Resilience of the human fetal lung following stillbirth: Potential relevance for pulmonary regenerative medicine

Abstract

Recent advances in pulmonary regenerative medicine have increased the demand for alveolar epithelial progenitor cells. Fetal lung tissues from spontaneous pregnancy losses may represent a neglected, yet ethically and societally acceptable source of alveolar epithelial cells. The aim of this study was to determine the regenerative capacity of fetal lungs obtained from second trimester stillbirths. Lung tissues were harvested from 11 stillborn fetuses (13–22 weeks’ gestation) at post-delivery intervals ranging from 10 to 41 hours and grafted to the renal subcapsular space of immune suppressed rats to provide optimal growth conditions. Histology, epithelial and alveolar type II cell proliferation, and surfactant protein-C mRNA expression were studied in preimplantation lung tissues and in xenografts at post-transplantation week 2. All xenografts displayed advanced architectural maturation compared with their respective preimplantation tissues, regardless of gestational age and post-delivery interval. The proliferative activity of the grafts was significantly higher than that of the preimplantation tissues (mean Ki-67 labeling index 26.7 ± 7.7% versus 14.7 ± 10.5%, P < 0.01). The proliferative activity of grafts obtained after a long (> 36 h) post-delivery interval was significantly higher than that of the corresponding preimplantation tissue, and equivalent to that of grafts obtained after a short post-delivery interval (< 14 h). The regenerative capacity of fetal lung tissue was greater at younger (13–17 weeks) than at older (19–22 weeks) gestational ages. The presence of inflammation/chorioamnionitis did not appear to affect graft regeneration. All grafts studied displayed robust surfactant protein-C mRNA expression. In conclusion, fetal lung tissues from second trimester stillbirths can regain their inherent high regenerative potential following short-term culture, even if harvested more than 36 hours after delivery.

Intussusceptive-like angiogenesis in human fetal lung xenografts: Link with bronchopulmonary dysplasia-associated microvascular dysangiogenesis?

“…Samples for transplantation (1–2 mm 3 pieces) were taken from the peripheral parenchyma of the right lung. Transplantation was performed at the Xenotransplant Core Facility at Brown University (Providence, RI), as previously described 20, 21 . Recipients of the renal subcapsular xenografts were 6 to 12-week-old male SCID-beige mice (Fox Chase SCID beige, Charles River, Wilmington, MA).…”

“…In the course of recent studies that employed a human-to-rodent fetal lung xenograft model 20, 21 , we identified unusual patterns of microvascular growth in a subset of human fetal lung grafts. The microscopic appearance of these aberrant vascular patterns was strongly reminiscent of the microvascular dysmorphism previously described in postmortem studies of premature ventilated infants and infants with BPD 6 .…”

A Human Fetal Prostate Xenograft Model of Developmental Estrogenization

“…This period was chosen for tissue acquisition because it is an important period of organogenesis in human fetal prostate 12 . De Paepe et al provides a detailed description of tissue procurement 22 . Briefly, written and informed consent is obtained from donors, and a board certified pathologist evaluated the condition of the human tissue prior to implantation.…”

Xenotransplantation Models to Study the Effects of Toxicants on Human Fetal Tissues

“…This model has shown promise for toxicologic studies. In general, we have found that human fetal lung xenotransplants are viable and exhibit brisk proliferative and secretory activity (De Paepe et al., , ). However, lung grafts have a mildly dysplastic appearance, reminiscent of the previously described features of fetal lungs following in utero tracheal occlusion (De Paepe et al., ).…”

“…In this review, we describe our recent development of xenotransplant models with the goal of studying the effects of xenobiotics in human fetal testis (Heger et al., ; Spade et al., ), prostate (Saffarini et al., ), lung (De Paepe et al., , ), liver, and adipose tissue (Garcia et al., ). We do not aim to conduct an exhaustive review of the extensive literature on xenotransplantation.…”