Stem cells (VSELs) and progenitors (OSCs, SSCs) in ovary and testis
VSELs are the quiescent stem cell population in the gonads and survive oncotherapy
PMSG (5 IU) treatment to chemoablated mice
Adult mouse ovary8
0.02 ± 0.008 %
0.03 ± 0.017 %
0.08 ± 0.03 %
Adult mouse testis25
0.03 ± 0.002 %
0.05 ± 0.005 %
0.1 ± 0.03 %
Testicular function restoration in cancer survivors
Hsiao et al., 2015 
Six to eight-week-old Sprague–Dawley rats underwent torsion for 3 h, followed by detorsion on the left testis. 3 × 104 MSCs from human orbital fat tissues (OFSCs) were injected via local injection into the left testis 30 min before detorsion.
Animals were sacrificed 7 days after torsion-detorsion. Local injections of OFSCs prevented torsion-induced infertility. Serum testosterone secretion was increased, while the elevation of FSH triggered by testicular injury was balanced. OFSCs also produced SCF in the damaged testis. Immunofluorescence staining revealed that most transplanted cells surrounded the Leydig cells. Some of transplanted cells differentiated into p450 expressing cells within 7 days.
Mehrabani et al., 2015 
Rat adipose tissue derived mesenchymal stem cells (ATMSCs) were injected in chemoablated testis (two doses of 10 mg/kg of busulfan with 21 days interval) into the efferent duct of right testes. Seminiferous tubules treated with ATMSCs had normal spermatogenesis whereas the untreated seminiferous tubules were empty.
Abd El Dayem et al., 2015 
Studies were done to restore fertility and reproductive functions after testicular failure induced by butributyltin oxide. Rats were injected a single dose of intravenous MSCs (3×106 cells) and followed up after 5 months. Transplantation of MSCs restored body weight, fertility rate, serum testosterone, LH, FSH hormones, testicular enzymes, sperm counts and improved testicular DNA fragmentation. MSCs transplantation showed normal spermatogenesis and complete recovery in germinal layers. A new therapeutic concept for male infertility treatment.
Zahkook et al., 2014 
MSCs were transplanted (1×108 cells via efferent ducts into the seminiferous tubules) in chemoablated rat induced by busulphan treatment. Some restoration of spermatogenesis was noted associated with increase in size of testis. MSCs have potential to trans-differentiate into germ cells and sperm in vivo in testicular microenvironment.
Anand et al., 2014 
Intertubular injection of Sertoli/ bone marrow derived MSCs (1×104 cells) in chemoablated (25 mg/Kg busulphan) mouse testis. Effects were studied after 2 months. The transplanted Sertoli/MSCs aligned as neo-tubules and were a source of growth factors to the VSELs that survived in chemoablated tubules and restored spermatogenesis. GFP tagged MSCs and Sertoli cells invariably always yielded non-green wild type sperm. Thus MSCs did not trans-differentiate, rather provided a healthy niche for VSELs to differentiate into sperm. Chemoablated mice could not mate and hence IVF was carried out using the sperm which resulted in early stage cleavage embryo.
Zhang et al., 2014 
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. Donor cells survived in recipient seminiferous tubules. 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. BMSCs might provide the potential to trans-differentiate into spermatogenic-like-cells, enhancing endogenous fertility recovery.
Cakici et al., 2013 
Busulfan treated rats were injected GFP tagged MSCs via rete testes. After 12 weeks, spermatogenesis was detected in few tubules and GFP+/VASA+ and GFP+/SCP1+ cells in testes indicated the trans-differentiation of MSCs into spermatogenetic cells in the appropriate microenvironment. Rats withcell treatment were mated to show the full recovery of spermatogenesis, and continuous generations were obtained. GFP tagged sperm were noted in offspring also.
Monsefi et al., 2013 
Donor MSCs from bone marrow were transplanted in busulphan (40 mg/Kg) treated rat testis. BrdU labeled MSCs (1.75×105) were transplanted into the seminiferous tubules. The injected BrdU labeled MSCs differentiated to spermatogonia and spermatozoa in the seminiferous tubules of the infertile testis and also to the interstitial cells between tubules.
Sabbaghiet al, 2012 
Rat bone marrow MSCs (5-10×106 cells) were cultured and transplanted via rete testis into torsionedazoospermic testis. Germ cell specific markers (Oct4, Vasa and c-Kit) were monitored for the differentiation of MSCs after transplantation. They did not observe recovery of spermatogenesis.
Aziz et al., 2011 
Bone marrow derived MSCs were transplanted into busulphan treated rats. One group received undifferentiated MSCs while another received transdifferentiated MSCs. Results showed that MSCs have potential for in vitro transdifferentiation into germ cells and in vivo transdifferentiation into spermatids and spermatocytes.
Lassalle et al., 2008 
Total bone marrow cells were transplanted into the seminiferous tubules of germ cells deficient C57B16J mice after one month of busulphan treatment. Found no evidence for transdifferentiation of bone marrow cells into gametes.
Lue et al., 2007 
Bone marrow cells from adult green fluorescent protein (GFP) mice were transplanted into seminiferous tubules and testicular interstitium of busulfan-treated wild-type or c-kit mutant (W/Wv) mice. 10–12 weeks after transplantation, cells were found to survive in recipient testes. Some GFP-positive donor cells appeared like Sertoli cell and expressed FSHR within the seminiferous tubules. GFP-positive cells in the interstitium expressed cytochrome P450 side chain cleavage enzyme (P450scc). Few GFP-positive donor cells had the appearance of spermatogonia or spermatocytes and expressed VASA. However, this was not found in the seminiferous tubules of W/Wv mice. Thus adult bone marrow cells, in a favorable testicular environment, differentiate into somatic and germ cell lineages. The resident neighboring cells in the recipient testis may control site-appropriate stem cell differentiation.
Ovarian function restoration in cancer survivors
Lai et al., 2015 
Mouse ovaries were damaged by treatment with busulfan and cyclophosphamide. Human endometrial mesenchymal stem cells (EnSCs) were transplanted via tail vein. EnSCs transplantation increased body weight and improved estrous cyclicity as well as restored fertility. Reduced loss of germ stem cells pool. Live pups were born in the transplanted group.
Zhu et al., 2015 
Human cord blood MSCs injected in cyclophosphamide treated rats resumed pregnancy. Direct injection into the ovary was better than tail vein injection. It led to resumption of estrus cycles, normal levels of sex hormones, restoration of fertility and normal offspring were born
Liu et al., 2014 
Human Menstrual blood stem cells were injected into a cyclophosphamide-induced mouse model of POF. The transplanted cells survived in mouse ovaries for at least 14 days in vivo and the transplanted ovaries expressed higher levels of ovarian markers [AMH, inhibin α/β, and follicle-stimulating hormone receptor (FSHR)], and the proliferative marker Ki67]. Ovarian weight, plasma E2 level, and number of normal follicles increased over time in the HuMenSC group compared with the control group.
Further, microarray analysis of cDNA expression patterns revealed that, after HuMenSC transplantation, the gene mRNA expression patterns in the ovarian cells following stimulation of the host ovarian niche became increasingly similar to those observed in human ovarian tissue compared with the pretransplantation mRNA expression pattern in HuMenSCs.
Terraciano et al., 2014 
Female mice were treated with cisplatin to induce ovarian failure. Later GFP tagged ADSCs, FGSCs, or ovary cell suspension was transplanted in the ovary. This resulted in increased numbers of follicles and improved ovarian function.
Kilic et al., 2014 
Female rats were treated with cyclophosphamide to induce ovarian failure. Bone marrow MSCs were transplanted along with cyclophosphamide to one group. Number of follicles were higher in the MSCs transplanted group.
Abd-Allah et al., 2013 
Rabbits were treated with cyclophosphamide to induce ovarian damage. MSCs from male rabbit were transplanted through intravenous route. Increased follicle numbers with apparent normal structure of ovarian follicles were observed in the MSC recipient group
Guo et al. 2013 
Bone marrow derived mesenchymal cells reduced rat granulosa cell apoptosis induced by cisplatin and age
Ghadami et al., 2012 
Bone marrow transplantation restored follicular maturation and steroid hormones production in a FORKO mouse model for primary ovarian failure. 24 h after transplantation, treated mice showed changes in vaginal smears and significant increase in both maturation and total number of follicles in treated animals. FSH dropped to 40–50 % and estrogen increased 4–5.5 times in the serum of treated animals compared to controls.
Fu et al., 2008 
Bone marrow mesenchymal stem cells transplantation improved function of chemoablated rat ovaries. MSC released factors like VEGF, HGF and IGF-1 in vitro.