Richard A. Lang
The role of macrophages in developmental tissue regression
The mechanism by which tissues regress during normal development is not understood. Macrophages are implicated in this process by their presence and are mostly believed to have a passive scavenger function in the clearance of cell debris. In some circumstances however, there is evidence that macrophages are required for the induction of cell death. We are interested in determining how macrophages might induce cell death during normal development.
Development of the mammalian eye involves the formation of a capillary network called the hyaloid vasculature and pupillary membrane (PM). In rodents, the PM (spanning the anterior surface of the iris diaphragm and the pupil) regresses in week two, just prior to parting of the eyelids. Cellular ablation transgenic mice have shown that macrophages are required for the regression of these capillaries and imply that macrophages may actively induce the death of vascular endothelial cells (VECs) during the regression process. It is our long term aim to determine the mechanism of capillary regression.
Our previous analysis of developmental capillary regression using the PM as a model system has indicated that the death of VECs occurs through apoptosis. Furthermore, we have shown that apoptosis can occur in isolated VECs in otherwise healthy capillaries, or synchronously along the entire length of a capillary segment. These observations imply a two-step regression mechanism (Fig. 1) where macrophages kill a limited number of target cells and as a consequence cause plasma flow in the capillary to cease. We suggest that cessation of plasma flow leads to the observed synchronous apoptosis of VECs due to plasma survival factor deprivation.
Fig. 1: Model for macrophage-mediated developmental capillary regression
(A) step one of capillary regression involves the induction of VEC apoptosis by macrophages. Induced cell death is proposed to lead to a block to plasma flow (B) and subsequent synchronous apoptosis of VECs (C).
We have chosen to test a number of aspects of this model using a vital cell imaging system. Comparison of vital images with histological preparations of the PM have indicated
- that VEC apoptosis causes either a capillary narrowing or blockage and
- that synchronous apoptosis occurs after a block to plasma flow has occurred.
These observations largely confirm the proposed model and show that there is an inverse relationship between flow status and VEC death. Our future work will be aimed at determining the molecular signalling events leading to developmental capillary regression.