PP Anlage Formation and Mesenchymal Cell Differentiation

Visceral mesoderm in vertebrates differentiates into a complex array of cell types, including the smooth muscle layers of the intestine, endothelial cells, and stromal cells. VCAM-1+ MAdCAM-1+ ICAM-1+ stromal cells found in PPs and LNs were termed organizer cells because of their capacity to establish lymphoid tissue compartments and to induce the recruitment of mature lymphocytes via chemokines (Adachi et al. 1997; Nishikawa et al. 2003; Yoshida et al. 1999). The organizer cells express mesenchymal marker such as PDGFRa and PDGFRß (Hong et al. 2002). Dependent on the expression levels of adhesion molecules, two different types of mesenchymal cells were described in mesenteric or peripheral LNs of newborn mice (Cupedo et al. 2004b).

The two populations express different levels of the homeostatic chemokines CXCL13, CCL19, and CCL21, suggesting that they may differ in the capacity to recruit mature lymphocytes. The initial mesenchymal specification of organizer cells in developing mesenteric LNs and PPs is independent of LTap, as single VCAM-1+ organizer cells are found in the fetal gut of LTa-deficient mice (Finke et al. 2002). PP organogenesis proceeds through distinct steps that have been identified histologically. The earliest sign of PP anlage formation are clusters of VCAM-1+ LTp-R+ mesenchymal cells forming at day 15 of gestation, which appear from the cranial to caudal axis of the small intestine (Adachi et al. 1997). The clustering of mesenchymal cells requires cell-to-cell contact with fetal hematopoietic cells expressing LTa1p2. Hashi and colleagues could show that cluster formation is detectable even in scid/scid mice, indicating that this process proceeds independently of mature lymphocytes (Hashi et al. 2001). Ligation of LTpR on the stromal cells leads to activation of two nuclear factor-KB (NF-kB) signaling pathways followed by production of homeostatic chemokines (CXCL12, CXCL13, CCL19, CCL21), proinflammatory chemokines (CCL4, CCL5, CXCL9, CXCL10), adhesion molecules (VCAM-1, MAdCAM-1, ICAM-1, PNAd), IL-7, and TRANCE (Dejardin et al. 2002; Drayton et al. 2003; Ngo et al. 1999; Nishikawa et al. 2000). Similarly, the FAE starts to become specified, to express CCL20 in a LTai p2-dependent manner (Rumbo et al. 2004) and to recruit cells expressing the corresponding receptor CCR6 such as subepithelial DCs and diverse subsets of memory T cells (Cook et al. 2000; Ebert and McColl 2002; Liao et al. 1999). In addition to CCL20, CCL9 is specifically expressed by the FAE but not by the villus enterocytes (Zhao et al. 2003). Mice lacking CCL9 have a severe reduction of CD11b+ DCs in the subepithelial dome indicating an important role of CCL9 for recruitment of DCs. HEVs forming in the developing PP express MAdCAM-1 and PNAd (Hashi et al. 2001). MAdCAM-1 is the ligand for a4p7 integrin and leukocyte homing receptor L-selectin and is known to function predominantly in the mucosa (Butcher and Picker 1996), but is also transiently expressed in developing peripheral LNs (Mebius et al. 1996). Mature lymphocytes enter the developing PPs via HEV around E18.5. B220+ B cells and CD3+ T cells are diffusely distributed before compartmentalization into B and T cell zones occurs during the first week after birth.

By comparing PP development with formation of other organs, it is likely that morphogens and growth factors are mandatory for the initial differentiation of the mesenchymal cells. During ontogeny, gut morphogenesis occurs through epithelial-mesenchymal cell interactions and is controlled by signaling pathways involving the fibroblast growth factor (FGF), Wnt, bone morphogenetic protein (BMP)/transforming growth factor (TGF-p), Sonic Hedgehog (Shh), and Notch ligands (Finke and Kraehenbuhl 2001).

These morphogens are developmental regulators providing positional information and organizing pattern formation (Christian 2000). Foxl1, a member of the winged helix/forkhead family of DNA binding proteins, is expressed by mesenchymal cells of the developing gut and is required for the control of gastrointestinal proliferation and differentiation (Kaestner et al. 1997). Importantly, in Foxl1-/- mice, a delay in fetal PP development was reported that was correlated with reduced responsiveness of mesenchymal cells to LTap as revealed by the downmodulation ofLT0R in the fetal gut (Fukuda et al. 2003).

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