BACKGROUND: 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. AIM: The aim of this study was to determine the fate of the endogenous (human-derived) microvasculature in fetal lung xenografts. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND: 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. AIM: The aim of this study was to determine the fate of the endogenous (human-derived) microvasculature in fetal lung xenografts. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Authors: Horace M DeLisser; Brian P Helmke; Gaoyuan Cao; Patricia M Egan; Darren Taichman; Melane Fehrenbach; Aisha Zaman; Zheng Cui; Gopi S Mohan; H Scott Baldwin; Peter F Davies; Rashmin C Savani Journal: J Biol Chem Date: 2005-12-23 Impact factor: 5.157
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Authors: Daniel J Spade; Elizabeth V McDonnell; Nicholas E Heger; Jennifer A Sanders; Camelia M Saffarini; Philip A Gruppuso; Monique E De Paepe; Kim Boekelheide Journal: Birth Defects Res B Dev Reprod Toxicol Date: 2014-12-04
Authors: Monique E De Paepe; Sharon Chu; Susan J Hall; Elizabeth McDonnell-Clark; Nicholas E Heger; Christoph Schorl; Quanfu Mao; Kim Boekelheide Journal: Exp Lung Res Date: 2015 Impact factor: 2.459
Authors: Marko Z Nikolić; Eva M Garrido-Martin; Flavia R Greiffo; Aurélie Fabre; Irene H Heijink; Agnes Boots; Catherine M Greene; Pieter S Hiemstra; Sabine Bartel Journal: ERJ Open Res Date: 2019-05-10