluripotent stem cells (iPSCs), spermatogen stem cells (SSCs) and ovarian stem cells according to their sources. With minimal ethical concerns and access to cell sources, scientists are conducting extensive research on induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs) with a view to their potential applications in reproductive medicine, particularly infertility due to azoospermia and premature ovarian failure.
Mesenchymal stem cells (MSCs)
MSCs are a type of stem cell that has received widespread attention in recent years due to its advantages of rich sources, low immunogenicity, and few ethical issues. Various preclinical and clinical studies have reported potential applications of MSCs in the treatment of infertility caused by ovarian and endometrial dysfunction.
Studies [3] show that MSCs can chemotaxis into and settle in the damaged ovaries, releasing various cytokines (such as vascular endothelial growth factor, insulin-like growth factor, and hepatocyte growth factor) through paracrine mechanisms, inducing the formation of new blood vessels, preventing apoptosis and fibrosis, thereby improving ovarian dysfunction. In addition, MSCs also help the endometrium regenerate and restore fertility by releasing various bioactive molecules to regulate inflammation and other immune responses and activate tissue-specific progenitor cells.
Image from literature[1]
Induced pluripotent stem cells (iPSCs)
iPSCs are the reprogramming of already highly differentiated human adult cells into pluripotent stem cells with the potential for multidirectional differentiation, which avoids the ethical issues of using embryos because they come from adult cells, and they are readily available. In addition, iPSCs are developed from the patient's own somatic cells, so immune rejection is less likely to occur. At present, various in vitro studies have been conducted on the differentiation of iPSCs into germ cells.
Image from literature[1]
In one study[4] skin cells were isolated from azoospermia patients and fertile men, reprogrammed and cultured and amplified, and then xenotranslated into the testicles of immunodeficient nude mice, the results showed that iPSCs transplanted into seminal tubules could differentiate into germ cell-like cells (GCLCs). In addition, other studies [5] have also explored the feasibility of differentiating iPSCs into ovarian cells, which gives hope to couples with insufficient ovarian reserve or inability to produce functional eggs.
03 Stem cell treatment of infertility clinical research specific cases
Currently, a number of preclinical and clinical studies on stem cell therapy for infertility have demonstrated that stem cell therapy may be a viable treatment for infertility. From https://clinicaltrials.gov/ website, we found that there are currently 39 stem cell therapies related to infertility registered in the clinic.
Asherman syndrome (AS) is caused by uterine adhesions and partial or complete occlusion of the uterine cavity, which can lead to infertility or recurrent miscarriages and chronic pelvic pain and amenorrhea. Conventional treatments include repair of the uterine cavity by adhesion and replacement of the normal endometrium with hormone therapy. However, these methods have been found to be associated with various obstetric complications, such as preterm birth. The safety and efficacy of stem cell therapy for the treatment of AS are currently being evaluated.
One study [6] used autologous menstrual blood mesenchymal stem cells (MB-MSCs) to treat seven patients with drug-resistant Asherman syndrome who received MB-MSC transplants followed by hormone therapy. After MB-MSC transplantation, 5 patients reached an endometrial thickness of 7 mm, 1 patient became pregnant naturally and 2 were conceived by assisted reproductive technology.
The picture shows the change in the thickness of the endometrium before and after stem cell transplantation Picture from the literature[6]
Azoospermia is characterized by the absence of mature, morphologically and functionally normal sperm in semen, and about 30% of infertility is associated with the male factor. With its strong differentiation potential and regulatory properties, stem cell therapy can bring a silver lining for reproduction for azoospermia patients. Currently, several clinical trials have been or are underway (NCT02025270, NCT02641769, NCT02414295) in which bone marrow-derived MSCs are injected into the testicular network of patients with azoospermia to assess hormone levels as well as testicular size and sexual potential.
brief summary:
Globally, about 15% of couples have difficulty conceiving. As the reproductive age increases, so does the incidence of infertility. Nearly 80% of the problems can be solved with the help of assisted reproductive technologies, etc. However, nearly 20% of couples are still unable to conceive.
In this case, stem cell therapy can bring hope to infertile couples. At present, the most popular research is induced pluripotent stem cells and mesenchymal stem cells, as well as stem cell-derived exosomes, etc., and they have shown their prominence in the treatment of infertility. However, the current research is still in its infancy, and further exploration of the mechanism of action of stem cells and their derivatives to restore fertility is needed in the future, and more large-scale clinical trials are needed to obtain evidence of safety and efficacy.
bibliography:
[1] Saha S, Roy P, Corbitt C, Kakar SS. Application of Stem Cell Therapy for Infertility. Cells. 2021;10(7):1613. Published 2021 Jun 28.
https://pubmed.ncbi.nlm.nih.gov/34203240/
[2]https://www.singlecare.com/blog/news/infertility-statistics/
[3] Zhao YX, Chen SR, Su PP, et al. Using Mesenchymal Stem Cells to Treat Female Infertility: An Update on Female Reproductive Diseases. Stem Cells Int. 2019;2019:9071720. Published 2019 Dec 6.
https://pubmed.ncbi.nlm.nih.gov/31885630/
[4] Ramathal C, Durruthy-Durruthy J, Sukhwani M, et al. Fate of iPSCs derived from azoospermic and fertile men following xenotransplantation to murine seminiferous tubules. Cell Rep. 2014;7(4):1284-1297.
https://pubmed.ncbi.nlm.nih.gov/24794432/
[5] Yamashiro C, Sasaki K, Yabuta Y, et al. Generation of human oogonia from induced pluripotent stem cells in vitro. Science. 2018;362(6412):356-360.
https://pubmed.ncbi.nlm.nih.gov/30237246/
[6] Tan J, Li P, Wang Q, et al. Autologous menstrual blood-derived stromal cells transplantation for severe Asherman's syndrome. Hum Reprod. 2016;31(12):2723-2729.
https://pubmed.ncbi.nlm.nih.gov/27664218/