JCI | Journal of Clinical Investigation

Cystic fibrosis is caused by mutations in CFTR, a gene that encodes a sodium/chloride transporter that is expressed in multiple tissues. This protein regulates the composition of sweat, mucus, and digestive fluids and loss of the protein causes injury to the lungs, pancreas, liver, and intestine. Approximately 15% of babies with cystic fibrosis (CF) are born with an obstruction of the small intestine known as meconium ileus, frequently the first sign of CF. Unlike in humans, meconium ileus occurs in 100% of newborn CF pigs. David Stoltz and colleagues found that transgenic expression of CFTR cDNA in the intestine of CF pigs alleviated meconium ileus; over time, the pigs still exhibited other manifestations of CF, including liver and lung disease, reduced weight gain, and pancreatic destruction. These findings provide insight into the pathophysiology of CF. The accompanying image shows CFTR expression (green) in the ileus of wild type pigs, pigs lacking intestinal CFTR, and pigs expressing recombinant CFTR.

The placenta serves as the conduit for communication between the mother and fetus during pregnancy. To ensure that the growing fetus has access to sufficient oxygen and nutrients, the spiral arteries that supply blood to the endometrium must undergo remodeling. Poor remodeling leads to preeclampsia, a common and life threatening complication of pregnancy. Currently, it is unclear exactly which factors govern spiral artery remodeling. Using transgenic mice, Manyu Li and colleagues demonstrated that fetal expression of the peptide adrenomedullin and its receptor is required for recruitment and activation of uterine natural killer cells (uNKs) to the placenta to facilitate remodeling of maternal spiral arteries. In the accompanying images they used scanning electron microscopy to examine vascular corrosion casts of the maternal placental vasculature at low power (top panels) and higher magnification (bottom panels). Compared to wild type mice (left), mice lacking adrenomedullin (right) exhibited wider spacing between the maternal blood sinuses, the area in which the maternal blood comes into contact with the  fetus, which is indicative of reduced branching of fetal labyrinth vessels. These findings demonstrate that fetal-derived adrenomedullin plays a critical role in pregnancy-associated vascular remodeling.

Pancreatic beta cells produce insulin and play a critical role in maintaining blood glucose levels; loss of these cells results in the development of diabetes. A primary goal in diabetes therapy is beta cell replacement; however, there is a short supply of donor pancreases and a need for alternative sources of beta cells. Xiangwei Xiao and colleagues examined adult mouse pancreases to determine if they are capable of making new beta cells (beta cell neogenesis). They generated mice that express different fluorescent reporters in a time sensitive manner, so that insulin producing cells produce GFP (green) while all other cells produce mTomato (red). Cells that develop into beta cells should transiently co-express both GFP and mTomato, appearing yellow. By tracking the mice throughout their development, Xiao and colleagues found that beta cell neogenesis primarily takes place during embryogenesis, decreases dramatically after birth, and is completely absent in adult mice. The accompanying confocal microscopy image shows the developing embryonic mouse pancreas. Developing beta islets (yellow) are visible in the left and middle panels (Embryonic day 13.5 and 14.5, respectively), but have completely disappeared by embryonic day 15.5 (right panel), leaving only fully-developed beta islets (green). These results demonstrate that beta cell neogenesis only occurs for a short period of time during development, but not in adult mice.

Platinum compounds, such as cisplatin and carboplatin, induce DNA cross-linking, prohibiting DNA synthesis and repair in rapidly dividing cells. They are first line therapeutics in the treatment of many solid tumors, but cancer cells frequently develop resistance to these drugs. Mechanisms of resistance typically include reduced platinum uptake and increased platinum export. Myrthala Moreno-Smith and colleagues identified a membrane protein, ATP11B, that mediates cisplatin resistance in ovarian cancer cells. They found that ATP11B expression was correlated with higher tumor grade in human ovarian cancer samples and with cisplatin-resistance in human ovarian cancer cell lines. Further, ATP11B gene silencing restored the sensitivity of ovarian cancer cell lines to cisplatin in vitro and combined cisplatin/ATP11B shRNA therapy reduced ovarian tumor growth in mice. The accompanying image shows ATP11B (red) and Lamin B (green) expression in A2780 ovarian cancer cells (the nuclei are blue) treated with cisplatin, demonstrating that ATP11B moves from the nucleus to the cytoplasm upon exposure to cisplatin. These findings suggest that ATP11B could serve as a therapeutic target to overcome cisplatin resistance.

The retina is a highly vascularized tissue, but too much or too little vascularization can lead to visual impairment and diseases such as familial exudative vitreoretinopathy or macular degeneration. Christine Weinl and colleagues identified the transcription factor SRF and its cofactors MRTF-A and MRTF-B as critical regulators of vascularization in the postnatal mouse eye. They developed transgenic mice in which expression of SRF could be blocked at different points in development. Weinl and colleagues used a confocal scanning laser opthalmoscope (SLO) and fluorescein angiography, which highlights blood vessels, to examine the retinal vasculature of wild type (top left) and Srf-depleted mice (top middle and top right). The bottom panels of the accompanying image show retinal flat mounts from wild type (bottom left) and Srf-depleted mice (bottom middle, bottom right) stained for ILB4, a marker of the retinal primary plexus, which forms the eye’s blood supply. Loss of vascular Srf in adult mice led to the formation of microaneurysms and excess blood vessel formation similar to human retinal diseases such as retinal angiomatous proliferation and macular telangiectasia. These studies demonstrate that SRF plays an integral role in the development and homeostasis or the retinal vasculature and suggest that SRF could potentially serve as a therapeutic target in human retinal diseases.