Michael N. Hall was recently announced as the recipient of the 2017 Albert Lasker Basic Medical Research Award for the discovery of TOR proteins, which play a central role in the nutrient-sensing system that controls cell growth. This breakthrough finding paved the way for key insights into the pathogenesis and the treatment of wide-ranging human diseases. Hall joined JCI’s Editor at Large Ushma Neill to discuss his international upbringing and the circumstances that led to his team’s characterization of this essential signaling pathway. In the interview, he also reveals why the research project nearly failed before it began and how TOR got its name.
Pathogenic remodeling following heart injury is due, in part, to the limited regenerative capacity of adult cardiomyocytes. Cell cycle induction has been recently explored as a therapeutic approach for heart failure, and to this end, expression of cyclin D2 in cardiomyocytes improves outcomes in mouse models follwoing myocardial infarction. In this episode, Gerd Hasenfuß, Loren Field, and Karl Toischer discuss their collaborative effort to further evaluate the effect of increased cyclin D2 on outcomes in response to other forms of heart failure. Cyclin D2 expression improved survival and cardiac function in mice exposed to pressure overload; however, cyclin D2-espressing mice were not protected from adverse effects in response to chronic volume overload. These results support further effort into the development of strategies to improve cardiomyocyte proliferation for some types cardiac injury.
Necrotizing enterocolitis is a leading cause of death in preterm infants and is characterized by severe inflammation. The incidence of necrotizing enterocolitis is reduced in preterm infants fed human breast milk; however, the factors underlying the beneficial effects of human breast milk are not fully understood. In this episode, Mansour Mohamadzadeh and colleagues compared the microbiome of preterm infants fed either breast milk or formula and identified a propionobacterial strain (P. FU1) that was present in the gut microbiota of breastmilk fed- but not formula fed-infants. Moreover, introduction of this bacterial strain into murine models was protective against necrotizing enterocolitis-like inflammation and injury as well pathogenic intestinal pathogens. The results of this study provide important insight into the beneficial effects of human breast milk on intestinal flora.
Schlemm’s canal is a lymphatic-like vessel in the eye that is critical for proper drainage of aqueous humor. Glaucoma results from increased intraocular pressure due to decreased aqueous humor outflow from the eye; therefore, strategies to enhance Schlemm’s canal function have potential to relieve glaucoma symptoms. In this episode, Gou Young Koh, Jaeryung Kim, and Dae-Young Park investigate factors that underlie the maintenance and integrity of Schlemm’s’ canal. Their work reveals that that angiopoietin/Tie2 signaling is essential for Schlemm’s canal function and integrity. Importantly, increasing Tie2 activity with an agonist antibody restored Schlemm’s canal function and reduced glaucoma phenotypes in mouse models, suggesting Tie2 activation be further explored as a therapeutic strategy for reducing intraocular pressure.
Although anti-VEGF therapies are commonly used to treat macular degeneration, these angiogenesis inhibitors have also been approved to target tumor growth and metastasis in several cancers. Because tumors depend on access to circulating blood to grow and metastasize, preventing angiogenesis may limit cancer progression. The success of anti-VEGF therapies in cancer has been limited, however, due to the ability of tumors to rapidly develop treatment resistance.
This week in the JCI, a study led by Dai Fukumura at Harvard Medical School and Massachusetts General Hospital has determined that immunosuppressive effects of non-classical Ly6Clo monocytes contribute to resistance against anti-VEGF therapies in mouse models of colorectal cancer. Researchers observed that treating colorectal tumors with VEGF inhibitors led to elevated expression of the chemokine CX3CL1. Elevations in CX3CL1 levels enhanced the recruitment of Ly6Clo monocytes into tumors, which in turn increased neutrophil migration and immunosuppressive IL-10 production within the tumor. Preventing Ly6Clo monocyte infiltration or blocking the receptor for CX3CL1 on monocytes improved the outcome of anti-VEGF therapies in the murine models. Together, these findings reveal a previously undescribed immunosuppressive function for Ly6Clo monocytes that plays a critical role in the development of treatment resistance to anti-VEGF therapies.
In the highlighted video: Jung et al. used real-time in vivo imaging to determine that CX3CL1/CX3CR1 signaling is required for Ly6Clo monocyte recruitment into tumors. The video visualizes Ly6Clo CX3CR1-expressing monocytes (green) flowing, rolling, and crawling through a blood vessel (red) as they infiltrate tumors. A rolling monocyte is observed beginning in the lower left corner, while a flowing monocyte is seen quickly moving through the upper left quadrant of the image.