Macrophages Contribute to the Spermatogonial Niche in the Adult Testis

Abstract

Summary The testis produces sperm throughout the male reproductive lifespan by balancing self-renewal and differentiation of spermatogonial stem cells (SSCs). Part of the SSC niche is thought to lie outside the seminiferous tubules of the testis; however, specific interstitial components of the niche that regulate spermatogonial divisions and differentiation remain undefined. We identified distinct populations of testicular macrophages, one of which lies on the surface of seminiferous tubules in close apposition to areas of tubules enriched for undifferentiated spermatogonia. These macrophages express spermatogonial proliferation- and differentiation-inducing factors, such as colony stimulating factor 1 (CSF1) and enzymes involved in retinoic acid (RA) biosynthesis. We show that transient depletion of macrophages leads to a disruption in spermatogonial differentiation. These findings reveal an unexpected role for macrophages in the spermatogonial niche in the testis, and raise the possibility that macrophages play previously unappreciated roles in stem/progenitor cell regulation in other tissues.

Testicular abnormalities in mice with Y chromosome deficiencies†

“…Mature testicular macrophages play an important role in modulation of immune responses by either helping to maintain the immunosuppressive environment of the testis or stimulating the immune response through secretion of anti-inflammatory or proinflammatory cytokines, respectively [69,70]. Moreover, a distinct class of testicular macrophages that are enriched near spermatogonial precursors and are required for spermatogonia differentiation has recently been identified [46]. An increase in macrophage population and macrophage-stimulated neovascularization are a part of typical inflammatory response [71,72].…”

“…During development, they help to establish testicular architecture by promoting male-specific vascularization patterns and testis cord morphogenesis [62,63]. By birth and into adulthood, testicular macrophages are present only in the interstitial compartment of the testes [46,64] where they contribute to cellular maintenance of the immunoprivileged testis and are associated with the steroidogenic Leydig cells [65][66][67][68]. Mature testicular macrophages play an important role in modulation of immune responses by either helping to maintain the immunosuppressive environment of the testis or stimulating the immune response through secretion of anti-inflammatory or proinflammatory cytokines, respectively [69,70].…”

“…Limited Y chromosome gene contribution affected not only germ cells but also some components of the interstitial tissue. Interstitial tissue of the testis contains Leydig cells, macrophages, peritubular myoid cells, and vasculature [46]. A major role for this tissue is the steroidogenic regulation of spermatogenesis in the seminiferous tubules as well as delivery of other standard blood components [47,48].…”

Retinoid signaling controls spermatogonial differentiation by regulating expression of replication-dependent core histone genes

“…We and others have demonstrated that testicular RA mainly originates from Sertoli cells especially in puberty; however, it remains elusive whether the action of RA on spermatogonial differentiation is through germ cells or Sertoli cells, or both Sertoli and germ cells, as its receptors, RARs and RXRs, are expressed in both Sertoli cells and the undifferentiated spermatogonia (Gely-Pernot et al, 2012;Tong et al, 2013;Vernet et al, 2006b;Gaemers et al, 1998;DeFalco et al, 2015). For instance, genetic ablation of Rarg in germ cells resulted in only mild spermatogonial differentiation defects in mutants younger than one year old, indicating that either retinoid signaling in Sertoli cells is involved in spermatogonial differentiation, or that other subtypes of RARs in spermatogonia compensate for loss of RARγ function, as it is the case for many other developmental process (Gely-Pernot et al, 2012;Mark et al, 2009).…”

Multipotent male germline stem cells (mGSCs) from neonate porcine testis

“…In this study, we used Laminin in combination with differentiating plating (DP) method to isolate SSCs from postnatal porcine testicular cells. Niche and microenvironments play important roles in the fate and behavior of stem cells (Griswold et al 2013;DeFalco et al 2015). Recent studies demonstrate the importance of growth factors and extracellular matrix (ECM) on stem cell and germ cell behavior (Kuijk et al 2009;Zhu et al 2012).…”