Cytodifferentiation of human fetal lung tissue following transplantation into ?nude? mice

Abstract

Lung fragments from 10 human fetuses aged 10 to 14 weeks of gestation were implanted into athymic "nude" mice. Cytodifferentiation of the transplants was studied by both scanning and transmission electron microscopy. Two weeks after implantation mitotic figures of epithelial and stroma cells were observed. In five week old transplants ciliated as well as endocrine cells were found dispersed among undifferentiated bronchial epithelium. During further experimental period epithelial differentiation in the transplants proceeded. Thus, eight week old implants assumed the morphologic appearance of fetal lungs in the canalicular stage displaying prospective type I and II pneumocytes. In addition stroma cells also differentiated forming mature fibroblasts and myofibroblasts. Our study indicates that human fetal lung tissue transplanted into "nude" mice not only grow but even differentiate. Xenogeneic transplantation of human fetal cells and tissues, therefore, offers additional opportunities to investigate the prenatal development of human tissues.

Differentiation of xenografted human fetal lung parenchyma

“…This is in contrast to the previous studies that have examined human graft development at multiple time points. In one study where fetal lungs from 10-14 weeks of gestation were subcutaneously grafted into nude mice, grafts resembling canalicular stage of development were observed at 8 weeks post-grafting (Groscurth and Tondury, 1982). The time course of tissue differentiation also appears to be accelerated in the present model, as compared to another study where fetal lungs ranging from 8-12 weeks of gestation were grafted for 3, 6, 11, and 19 weeks (Peault et al, 1994).…”

“…Given the size restrictions of graft tissue, measurements of weight for comparisons of dry and wet tissue weights were impractical, although larger grafts were noted to have more lung fluid by gross observation. A considerable increase in the size of grafts after longer grafting times has been observed in both renal subcapsular (Vu et al, 2003) and subcutaneous (Cobb, 1975;Groscurth and Tondury, 1982;Peault et al, 1994;Phillips and Gazet, 1969) mouse fetal lung allograft models, although a comparison of these two engraftment sites has not been done previously. In the present study, initial transplantation of smaller pieces at both graft sites (subcapsular and subcutaneous) resulted in a more rapid vascularization of the entire area of the graft tissue and thus uniform growth and differentiation.…”

“…It has also been observed that (Phillips and Gazet, 1969) human fetal lung tissues grafted into a mouse treated with antilymphocytic serum (ALS, lymphocyte suppressing antibodies) could develop and grow in the host for up to 90 days. Others observed differentiation of lung-specific cell types in two, five, and eight week old transplant grafts (Groscurth and Tondury, 1982). More recently, a number of studies involving xenograft models of human upper airway development, have been reported (Delplanque et al, 2000;Puchelle and Peault, 2000).…”

“…Various xenograft models have been used extensively in cancer research to study mechanisms of carcinogenesis and the effects of different pharmacological agents on human tumor growth (Giovanella and Fogh, 1985;Malkinson, 2001), as well as in studies of transmission of infection in various tissues by pathogens (Howett et al, 1997;Howett et al, 1990;Howett et al, 1999;Kish et al, 2001;Kreider et al, 1985). With respect to lung embryogenesis, immunocompromised mice have been used to study whole organ lung development in mice (Schwarz et al, 2000;Vu et al, 2003), as well as lower (Groscurth and Tondury, 1982;Peault et al, 1994) and upper airway development in humans (Delplanque et al, 2000;Deutsch, 1997;Engelhardt et al, 1993;Filali et al, 2002;Pilewski et al, 1994;Puchelle and Peault, 2000). Allograft models have been used where whole embryonic mouse lungs were grafted into severe-combined immunodeficient (SCID) mice (Schwarz et al, 2000;Vu et al, 2003).…”

“…Based on the knowledge available from a number of lung xenograft models (Cobb, 1975;Delplanque et al, 2000;Deutsch, 1997;Engelhardt et al, 1993;Filali et al, 2002;Groscurth and Tondury, 1982;Peault et al, 1994;Phillips and Gazet, 1969;Pilewski et al, 1994;Puchelle and Peault, 2000;Schwarz et al, 2000;Vu et al, 2003), we hypothesized that human fetal lung parenchyma grafted into immunocompromised mice will undergo changes that mimic the stages of in utero lung development in many respects. The assumption was that although grafted tissue may undergo accelerated maturation, this acceleration would not be as rapid as that seen in fetal lung explants, enabling one to study stage-specific processes of lung development.…”