According to the World Health Organisation, as many as one in six married couples in the world cannot conceive naturally. Of these, 20-30 per cent of infertility is related to men. Azoospermia is a condition that causes male infertility, of which non-obstructive azoospermia (NOA) is the most serious, mainly due to the dysfunction of spermatogenesis in the testes, which fails to produce functional spermatozoa.NOA accounts for 60% of the men with azoospermia, and more than 70% of patients with non-obstructive azoospermia are unable to obtain spermatozoa even with surgical manipulation.Currently there are no effective treatments available for patients with non-obstructive azoospermia. There is no effective treatment for patients with non-obstructive azoospermia.

 

 

Mesenchymal stem cells (MSCs) are increasingly being developed as a new approach to therapeutic tissue repair and regeneration due to their low immunogenicity, high differentiation capacity, and involvement in processes such as cell proliferation, migration, and immunomodulation.

What is non-obstructive azoospermia?

Azoospermia is a condition in which a man's semen does not contain sperm and is classified into obstructive azoospermia and non-obstructive azoospermia. Obstructive azoospermia, which accounts for 40% of azoospermia, is caused by obstruction of the testicular network and the vas deferens, and can be treated mainly by surgical means. The main cause of non-obstructive azoospermia is spermatogenic dysfunction, which includes disorders of the spermatogenesis process, sperm maturation blockage and single support cell syndrome; congenital causes of which include Klinefelter's syndrome and Y chromosome microdeletions, and acquired causes include testicular torsion, mumps, orchitis, cryptorchidism and medical problems (chemotherapy and radiotherapy) [1]. Most non-obstructive azoospermia is difficult to treat and has a low success rate.

Non-obstructive azoospermia

Treatment aims to restore fertility

Due to the irreversible nature of spermatogenesis damage in patients with NOA, testicular sperm biopsy and assisted reproductive techniques are the options to modify infertility in patients with NOA, with testicular sperm extraction (TesticuLar sperm extraction, TESE) and intracytoplasmic sperm injection (ICSI) being the the only options for fertility [1, 2].

However, the success of TESE-ICSI in patients with NOA is limited as spermatozoa are found to be present in the testicular tissue of approximately 50% of patients during testicular sperm extraction [3] and the probability of subsequent egg fertilisation after ICSI is approximately 50% [4]. Studies have shown that the final probability of successful fertilisation with this technique is about 13.4% [5]. Considering this low success rate, the success rate of egg fertilisation can be improved by pharmacologically improving male spermatogenesis.

 

 

Mesenchymal Stem Cells.

Potential for treating non-obstructive azoospermia

MSCs are popular among scientists and clinicians for their multilinear differentiation potential, low immunogenicity and active participation in tissue repair and regeneration after migration to damaged sites.

The therapeutic efficacy of MSCs is based on their ability to secrete a large number of signalling molecules that mimic the functional activity of various targets in vivo and are involved in processes such as cell survival, proliferation, migration, angiogenesis, and immunomodulation. Based on these advantages, MSCs transplantation is considered as a potential therapy for inducing spermatogenesis and treating male infertility.

 

Mesenchymal Stem Cells.

Into the NOA experimental animal model

Several possible mechanisms of testicular function recovery during MSC-induced tissue regeneration have been demonstrated in animal experiments:

(1) MSCs may be involved in inhibiting the production of anti-sperm antibodies to prevent azoospermia due to autoimmunity;

(2) MSCs may reduce factors leading to infertility by reducing spermatogenic cell apoptosis;

(3) MSCs may reduce spermatogenic cell damage induced by oxidative stress;

(4) MSCs can stimulate the production of testosterone, which is an important androgen;

(5) MSCs can differentiate into germ cells;

(6) MSCs cells secrete growth factors such as bone morphogenetic proteins and transforming growth factor β, which are androgen-inducing factors that stimulate the restoration of spermatogenic cell function;

(7) MSCs connect with endogenous cells to restore damaged cell function;

(8) MSCs reverse glycolysis and glycogen imbalance in spermatozoa by regulating the AKT/GSK3 axis;

(9) MSCs can alter the expression of spermatogenesis-related miRNAs and their target genes [6].

Preclinical studies in animal models have shown that transplantation of MSCs into the testes of chemical or surgical NOA animal models can both induce spermatogenesis and differentiate MSCs into germ cells, restoring male fertility (Table 1).

Table 1: Mesenchymal stem cell therapy studies in animal azoospermia model studies

 

MSC walks into NOA clinical treatment trial

Studies in animal models of MSC therapy for azoospermia have demonstrated the potential for application to the treatment of human azoospermia. Clinical studies of MSC for the treatment of male infertility are still in their infancy. Up to now, there are six studies on MSCs for the treatment of male infertility on the U.S. clinical trials website [6], all of which are in clinical phase I/II, see Table 2 [7].

 

Table 2: Clinical trials of MSCs for the treatment of male reproductive disorders

 

In the current decade, the emerging field of stem cell therapy has rapidly become the new era of regenerative medicine. The diverse potential of MSCs has been the focus of research by many scientists in the fields of molecular biology, genetic engineering, and even general medicine, for the development of new approaches to treating a wide range of diseases. Experimental methods based on MSCs are currently under development, and it is believed that there will be a breakthrough in the study of MSCs for male sterility in the near future.