Subfertility is of major clinical, social and economical concern in Western societies. In approximately half of the affected couples, subfertility is due to spermatogenic failure with complete spermatogenic arrest causing azoospermia being the most extreme clinical presentation. However, despite its clinical importance, very little is known about the etiology of spermatogenic arrest.
One of the most striking features of spermatogenesis is the continuously ongoing, rapid and profound change in composition and function of chromatin, the supra-molecular complex that packages, shapes and regulates the genome. Proper chromatin architecture and dynamics steer spermatogonial selfrenewal, differentiation and meiosis and safeguard genomic stability. Consequently, changes in the spatio-temporal organization of chromatin can lead to chromosomal aberrations or aneuploidies, initiate spermatogonial apoptosis or activate a male specific checkpoint that causes spermatogenic arrest leading to male infertility or, in the worst case, even lead to congenital malformations in the offspring.
Although chromatin is highly dynamic by nature, spermatogenesis has been predominately studied in fixed material because the appropriate live-cell imaging techniques and a functional in vitro culture system for human spermatogonial stem cells (SSCs) were not available. In the current study we aim to combine two breakthroughs: a unique culture system for human SSCs established in the host laboratory and a live imaging method further developed by the research fellow. These will enable us to study, for the first time, the dynamic nature of chromatin during the self-renewal and early differentiation stages of living human SSCs. In addition, by inducing controlled points of DNA damage on selected chromosomal areas in human spermatogonia, our experiments will shed light on the mechanisms behind spermatogonial DNA damage repair, apoptosis and consequently spermatogenic arrest.
Field of science
- /natural sciences/biological sciences/genetics and heredity/genome
- /natural sciences/biological sciences/genetics and heredity/dna
- /medical and health sciences/medical biotechnology/cells technologies/stem cells
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