Hirohiko Fujii

Hormone-induced morphogenesis and growth: role of mesenchymal-epithelial interactions.

Publisher Summary This chapter explains the role of mesenchymal–epithelial interactions in hormone induced morphogenesis and growth. The mechanism of steroid hormone action is thought to involve specific high-affinity receptor proteins. The hormone enters the cell, binds to the cytoplasmic receptor, which after activation translocates to the nucleus. The hormone–receptor complex in turn binds to nuclear acceptor sites on the chromatin. This activates a variety of metabolic processes, the most important being the stimulation of messenger RNA (mRNA) synthesis and the ultimate production of new proteins. The first indication that androgens can elicit their effects upon epithelial morphogenesis via the mediation of mesenchymal cells comes from studies in which urogenital epithelia from the embryonic seminal vesicle or urogenital sinus are grown in association with either urogenital mesenchyme or with non-target integumental mesenchyme. Urogenital mesenchyme induces specific epithelial morphogenesis, growth, and function within the genital tract and that the hormonal sensitivity of these morphogenetic processes resides in the mesenchyme that invariably contains nuclear hormone receptors. As morphogenetic processes are cyclic in adult genital tracts of many species, developmental properties are expressed in adulthood and, for this reason, appear to play a regulatory role in abnormal epithelial differentiation including carcinogenesis.

Effect of a single administration of testosterone on the immune response and lymphoid tissues in mice

Abstract Female mice were given a single intraperitoneal injection of testosterone immediately after irradiation and marrow reconstitution. Thirty days later testosterone had no suppressive effect on the recovery of thymus and spleen weights. Testosterone had no effect on the graft-versus-host reaction. Testosterone had no influence on the survival of the skin homografts. However, the plaque-forming cell response to sheep erythrocytes in the spleen was dramatically suppressed by testosterone. Histological observations revealed marked inhibition of lymphoid regeneration selectively in the thymus-independent areas of the peripheral lymphoid tissues. These results suggest that testosterone would act mainly on the differentiation of stem cells toward the population of bone marrow-derived B lymphocytes. The immune response to sheep erythrocytes was restored completely 90 days after testosterone administration. Testosterone given to normal adult mice can also have suppressive activity on the immune system 30 days after a single intraperitoneal injection.

Splenic marginal-zone macrophages and marginal metallophils in rats and mice

SummaryThe splenic macrophages of rats and mice were studied by light and fluorescence microscopy to determine their phagocytotic uptake of carbon and neutral polysaccharide (Fic-F), and their lysosomal enzyme activities. In rats, the large macrophages of the marginal zone (MZ) showed a moderate to strong acid phosphatase activity, and took up most of the Fic-F, even though they showed a weak phagocytotic activity to carbon particles. Red-pulp macrophages, however, ingested a large quantity of carbon particles, and are considered to be the major scavengers in the rat spleen. In contrast, the MZ macrophages in the mouse spleen were the major scavengers and showed a vigorous uptake of both carbon and Fic-F. In rats, the marginal metallophils (MM), located at the outer border of the periarterial lymphatic sheath and boundary between the MZ bridging channel and surrounding tissue, ingested Fic-F, whereas those located around the follicular area did not. In mice, on the other hand, the MM never ingested Fic-F. Lightly carbon-ladened small cells were constantly seen in the MZ of both rats and mice. They showed little acid phosphatase activity and did not ingest Fic-F. They were also present in the blood circulation.

Lymph macrophages enter the germinal center of lymph nodes of guinea pigs

To determine the fate of macrophages within the afferent lymph stream, the popliteal lymph nodes at various times (3 h to 6 months) after subcutaneous injection of india ink into the footpads of guinea pigs were examined. Two types of cells which had phagocytized india ink were observed in the germinal centers. A small number of type I phagocytes (engulfing india ink as small particles which were often found together with tingible bodies in their cytoplasm) were scattered through the germinal center. A large number of type II phagocytes (packed full of india ink) presented preferentially in the medullary portion of the germinal center, together with many pyroninophil lymphoblastoid cells. In the second experiment, the afferent lymphatics of the popliteal lymph node were ligated 15-20 min after india ink injection. Although the type I phagocytes were distributed as in the first experiment, the type II phagocytes were scanty. In the third experiment, the afferent lymphatics of the popliteal lymph node were ligated 7 days after india ink injection. The type II phagocytes disappeared rapidly from the germinal center, whereas the type I phagocytes remained and were not affected by ligature. These results suggest that the type I phagocytes are the fixed macrophages or tingible body macrophages in the germinal center, and that the type II phagocytes are the macrophages migrating from the peripheral tissues. It was also shown that many macrophages reaching the regional node via afferent lymphatics entered the germinal center through the medullary pole where the cap of small lymphocytes became thinner or disappeared.

Inhibition by testosterone of immune reactivity and of lymphoid regeneration in irradiated and marrow reconstituted mice

Nachweis, dass die Behandlung letal bestrahlter und mit isologem Knochenmark regenerierter Mäuse mit Testosteron zu starker Herabsetzung der immunologischen Reaktivität und zu eindeutiger Reduktion des lymphatischen Gewebes führt.

Post-capillary venules as the pathway for migrating B lymphocytes

SummaryHistological observation on the mesenteric lymph node and Peyers patches of C3H B mice, neonatally thymectomized, lethally irradiated and reconstituted with syngeneic bone marrow cells, showed that a large number of lymphocytes appeared selectively in the restricted territory surrounding the post-capillary venules. Severe depletion of lymphocytes persisted in most of the thymus-dependent areas. Lymphocytes were also observed passing through the walls of the post-capillary venules. Autoradiographic studies on the mesenteric lymph node of recipient B mice 30 minutes after intravenous injection of cells labelled with 3H-uridine and taken from lymph nodes of donor B mice showed that B lymphocytes could penetrate the walls of the post-capillary venules from the blood into the peripheral lymphoid tissues. The post-capillary venules, which are known as the recirculating route of T lymphocytes in normal animals, are thought to be the pathway of migrating B lymphocytes in B mice.

Stimulating Effect of Natural Estrogens on Proliferation of Hepatocytes in Adult Mice

A single oral administration of natural principal estrogens, estrone (E1), 17 beta-estradiol (E2) and estriol (E3), caused active proliferation of hepatocytes of adult mouse liver. Steroid hormones tested (testosterone, progesterone and cortisone) other than estrogens were not stimulants of proliferation of hepatocytes. Among these three natural estrogens, E3 was found to be the most potent stimulant of hepatocyte proliferation and E1 was the weakest. The possible mechanism of the hepatocyte-proliferating potency of estrogens was discussed in close relationship to their stimulating effect on the reticuloendothelial system.

Effects of estrogen on the lymphoid regeneration and immune response in irradiated and marrow-reconstituted mice

Various doses of estriol (E3) were given to mice intraperitoneally, immediately after lethal irradiation and marrow reconstitution. The assessment of the plaque-forming cell (PFC) response to sheep erythrocytes in the spleen and the histological assessment of lymphoid tissues were carried out 30 days later. The effects appeared to be dose-dependent and resulted in a marked suppression of the PFC response. The depletion of lymphocytes was dramatic and dose-dependent in the thymus, and in the thymus-dependent and in the thymus independent areas of the peripheral lymphoid tissues. These results suggest that E3 acts on the differentiation of stem or precursor cells toweard both the populations of T and B lymphocytes. Although E3, given on day 7 after irradiation and marrow reconstitution, suppressed the lymphoid regeneration and PFC response markedly, E3 given on day 14 had no effect. On day 7 the majority of regenerating lymphoid tissues were large pyroninophilic cells and on day 14, small lymphocytes. These results suggest that the precursor or immature lymphocytes are sensitive to E3, while mature lymphocytes are resistant. Lymphoid regeneration and PFC response were retarded in mice irradiated and reconstituted with bone marrow cells from donors pretreated with E3. These results suggest that E3 acts on the stem or precursor cells capable to differentiate in the direction of lymphoid populations and reduce their number in the bone marrow.

Promoting effect of estrogen on regeneration of the liver transplanted to an ectopic site in mice

A single oral administration of a pharmacological dose of estriol (E3) immediately after transplantation of small liver fragments of mice under the kidney capsule induced a remarkable growth of regenerating liver tissue. The hepatocytes were successfully arranged in cords with well developed sinusoids between them. The cytoplasm of the hepatocytes showed prominent basophilia. In mice injected with carbon intravenously, large numbers of carbon-laden endothelial lining cells and Kupffer cells apeared in the newly building sinusoids. E3 raised the mitotic activity of the regenerating hepatocytes markedly and for a long period. The act of E3 on mitosis was much more effective on the regenerating hepatocytes than on the recipients own hepatocytes.

Peritoneal macrophages introduced into mouse foot pads enter the germinal center of regional lymph nodes nonspecifically

Male mice were injected into their foot pads with sheep erythrocytes (SRBC) to form lymph follicles in the germinal centers in the popliteal lymph nodes. 4 weeks later, peritoneal macrophages labeled with carbon from syngeneic donors sensitized with SRBC or typhoid-paratyphoid bacilli (TAB) were separately injected into the foot pads as well. The popliteal lymph nodes were histologically examined at 6 h to 5 days after injection. Labeled macrophages appeared in the marginal sinus, migrated straight across the cortex from the marginal sinus to the lymph follicles and then entered the germinal centers. There was no difference in the mode of appearance, migration and localization of labeled macrophages in the regional lymph nodes between the mice given labeled macrophages from SRBC-sensitized donors and those given macrophages from TAB-sensitized donors. The entrance of lymph macrophages into the germinal centers of the regional lymph nodes would be immunologically nonspecific. After the injection of Pelikan ink into the foot pads, the macrophages which have taken up carbon in the peripheral tissue reached the regional lymph nodes via the afferent lymphatics and then entered the germinal centers, mainly through the medullary pole of the lymph follicles, after migrating along their immediate exterior from their marginal sinus to their medullary pole.