MMP-2 blockage (bottom) stops glomerulus formation by podocytes (blue).


Developmental biologists spend a great deal of time studying molecular signals that determine the when and where of organogenesis. But recent results indicate they may be overlooking something. Mechanical forces provided by the vasculature are also at work, according to a new study by Fabrizio Serluca, Ian Drummond, and Mark Fishman (Harvard Medical School, Boston, MA), who examine the development of the zebrafish kidney glomerulus.

The glomerulus is made up of unique layers of vessel endothelium that filter fluid from the blood without removing proteins or cells. Fluid flows between the endothelial cells, before moving sequentially through the basement membrane of the kidney and epithelial cells known as podocytes, and finally into the tubules of the kidney. During zebrafish embryogenesis, the podocytes form the glomerulus by migrating and coalescing to an area surrounding a vessel outgrowth of the aorta.

Now, it seems that mechanical forces from these vessel endothelium cells initiate podocyte cell migration. Fishman's group identified multiple mutants with disrupted glomerular assembly, each of which shares the common feature of impaired circulation. The group showed that hemodynamic forces from the aorta are essential for glomerular development by stimulating podocyte migration. “Cell fate in the mutants is normal; only organogenesis is affected,” says Fishman. “The cells just don't get together as they should.”

This force-initiated podocyte migration requires the collagen-degrading enzyme matrix metalloproteinase-2 (MMP-2). MMP-2 may be turned on by stretch-sensitive ion channels or by some other stretch-sensitive signal transduction pathway. In turn, MMP-2 may allow the vessels to migrate more easily into the epithelium by disrupting extracellular collagen. Alternatively, MMP-2 may activate matrix stores of inactive vessel-promoting signals. Homologues of the zebrafish signals may be involved in human disorders caused by hemodynamic forces, including atherosclerosis resulting from high blood pressure. ▪


Serluca, F., et al.
. Curr.