The transplantation of spermatogonial stem cells (SSCs) is a highly promising fertility restoration tool for former childhood cancer patients. However, the colonization efficiency of transplanted SSCs is low. Because mesenchymal stem cells (MSCs) have regenerative and cell supporting capacities, we hypothesized that (co-)transplanting MSCs might improve SSC transplantation efficiency. After developing an infertile mouse model which represented the clinical situation of infertility, we carried out four different transplantation strategies: (1) transplantation of SSCs (SSCT), transplantation of MSCs (MSCT), transplantation of both MSCs and SSCs (MS-SSCT), and transplantation of TGFß1-induced MSCs and SSCs (MSi-SSCT). The highest transplantation efficiency was obtained after MSi-SSCT. Moreover, even after injecting half the number of SSCs, the reproductive efficiency after MSi-SSCT was found to be similar to that after SSCT. Both SSCT and MSi-SSCT resulted in successful natural conception. Litter sizes were not different between MSi-SSCT and SSCT. Furthermore, we analyzed DNMT3A and H4K5ac expression patterns in both transplanted mice and their first-generation offspring. Compared to fertile controls, donor-derived germ cells showed lower expression levels of both DNMT3A and H4K5ac. However, the expression patterns were normal in the offspring. Since the expression levels of DNMT3A and H4K5ac were similar for SSCT and MSi-SSCT, we can assume that TGFß1-induced MSCs did not interfere with epigenetic modification.
From this thesis, the following conclusions could be drawn:
1- Co-transplanting TGFß1-induced MSCs improve SSC colonization efficiency in mice. TGFß1-treatment significantly lowers the expression of proteins playing a role in migration and, therefore, retracts MSCs in the testis where their paracrine contribution restores the testicular niche.
2- Co-transplanting SSCs and TGFß1-treated MSCs reach the reproductive potential of SSCT alone even after transplanting half the number of SSCs. Although lower expression of DNMT3A and H4K5ac were observed in donor-derived germ cells, normal levels were restored in offspring.
|Date of Award||19 Sep 2019|
|Supervisor||Ellen Goossens (Promotor), Dorien Van Saen (Co-promotor), Elena Vicini (Jury), Joachim Wistuba (Jury), Anne Delbaere (Jury), Leo van Grunsven (Jury), Ellen Anckaert (Jury) & Karen Sermon (Jury)|
- Speratogonial stem cell