Tcf21⁺mesenchymal cells contribute to testis somatic cell development, homeostasis, and regeneration

Abstract

2 Highlights • Multipotent Tcf21 + MPs can differentiate into somatic testis cell types • Tcf21 + cells contribute to testis and ovary somatic cells during gonadal development • Tcf21 + cells replenish somatic cells of the aging testis and in response to tissue injury • Testis Tcf21 cells resemble resident fibroblast populations in multiple organs 3 Summary Testicular development and function relies on interactions between somatic cells and the germline, but similar to other organs, regenerative capacity decline in aging and disease. Whether the adult testis maintains a reserve progenitor population with repair or regenerative capacity remains uncertain. Here, we characterized a recently identified mouse testis interstitial population expressing the transcription factor Tcf21. We found that Tcf21 + cells are bipotential somatic progenitors present in fetal testis and ovary, maintain adult testis homeostasis during aging, and act as reserve somatic progenitors following injury. In vitro, Tcf21 + cells are multipotent mesenchymal progenitors which form multiple somatic lineages including Leydig and myoid cells. Additionally, Tcf21 + cells resemble resident fibroblast populations reported in other organs having roles in tissue homeostasis, fibrosis, and regeneration. Our findings reveal that the testis, like other organs, maintains multipotent mesenchymal progenitors that can be leveraged in development of future therapies for hypoandrogenism and/or infertility.

Expression ofWnt5adefines the major progenitors of fetal and adult Leydig cells

“…PMCs and LCs (Shen et al, 2020), while the fate of Wnt5a + progenitors is mainly restricted to FLCs and ALCs, as reported here.…”

“…Consistent with its expression profile, our findings confirm that Wnt5a + cells are true steroidogenic progenitors giving rise to most FLCs and ALCs. Other genes expressed in steroidogenic progenitors might also have been potential candidates to use for genetically tracing the lineage of these cells, including Nr5a1, Nr2f2/CouptfII, Pdgfra and Tcf21/Pod1 (Brennan et al, 2003;Shen et al, 2020). However, the expression of these genes is not restricted to the steroidogenic progenitors and they usually display a more widespread expression, either at earlier stages of development and/or in other cell types.…”

“…The dramatic increase in the number of FLCs between E12.5 and E15.5 occurs through the recruitment and differentiation of Leydig progenitor cells via paracrine factors, rather than by mitotic division of differentiated FLCs (Barsoum et al, 2009; Barsoum and Yao, 2010;Bitgood et al, 1996;Brennan et al, 2003;Byskov, 1986;Kerr and Knell, 1988;Migrenne et al, 2001). During the first postnatal days, FLCs involute gradually and are replaced by ALCs, although some may persist in the adult testis (Haider, 2004;Shima et al, 2015;Wen et al, 2016). ALCs are not derived from pre-existing FLCs but, like their fetal counterparts, arise from uncharacterized LC progenitors located in the testicular interstitium (Barsoum et al, 2013;Davidoff et al, 2004;Kilcoyne et al, 2014;Shima et al, 2012).…”

The single-cell epigenetic regulatory landscape in mammalian perinatal testis development

“…Since PTMs and stromal cells were clustered into a single large cluster (Figure 1D) and PTMs are suggested to be derived from interstitial progenitors (Shen et al 2020) , PTMs and stromal cells were grouped together for subsequent analysis. Re-clustering of this cell group generated 10 clusters of cells (Supplementary Figure S11A and B).…”

Specific transcriptomic signatures and dual regulation of steroidogenesis between fetal and adult mouse Leydig cells

“…They arise from LC progenitors located in the testicular interstitium (Davidoff et al, 2004;Barsoum et al, 2013;Shima et al, 2013;Kilcoyne et al, 2014;Ademi et al, 2020). Two recent studies showed that both fetal and adult Leydig cells derive from a common pool of progenitor cells originating from the gonadal surface epithelium and mesonephric mesenchymal cells present from fetal life (Ademi et al, 2020;Shen et al, 2020). Evidence also shows that a subset of FLCs dedifferentiate at fetal stages to serve as potential ALC stem cells (Shima et al, 2018).…”