Potential Spermatogenesis Recovery with Bone Marrow Mesenchymal Stem Cells in an Azoospermic Rat Model

Abstract

Non-obstructive azoospermia is the most challenging type of male infertility. Stem cell based therapy provides the potential to enhance the recovery of spermatogenesis following cancer therapy. Bone marrow-derived mesenchymal stem cells (BMSCs) possess the potential to differentiate or trans-differentiate into multi-lineage cells, secrete paracrine factors to recruit the resident stem cells to participate in tissue regeneration, or fuse with the local cells in the affected region. In this study, we tested whether spermatogenically-induced BMSCs can restore spermatogenesis after administration of an anticancer drug. Allogeneic BMSCs were co-cultured in conditioned media derived from cultured testicular Sertoli cells in vitro, and then induced stem cells were transplanted into the seminiferous tubules of a busulfan-induced azoospermatic rat model for 8 weeks. The in vitro induced BMSCs exhibited specific spermatogonic gene and protein markers, and after implantation the donor cells survived and located at the basement membranes of the recipient seminiferous tubules, in accordance with what are considered the unique biological characteristics of spermatogenic stem cells. Molecular markers of spermatogonial stem cells and spermatogonia (Vasa, Stella, SMAD1, Dazl, GCNF, HSP90α, integrinβ1, and c-kit) were expressed in the recipient testis tissue. No tumor mass, immune response, or inflammatory reaction developed. In conclusion, BMSCs might provide the potential to trans-differentiate into spermatogenic-like-cells, enhancing endogenous fertility recovery. The present study indicates that BMSCs might offer alternative treatment for the patients with azoospermatic infertility after cancer chemotherapy.

Transplantation of Autologous Bone Marrow Mesenchymal Stem Cells into the Testes of Infertile Male Rats and New Germ Cell Formation

“…Some studies reported that MSCs had no positive effects on regeneration of germinal epithelium, nor could differentiate into GCs in the testis (25, 26). However others reported that transplanted MSCs not only had the potency for differentiation into GCs (28), but also they could fully differentiate into sperm and regenerate spermatogenesis (27, 29). A recent study has showed the supportive role of BM-MSCs for recovery of spermatogenesis after transplantation into the testes of busulfan-induced infertile male hamsters (30).…”

“…Although, no study reported similar quantitative data, in total, controversial reports existed regarding the viability of MSCs after transplantation into testes. A group of researchers have stated that MSCs could not survive in the testis (25), whereas others have shown that MSCs were alive 2 months after transplantation (27–29). This finding showed that, transplanted BM-MSCs decreased (died and absorbed) with progression of time.…”

“…Results were compared between three groups. Any of the previously stated studies used autologous stem cells for transplantation and none of them also reported quantitative information about the fate of transplanted MSCs (25, 27–29). Moreover, in any of them the fate of transplanted cells was assessed and compared in different periods of time after transplantation.…”

Induction of spermatogenesis after stem cell therapy of azoospermic guinea pigs

“…In another rodent species, hamsters, intra-seminiferous tubule injection of BM-MSCs activated spermatogenesis in a busulfan-induced azoospermic model . Furthermore, intra-seminiferous tubule injection (ZAHKOOK et al, 2014;ZHANG et al, 2014) and intra-testicular injection of BM-MSCs (MONSEFI et al, 2013) were also found to induce spermatogenesis in the seminiferous tubules of busulfan-induced azoospermic rats. Furthermore, the same results with BM-MSCs therapy were found in a testicular torsion model of azoospermia in rats (SABBAGHI et al, 2012).…”

The differentiation potential of adipose tissue-derived mesenchymal stem cells into cell lineage related to male germ cells

“…Although previous studies have shown that MSCs maintained in media containing RA differentiate into male germ cells (Nayernia et al, 2006;Drusenheimer et al, 2007;Zhang et al, 2014) and that TCC contributed to this differentiation (Huang et al, 2010;Kaviani et al, 2014) additional gene expression and other analyses should be performed to confirm whether the ATMSCs treated in the present study, differentiate into cell lineage related to male germ cells.…”