Xenografted human whole embryonic and fetal entoblastic organs develop and become functional adult-like micro-organs

Abstract

Background and aims: The aim of this study was to study the morphological and functional development in vivo of whole human embryonic and fetal stomachs, intestines, tracheas, and lungs, which would otherwise be ethically and technically impossible to perform in utero, by microsurgically grafting these organs into nude mice.

Materials and methods: Five hundred fifty-seven human organs obtained from legally aborted embryos and fetuses of 6-10 weeks were microsurgically grafted into nude mice for 1 to 273 days. Following different grafting times, biopsies were taken for optical and electron microscopy, in situ hybridization, and cellular kinetics studies. A catheter was introduced into the human organs in order to collect and analyze secretions.

Results: All of the grafts took successfully. Macroscopic growth was fast during the first 6 to 10 weeks, following which organ size was stable. In situ hybridization studies detected only a minute level of mouse mesenchymal chimerism in the grafts. The different epithelial cells differentiated, became of adult type, and remained normal during the remainder of the grafting periods. The pH of gastric juice from stomachs grafted for 10 to over 90 days dropped from 8.0 +/- 0.1 to 1.58 +/- 0.29 over this time period (P < 0.001), intrinsic factor levels were stable, and pepsin ranged from 6.8 +/- 7.8 to 134 +/- 51 units (P < 0.001).

Conclusions: These results demonstrate that the development of entoblastic organs from human embryos and fetuses microsurgically grafted into nude mice is similar to that occurring in utero. As such, this method provides a model for the analysis of whole human organs in development and later normal adult-like micro-organs for physiological, therapeutic, and pathological studies.