1: IL (Interleukin)-10-STAT3-Galectin-3 Axis Is Essential for Osteopontin-Producing Reparative Macrophage Polarization After Myocardial Infarction

CIRCULATION,

OCT 30 2018, 138 (18):2021-2035; 10.1161

Shirakawa K, Endo J, Kataoka M, Katsumata Y, Yoshida N, Yamamoto T, Isobe S, Moriyama H, Goto S, Kitakata H, Hiraide T, Fukuda K, Sano M

In this study, we discovered an immune cell (osteopontin-producing macrophage) that is crucial for tissue repair and reinforcement after myocardial infarction, and we clarified the mechanism of its proliferation and differentiation. When the myocardium becomes necrotic due to acute myocardial infarction, the heart muscle in the infarcted area thins because cardiomyocytes lack regenerative capacity, preventing the heart from pumping enough blood to the body. It is believed that promoting the repair of damaged heart tissue, reinforcing the thinned myocardial tissue, and restoring cardiac function will lead to improved survival rates for patients with myocardial infarction. Various immune cells gather at the site of a myocardial infarction, and among them, macrophages are considered to play a crucial role in wound healing. In this study using mice, we discovered that macrophages that gather in necrotic tissue produce a substance called osteopontin, which allows them to phagocytose the debris of destroyed tissue and, furthermore, act on fibroblasts to promote the synthesis of fibrous tissue material, thereby repairing and reinforcing the tissue. Furthermore, we clarified the mechanism by which monocytes, mobilized from the bone marrow and entering the myocardial infarction site, differentiate into osteopontin-producing macrophages (involving IL-10 and galectin-3). The results of this research are expected to contribute to the development of groundbreaking therapies that enhance a patient's own healing power by increasing the number of macrophages with high tissue repair and reinforcement capabilities in the infarcted tissue, thereby preventing the onset of heart failure. The findings of this study were published in "Circulation," a journal of the American Heart Association.

(Motoaki Sano, '71, and Kosuke Shirakawa, '88, Department of Cardiology)

CELL STEM CELL,

DEC 6 2018,23 (6):787-+; 10.1016

Fujii M, Matano M, Toshimitsu K, Takano A, Mikami Y, Nishikori S, Sugimoto S, Sato T

Many tissues in the body form beautiful three-dimensional structures. Each tissue cell has its own specific rules, and it is believed that emergent self-organization occurs based on these rules. While conventional cell culture methods typically involve growing a single type of cell as a monolayer on a culture dish, a technique for creating three-dimensional structures called "organoids," which utilizes the self-organizing ability of tissue cells, is gaining attention. We have reported that organoids with a glandular structure can be created from just a single intestinal epithelial stem cell, and various researchers in Japan and abroad are developing organoid technologies for all kinds of tissues. While mouse intestinal epithelial organoids can produce all differentiated cell types, human intestinal epithelial organoids could only produce some, and it was difficult to form "cloned" organoids from a single cell. In this study, we aimed to develop an optimal culture technique for human intestinal organoids. With the new culture method, using the growth factors IGF1 and FGF2, we succeeded in creating human intestinal organoids capable of differentiating into all types of intestinal epithelial cells and in the long-term culture of rat intestinal organoids, which had previously been difficult. This technology is expected to be applied to human intestinal disease models and regenerative medicine in the future.

(Toshiro Sato, '76, Organoid medical sciences)

GASTROENTEROLOGY,

NOV 2018, 155 (5):1474-+; 10.1053

Katagiri R, Goto A, Nakagawa T, Nishiumi S, Kobayashi T, Hidaka A, Budhathoki S, Yamaji T, Sawada N, Shimazu T, Inoue M, Iwasaki M, Yoshida M, Tsugane S

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION,

DEC 4 2018, 320 (21):2234-2244;10.1001

Inohara T, Manandhar P, Kosinski AS, Matsouaka RA, Kohsaka S, Mentz RJ, Thourani VH, Carroll JD, Kirtane AJ, Bavaria JE, Cohen DJ, Kiefer TL, Gaca JG, Kapadia SR, Peterson ED, Vemulapalli S

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY,

DEC 2018, 142 (6):1818-+;10.1016

Muramatsu K, Ujiie H, Kobayashi I, Nishie W, Izumi K, Ito T, Yoshimoto N, Natsuga K, Iwata H, Shimizu H

PNAS,

NOV 27 2018, 115 (48):12259-12264; 10.1073

Ando H, Hirose M, Mikoshiba K