Differentiation of xenografted human fetal lung parenchyma

Pavlović, Jelena; Floros, Joanna; Phelps, David S.; Wigdahl, Brian; Welsh, Patricia A.; Weisz, Judith; Shearer, Debra; Pree, Alphonse Leure du; Myers, Roland L.; Howett, Mary K.

doi:10.1016/j.earlhumdev.2007.04.002

Cited by 10 publications

(20 citation statements)

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“…First, unlike all currently used humanized models for HCMV, this model utilizes the human fetal lung, one of the major targets of HCMV in fetuses and premature infants (8,25). Second, fetal lung development in the SCID-hu mouse closely resembles human lung development in utero (49). Third, we show here that this system is highly permissive for HCMV replication, enabling the study of virus pathogenesis and antiviral treatment in both epithelial and mesenchymal lung cells in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…The nonobese diabetic (NOD)-scid IL2R␥ Ϫ/Ϫ humanized mouse model was developed for the study of HCMV latency and reactivation in human CD34 ϩ hematopoietic cells (61) and for the identification of viral genes involved in viral replication and dissemination (66). In addition, CBA/lac mice have been used to establish a model of human fetal lung development (15), and fetal lungs implanted subcutaneously or under the kidney capsule of NCr-nu mice differentiated extensively, recapitulating human lung development in utero (49).…”

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confidence: 99%

“…Currently developed humanized mouse models for the long-term replication of HCMV are valuable platforms for drug development, but none of them utilize key target organs of congenital and neonatal HCMV infection, as we report here. Because human lung maturation and differentiation in the SCID-hu mouse are considerably similar to normal human intrauterine lung development (49), this small-animal model allows the study of the congenital and neonatal lung pathogenesis of HCMV as well as human respiratory viruses.…”

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confidence: 99%

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Impaired Surfactant Production by Alveolar Epithelial Cells in a SCID-hu Lung Mouse Model of Congenital Human Cytomegalovirus Infection

Maidji

Kosikova

Joshi

et al. 2012

J Virol

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Human cytomegalovirus (HCMV) is the leading viral cause of birth defects and life-threatening lung-associated diseases in premature infants and immunocompromised children. Although the fetal lung is a major target organ of the virus, HCMV lung pathogenesis has remained unexplored, possibly as a result of extreme host range restriction. To overcome this hurdle, we generated a SCID-hu lung mouse model that closely recapitulates the discrete stages of human lung development in utero. Human fetal lung tissue was implanted into severe combined immunodeficient (CB17-scid) mice and inoculated by direct injection with the VR1814 clinical isolate of HCMV. Virus replication in the fetal lung was assessed by the quantification of infectious virus titers and HCMV genome copies and the detection of HCMV proteins by immunohistochemistry and Western blotting. We show that HCMV efficiently replicated in the lung implants during a 2-week period, forming large viral lesions. The virus productively infected alveolar epithelial and mesenchymal cells, imitating congenital infection of the fetal lung. HCMV replication triggered apoptosis near and within the viral lesions and impaired the production of surfactant proteins in the alveolar epithelium. Our findings highlight that congenital and neonatal HCMV infection can adversely impact lung development, leading to pneumonia and acute lung injury. We have successfully developed a small-animal model that closely recapitulates fetal and neonatal lung development and provides a valuable, biologically relevant tool for an understanding of the lung pathogenesis of HCMV as well as other human respiratory viruses. Additionally, this model would greatly facilitate the development and testing of new antiviral therapies for HCMV along with select human pulmonary pathogens.H uman cytomegalovirus (HCMV) infection of the fetus and premature infants is a major global health problem, and in the United States, HCMV is the leading viral cause of birth defects, affecting about 1% of all live births (16). In congenital infection, HCMV spreads extremely efficiently into fetal organs following fetal viremia. Although pneumonitis is rarely the sole manifestation of congenital HCMV disease in the neonate (62), histological examinations of HCMV-infected fetuses identified the lung as a major target organ, with a large number of HCMV-infected cells (8,25). The main burden of lung-associated HCMV diseases occurs during postnatal infection in premature infants (3,22,34,65) and in immunocompromised children (predominantly after organ or bone marrow transplantation) (27,30,67). Some authors reported high rates (up to 37%) of postnatal cytomegalovirus transmission from seropositive breastfeeding mothers to premature infants (31,41,69). A significant proportion of infected infants develop pneumonitis along with hepatosplenomegaly, lymphadenopathy, enteritis, and aseptic meningitis (12, 36). Although breast milk containing HCMV is not considered dangerous to healthy full-term infants, the risk of development of early...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Impaired Surfactant Production by Alveolar Epithelial Cells in a SCID-hu Lung Mouse Model of Congenital Human Cytomegalovirus Infection

Maidji

Kosikova

Joshi

et al. 2012

J Virol

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“…To test the regenerative potential of fetal lung tissues under ideal culture conditions, we opted for the human-to-rodent xenograft model. The renal subcapsular space of immune suppressed rodents has been utilized for more than four decades as a near-physiological “incubator” milieu that supports optimal growth and development of adult and fetal human lung tissue 11,12 . Previous studies have demonstrated that human embryonic lung tissue derived from legal abortions can be successfully differentiated in immune suppressed mice 12 .…”

Section: Introductionmentioning

confidence: 99%

“…The renal subcapsular space of immune suppressed rodents has been utilized for more than four decades as a near-physiological “incubator” milieu that supports optimal growth and development of adult and fetal human lung tissue 11,12 . Previous studies have demonstrated that human embryonic lung tissue derived from legal abortions can be successfully differentiated in immune suppressed mice 12 . Although the duration of the interval between induced abortion and implantation of the lung tissues was not explicitly mentioned, it seems fair to assume that the post-delivery interval may have been relatively short after these planned abortions.…”

Section: Introductionmentioning

confidence: 99%

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

Paepe

Chu

Heger

et al. 2011

Experimental Lung Research

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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.

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

Spade

McDonnell

Heger

et al. 2014

Birth Defects Research Pt B

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Many diseases that manifest throughout the lifetime are influenced by factors affecting fetal development. Fetal exposure to xenobiotics, in particular, may influence the development of adult diseases. Established animal models provide systems for characterizing both developmental biology and developmental toxicology. However, animal model systems do not allow researchers to assess the mechanistic effects of toxicants on developing human tissue. Human fetal tissue xenotransplantation models have recently been implemented to provide human-relevant mechanistic data on the many tissue-level functions that may be affected by fetal exposure to toxicants. This review describes the development of human fetal tissue xenotransplant models for testis, prostate, lung, liver, and adipose tissue, aimed at studying the effects of xenobiotics on tissue development, including implications for testicular dysgenesis, prostate disease, lung disease, and metabolic syndrome. The mechanistic data obtained from these models can complement data from epidemiology, traditional animal models, and in vitro studies to quantify the risks of toxicant exposures during human development.

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Differentiation of xenografted human fetal lung parenchyma

Cited by 10 publications

References 62 publications

Impaired Surfactant Production by Alveolar Epithelial Cells in a SCID-hu Lung Mouse Model of Congenital Human Cytomegalovirus Infection

Impaired Surfactant Production by Alveolar Epithelial Cells in a SCID-hu Lung Mouse Model of Congenital Human Cytomegalovirus Infection

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

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

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