Experimental methods to preserve male fertility and treat male factor infertility

This article describes experimental stem cell and gene therapies that might be used to treat male factor infertility.

Kathrin Gassei, Ph.D., Kyle E. Orwig, Ph.D.

Volume 105, Issue 2, Pages 256-266


Infertility is a prevalent condition that has insidious impacts on the infertile individuals, their families, and society, which extend far beyond the inability to have a biological child. Lifestyle changes, fertility treatments, and assisted reproductive technology (ART) are available to help many infertile couples achieve their reproductive goals. All of these technologies require that the infertile individual is able to produce at least a small amount of functional gametes (eggs or sperm). It is not possible for a person who does not produce gametes to have a biological child. This review focuses on the infertile man and describes several stem cell-based methods and gene therapy approaches that are in the research pipeline and may lead to new fertility treatment options for men with azoospermia.

  • deepabhartiya

    Dear Prof Orwig

    Your article nicely reviews various options available to overcome infertility in men arising due to treatment for cancer and other indications or in cases with idiopathic non-obstructive azoospermia. You have discussed expansion and transplantation of isolated spermatogonial stem cells (SSCs) or intact testicular tissue and the use of pluripotent stem cells (embryonic or induced pluripotent stem cells) to differentiate into gametes.

    We have reported a sub-population of pluripotent and relatively quiescent very small embryonic-like stem cells (VSELs) among SSCs in adult mammalian testis (1,2). They will prove to be complete game changers in the field of oncofertility as they survive oncotherapy in both mice (2) and human (3) testis. Cells (comprising VSELs and Sertoli cells) isolated from seminiferous tubules of chemoablated mouse testis (25 mg/Kg busulphan) spontaneously differentiate into sperm in culture (4). Also transplanting niche (Sertoli or mesenchymal) cells restores spermatogenesis in chemoablated mouse testis (2). Thus there is no merit in banking and transplanting SSCs. The conversion of ES/iPS cells into primordial germ cells (PGCs) is a major road block while attempting to differentiate them into gametes whereas VSELs are PGCs which survive in few numbers in adult gonads and thus spontaneously differentiate into sperm in vitro (5). Please feel free to refer to following references.

    1. Bhartiya D, Kasiviswanathan S, Unni SK, Pethe P, Dhabalia JV, Patwardhan S, Tongaonkar HB. Newer insights into premeiotic development of germ cells in adult human testis using Oct-4 as a stem cell marker. J Histochem Cytochem. 2010; 58(12):1093-1106. doi: 10.1369/jhc.2010.956870.

    2. Anand S, Bhartiya D, Sriraman K, Patel H, Manjramkar DD. Very small embryonic-like stem cells survive and restore spermatogenesis after busulphan treatment in mouse testis. J Stem Cell Res Ther 2014; 4:216. doi: 10.4172/2157-7633.1000216.

    3. Kurkure P, Prasad M, Dhamankar V, Bakshi G. Very small embryonic-like stem cells (VSELs) detected in azoospermic testicular biopsies of adult survivors of childhood cancer. Reprod Biol Endocrinol. 2015 Nov 9;13:122. doi: 10.1186/s12958-015-0121-1.

    4. Anand S, Patel H, Bhartiya D. Chemoablated mouse seminiferous tubular cells enriched for very small embryonic-like stem cells undergo spontaneous spermatogenesis in vitro. Reprod Biol Endocrinol. 2015; 13(1):33. doi: 10.1186/s12958-015-0031-2.

    5. Bhartiya D, Hinduja I, Patel H, Bhilawadikar R. Making gametes from pluripotent stem cells- A promising role for very small embryonic-like stem cells. Reprod Biol Endocrinol. 2014; 12:114. doi: 10.1186/1477-7827-12-114.

    Sandhya Anand and Deepa Bhartiya
    Stem Cell Biology Department
    National Institute for Research in Reproductive Health
    Mumbai, INDIA 400 012

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