Research on the differentiation of fetal tissues by means of heterotransplantation and its application to developmental toxicology

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Pieces of various organs of human therapeutic abortuses (32-54 days of gestation) were transplanted subcutaneously or intratesticularly in athymic (nude) mice. Most grafts of the limb, lung, and digestive tube were accepted and showed substantial growth and tissue differentiation for up to 18 weeks. The retinal tissue was readily accepted when grafted in testes but not in the subcutaneous tissue. The tissue differentiation of accepted organs generally simulated that occurring in vivo.On the other hand, limb buds of day 14 rat fetuses were cut into pieces and transplanted into the subcutaneous tissue of athymic (nude) mice. In day 14 fetal limbs, mesenchymal cells have begun to condense to form cartilaginous anlage, but no cartilage has been formed. Within 7 days after grafting, masses of hyaline cartilage developed, and new bone formation began by 14 days. By 20 days, osteoclasts appeared, and the formation of bone trabeculae and marrow cavities progressed. The cytological characterist … More ics of chondrocytes, osteoblasts and osteoclasts were essentially the same as those seen in vivo. Many grafts developed into long bones, having the diaphysis and epiphysis. The mode of chondrogenesis and osteogenesis in the grafts was histologically similar to the corresponding process in vivo, although the differentiation was slower in the grafted limbs.In order to evaluate the applicability of the heterotransplantation method to developmental toxicology, the host nude mice were treated with various drugs including rat teratogens on the 7th, 9th, and llth days after grafting fetal rat limbs. On the 20th day after grafting, the grafted tissue was examined macroscopically and histologically. While control grafts showed substantial growth and tissue differentiation similar to that observed in vivo, the differentiation of grafts was significantly inhibited by the treatment with 5-fluorouracil, cyclophosphamide, hydroxyurea, cycloheximide, mitomycin C, caffeine, aspirin, retinol palmitate, all-trans-retinoic acid and ascorbic acid. Hydrocortisone, tetracycline and thalidomide did not adversely affect the differentiation of grafts. Thus, the susceptibility of transplanted rat limb buds was generally close to the teratologic sensitivity of rat fetuses in vivo. The heterotransplantation method of embryonic tissues may be useful as a new experimental system in developmental toxicology. Less