Generation, localization and functions of macrophages during the development of testis

Abstract

In the testis, interstitial macrophages are thought to be derived from the yolk sac during fetal development, and later replaced by bone marrow-derived macrophages. By contrast, the peritubular macrophages have been reported to emerge first in the postnatal testis and solely represent descendants of bone marrow-derived monocytes. Here, we define new monocyte and macrophage types in the fetal and postnatal testis using high-dimensional single-cell analyses. Our results show that interstitial macrophages have a dominant contribution from fetal liver-derived precursors, while peritubular macrophages are generated already at birth from embryonic precursors. We find that bone marrow-derived monocytes do not substantially contribute to the replenishment of the testicular macrophage pool even after systemic macrophage depletion. The presence of macrophages prenatally, but not postnatally, is necessary for normal spermatogenesis. Our multifaceted data thus challenge the current paradigms in testicular macrophage biology by delineating their differentiation, homeostasis and functions.

Contributions of Embryonic HSC-Independent Hematopoiesis to Organogenesis and the Adult Hematopoietic System

“…Based on CD206 and MHCII expression, three testis subpopulations of TRM can be distinguished. These populations possess different levels of phagocytic capacity ( Lokka et al, 2020 ). Tracing (E8.5 pulsed Csf1r -Mer-iCre-Mer, E13.5 pulsed Cx3cr1 -CreER) and KO ( Ccr2 , Nur77 , Plvap ) studies have shown that all three waves of hematopoiesis contribute to adult testis TRM.…”

“…Tracing (E8.5 pulsed Csf1r -Mer-iCre-Mer, E13.5 pulsed Cx3cr1 -CreER) and KO ( Ccr2 , Nur77 , Plvap ) studies have shown that all three waves of hematopoiesis contribute to adult testis TRM. Strikingly, antibody-based macrophage depletion experiments have demonstrated that adult BM-derived cells play no part in testis TRM maintenance ( Lokka et al, 2020 ).…”

“…During gonad development, macrophages associate with and engulf mislocated germ (E10.5–E11.5) and Sertoli (E12.5) cells, and their absence ( Cx3cr1 -Cre/diphtheria toxin) results in irregularly branched and shortened testis cords ( DeFalco et al, 2014 ). Furthermore, depletion of macrophages during embryogenesis ( Csf1 op/op , anti-CSF1R depletion) but not postnatally ( Ccr2 KO, anti-CSF1 depletion at birth) results in impaired spermatogenesis after birth ( Lokka et al, 2020 ). Similar observations have been made in kidney development where the clearance of rostral nephrogenic cells and uretic bud formation are delayed in the absence of YS-macrophages ( Cx3cr1 -Cre/diphtheria toxin) ( Munro et al, 2019 ).…”

Immune and vascular contributions to organogenesis of the testis and ovary

“…These gene expression patterns in the fetal gonad may contribute to a tissue microenvironment conducive to M2 macrophage activation. In addition, there are two macrophage populations from E14.5 until birth found in the testis: F4/80 Hi macrophages and F4/80 Int macrophages that highly express the M2 marker CD206 and monocyte marker LY6C, respectively [14]. M2 macrophages are generally considered to be immunosuppressive and are associated with vascular and tissue remodeling during development and cancer [37,46]; therefore, M2 macrophages are well-suited to play an important role in fetal testis vascularization and development.…”

“…The heterogeneity of TM in adult mice has been demonstrated based on distinct surface marker expression patterns, anatomical localization, gene expression profiles, and lineage of origin. There are at least 2 TM populations: (a) macrophages located in the interstitium (also called interstitial TM), which highly express CD64 and CSF1R; and (b) macrophages located on the surface of the seminiferous tubules (also called peritubular TM), which express MHCII [7,14,47]. A recent study using high-dimensional mass cytometric analyses revealed the presence of a CD206 -MHCIImacrophage population, which declines in number during postnatal testis development, with the concurrent emergence of a CD206 -MHCII + macrophage population [14], indicating that CD206 -MHCIImacrophages may be the precursor of peritubular TM.…”