“The 81th of Stem Cell Biology and Regenerative Medicine Forum”
Date：May 22nd (Fri) 2015
Time : 18:00 〜 19:30
Place：8th fl of New Hospital Building------------------------------------------------------------------------------------------------------------------------------------（Internal Speaker）
18:00-18:30
Munakata Shinya (Laboratory of Stem Cell Regulation, Center for Stem Cell
Biology and Regenerative Medicine, IMUST/ Department ofColoproctological Surgery, Juntendo University Faculty of Medicine)
Inhibition of plasmin protects against experimental colitis by suppressing
inflammatory cytokine release（External Speaker）
18:30-19:30
Katsuhiko Asanuma (Associate Professor Kyoto University Graduate Schoolof Medicine Medical Innovation Center, TMK Project)
The role of Notch2 activation in injured kidney podocytes-------------------------------------------------------------------------------------------------------------------------------------

Hosted by Center for Stem Cell Biology and Regenerative Medicine---Information--＊ Please register attendance at the reception desk.

＊ Next forum（the82st）will be held on

Jun. 24nd（Wed）18:00〜 at Auditorium in 1st Building.

＊ Please contact tatsu-m@ims.u-tokyo.ac.jp, for Forum speaker recommendations

Inhibition of plasmin protects against experimental colitis by suppressing
inflammatory cytokine release
Munakata Shinya (Laboratory of Stem Cell Regulation, Center for Stem Cell
Biology and Regenerative Medicine, IMUST/Department of ColoproctologicalSurgery, Juntendo University Faculty of Medicine)
BACKGROUND & AIMS: Activated proteases such as plasmin and matrix
metalloproteinases (MMPs) are activated in intestinal tissues of patients with active
inflammatory bowel diseases. We investigated the effect of plasmin on progressionof acute colitis.
METHODS: Colitis was induced in Mmp9–/–, Plg–/–, and C57BL/6 (control) miceby administration of dextran sulfate sodium, trinitrobenzene sulfonic acid, or CD40
antibody. Plasmin was inhibited in control mice by intraperitoneal injection ofYO-2, which blocks its active site. Mucosal and blood samples were collected andanalyzed by reverse transcription polymerase chain reaction andimmunohistochemical analyses, as well as for mucosal inflammation and levels ofcytokines and chemokines.
RESULTS: Circulating levels of plasmin were increased in mice with colitis,compared with controls. Colitis did not develop in control mice injected with YO-2
or in Plg–/– mice. Colons from these mice had reduced infiltration of Gr1+
neutrophils and F4/80+ macrophages, and reduced levels of inflammatory
cytokines and chemokines. Colonic inflammation and colitis induction required
activation of endogenous MMP9. Following colitis induction, mice given YO-2,Plg–/– mice, and Mmp9–/– mice had reduced serum levels of tumor necrosis factor
and CXCL5, compared to control mice.
CONCLUSIONS: In mice, plasmin induces a feedback mechanism in which
activation of the fibrinolytic system promotes development of colitis, via activationof MMP9 or proteolytic enzymes. The proteolytic environment stimulates influx ofmyeloid cells into the colonic epithelium and production of tumor necrosis factorand CXCL5. In turn, myeloid CD11b+ cells release the urokinase plasminogenactivator, which accelerates plasmin production. Disruption of the plasmin-induced
chronic inflammatory circuit might therefore be a strategy for treatment of colitis.

The role of Notch2 activation in injured kidney podocytes
Katsuhiko Asanuma (Associate Professor Kyoto University Graduate Schoolof Medicine Medical Innovation Center, TMK Project)
Kidneys serve the body by filtering blood and removing water-soluble wastes. The
glomerulus filters waste products from the blood and initiates urine formation.
Glomerular visceral epithelial cells, also called podocytes, are highly specialized
epithelial cells that attach to the outer layer of the glomerular basement membrane(GBM). Podocytes form the final barrier to protein loss, and this explains why
podocyte injury is typically associated with marked proteinuria. Chronic podocyte
injury may cause podocyte detachment from the GBM, leading toglomerulosclerosis and chronic kidney disease (CKD). Notch signaling pathway isan evolutionarily conserved intracellular signaling pathway that regulates cell fate.
Recently, it was reported that the regulation of Notch2 activation plays animportant role in the development of proximal nephron structure including
podocytes. However, details of the Notch2 signaling pathway in injured podocytes
remain unclear. In this seminar, I would like to talk about the role of Notch2
activation in injured podocytes and propose the possibility of using a Notch2
agonistic antibody as a new target for the treatment of glomerular diseases.