| Popis: |
Coordinated remodeling of epithelium and vasculature is essential for normal postglandular lung development. The value of the human-to-rodent lung xenograft as model of fetal microvascular development remains poorly defined.The aim of this study was to determine the fate of the endogenous (human-derived) microvasculature in fetal lung xenografts.Lung tissues were obtained from spontaneous pregnancy losses (14-22 weeks' gestation) and implanted in the renal subcapsular or dorsal subcutaneous space of SCID-beige mice (T, B, and NK-cell-deficient) and/or nude rats (T-cell-deficient). Informed parental consent was obtained. Lung morphogenesis, microvascular angiogenesis, and epithelial differentiation were assessed at 2 and 4 weeks post-transplantation by light microscopy, immunohistochemical, and gene expression studies. Archival age-matched postmortem lungs served as control.The vascular morphology, density, and proliferation of renal subcapsular grafts in SCID-beige mice were similar to age-matched control lungs, with preservation of the physiologic association between epithelium and vasculature. The microvasculature of subcutaneous grafts in SCID-beige mice was underdeveloped and dysmorphic, associated with significantly lower VEGF, endoglin, and angiopoietin-2 mRNA expression than renal grafts. Grafts at both sites displayed mild airspace dysplasia. Renal subcapsular grafts in nude rats showed frequent infiltration by host lymphocytes and obliterating bronchiolitis-like changes, associated with markedly decreased endogenous angiogenesis.This study demonstrates the critical importance of host and site selection to ensure optimal xenograft development. When transplanted to severely immune suppressed, NK-cell-deficient hosts and engrafted in the renal subcapsular site, the human-to-rodent fetal lung xenograft provides a valid model of postglandular microvascular lung remodeling. |
