Identification of dynamic undifferentiated cell states within the male germline

• Published in: Nature communications 2018-07, Vol.9 (1), p.2819-18, Article 2819
• Main Authors: La, Hue M., Mäkelä, Juho-Antti, Chan, Ai-Leen, Rossello, Fernando J., Nefzger, Christian M., Legrand, Julien M. D., De Seram, Mia, Polo, Jose M., Hobbs, Robin M.
• Format: Article
• Language: English
• Subjects: 13/100; 13/106; 13/31; 13/51; 14/19; 38/1; 38/39; 38/91; 45/61; 631/532/2118; 631/532/2139; 631/532/489; 64/60; Animal models; Animals; Cell culture; Cell Differentiation; Cell Lineage - genetics; Cell self-renewal; Differentiation; Dynamic stability; Embryogenesis; Founder Effect; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Developmental; Genes, Reporter; Homeobox; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humanities and Social Sciences; Integrases - genetics; Integrases - metabolism; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Male; Mice; Mice, Transgenic; Molecular chains; multidisciplinary; Octamer Transcription Factor-3 - genetics; Octamer Transcription Factor-3 - metabolism; Pattern formation; Promyelocytic Leukemia Zinc Finger Protein - genetics; Promyelocytic Leukemia Zinc Finger Protein - metabolism; Proto-Oncogene Proteins c-kit - genetics; Proto-Oncogene Proteins c-kit - metabolism; Red Fluorescent Protein; Science; Science (multidisciplinary); Single-Cell Analysis; Spermatogonia; Spermatogonia - cytology; Spermatogonia - metabolism; Stem cell transplantation; Stem cells; Stem Cells - cytology; Stem Cells - metabolism; Testis - cytology; Testis - growth & development; Testis - metabolism; Trans-Activators - genetics; Trans-Activators - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04827-z

The role of stem cells in tissue maintenance is appreciated and hierarchical models of stem cell self-renewal and differentiation often proposed. Stem cell activity in the male germline is restricted to undifferentiated A-type spermatogonia (A undiff ); however, only a fraction of this population act as stem cells in undisturbed testis and A undiff hierarchy remains contentious. Through newly developed compound reporter mice, here we define molecular signatures of self-renewing and differentiation-primed adult A undiff fractions and dissect A undiff heterogeneity by single-cell analysis. We uncover an unappreciated population within the self-renewing A undiff fraction marked by expression of embryonic patterning genes and homeodomain transcription factor PDX1. Importantly, we find that PDX1 marks a population with potent stem cell capacity unique to mature, homeostatic testis and demonstrate dynamic interconversion between PDX1+ and PDX1− A undiff states upon transplant and culture. We conclude that A undiff exist in a series of dynamic cell states with distinct function and provide evidence that stability of such states is dictated by niche-derived cues. Sustained spermatogenesis depends on stem cell activity which is contained within a population of undifferentiated spermatogonia. Here, the authors identify a new population of undifferentiated spermatogonia in adult testis that expresses the transcription factor PDX1 and has stem cell capacity.