Reconstruction of central lacteals in the murine jejunum following ischemia-reperfusion injury

Abstract

The intestinal mucosa is vulnerable to an ischemia-reperfusion (I/R) attendant on some bowel diseases and surgery; thus, the restoration of the mucosal integrity is critical to achieving functional recovery of the intestine injured by I/R. In this histochemical study, we investigated the alteration of the central lacteals--which are essential for the transport of fat, tissue fluid, and immune cells in the intestinal mucosa--in the murine jejunum after I/R. The intestine inflicted with I/R demonstrated mucosal injury involving the inflammatory response, with interstitial edema, disruption of the villous tissue, and subsequent tissue regeneration of the villi. The regenerative villous tissue revealed lymphatic regrowth showing proliferative activity from the residual mucosal lymphatics behind the regenerated blood vasculature. During the regenerative phase, the blood vascular pericytes expressed an intense immunoreaction for VEGF-A, an inducer for monocyte/macrophage recruitment as well as angiogenesis. Also, the F4/80-immunopositive macrophages significantly increased in number in the regenerating villous stroma. Furthermore, the macrophages recruited around the regrowing lacteals expressed the immunoreactivity for VEGF-C, which is a highly specific lymphangiogenic factor. The present study is first to delineate alterations in the central lacteals in the small intestine following I/R, thereby suggesting that the recruitment of the macrophages induced by upregulation of VEGF-A in the pericytes of regenerative blood vessels might promote reconstruction of the central lacteals through their release of VEGF-C.

Endothelial FOXC1 and FOXC2 promote intestinal regeneration after ischemia-reperfusion injury

“…The vascular recovery of villus BECs and LECs after I/R injury proceeds via a stepwise process in which blood capillaries (BECs) regrow earlier than lacteals (LECs) in the villous stroma 46 . We found that the EC- Foxc -DKO mutation was associated with defective vascular repair of intestinal BECs and LECs after I/R injury (Figure 5).…”

“…7). The vascular regrowth of villus BECs and LECs after I/R injury proceeds via a stepwise, interactive process, and regeneration of villus blood vessels precedes reconstruction of lacteals ( 51 ) (Fig. 4, Movies S1 and S2).…”

“…Consistently, impaired vascular recovery of the EC- Foxc -DKO mice after intestinal I/R injury is rescued by CXCL12 treatment (Figure 9). Since the vascular regrowth of villus BECs and LECs after I/R injury proceeds via a stepwise, interactive process, and regeneration of villus blood vessels precedes reconstruction of lacteals 46 (Figure 6 and Supplementary Videos), the severity of mucosal damage is greater in the EC- Foxc -DKO mice than in the LEC- Foxc -DKO mice. When the CXCR4 receptor in intestinal epithelial cells is activated by treatment with CXCL12- overexpressing MSCs, canonical Wnt/β-catenin is stimulated in the ISCs 25 .…”

“…The vascular recovery of villus BECs and LECs after I/R injury proceeds via a stepwise process in which blood capillaries (BECs) regrow earlier than lacteals (LECs) in the villous stroma 46 .…”

Endothelial FOXC1 and FOXC2 promote intestinal regeneration after ischemia–reperfusion injury

“…Consistently, impaired blood vascular recovery of the EC‐ Foxc ‐DKO mice after intestinal I/R injury is rescued by CXCL12 treatment (Fig 10H and I). Since the vascular regrowth of villous BECs and LECs after I/R injury proceeds via a stepwise, interactive process, and regeneration of villus blood vessels precedes the reconstruction of lacteals (Meng et al , 2007) (Fig 4 and Movies EV1 and EV2), the severity of mucosal damage is greater in the EC‐ Foxc ‐DKO mice than in the LEC‐ Foxc ‐DKO mice. Moreover, consistent with the role of the CXCL12/CXCR4 pathway in lymphangiogenesis (Zhuo et al , 2012), impaired lacteal length of the EC‐ Foxc ‐DKO mice after intestinal I/R injury is rescued by CXCL12 treatment (Fig 10H and J).…”