Fetal lung transcriptome patterns in an ex vivo compression model of diaphragmatic hernia

Fox, Zachary D.; Jiang, Guihua; Ho, Kenneth K. Y.; Walker, Kendal; Liu, Allen; Kunisaki, Shaun M.

doi:10.1016/j.jss.2018.06.064

Cited by 12 publications

(14 citation statements)

References 37 publications

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“…Our data are also concordant with previous work based on our ex vivo compression apparatus used to assess changes in fetal rat lungs. 34 In that study, we found that mechanical compres- expressed by alveolar myofibroblasts, has been shown to be critical for early lung branching and alveolarization. 67,68 Approximately 10% of ECM-related genes, many associated with proximal/bronchial airway formation, were significantly upregulated in day 40 CDH LOs in microarray analyses ( Figure 3D).…”

Section: Discussionmentioning

confidence: 89%

“…To study the contribution that extrinsic compression may play in the development of the CDH lung phenotype, we used an ex vivo mechanical compression apparatus as previously described 33,34 and tested its effect on day 40 LOs that were otherwise cultured under the same growth conditions (Figure 6A). This time point was chosen since LOs differentiation was analogous to the pseudoglandular stage of lung development based on previous work 31,38 .…”

Section: Resultsmentioning

confidence: 99%

“…74 Given the findings in our study, the application of mechanical compression may represent a "second hit" in which lung hypoplasia is further aggravated, perhaps by aberrant mesenchymal-epithelial responses to compression stimuli as we and others have previously suggested in rodent models. 22,34 Some experimental evidence supports an underlying dysfunction in mesenchymal cells associated with defective alveolarization in CDH. [75][76][77] Investigators have also shown that soluble factors secreted by the mesenchyme can have effects on alveolar progenitor cell differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…The compression device was based on work described elsewhere 33 with some modifications ( Figure 6A) and has been previously reported. 34 Briefly, day 40 CDH LOs (n = 10 per drop) were encapsulated into 50 μL of Matrigel and placed onto 0.4 μm pore size polyster (PET) transwell membranes (Fisher Scientific, 07-200-170, Waltham, Massachusetts). CDH and normal LOs were overlaid with a 1% agarose gel cushion (Invitrogen, Ultra-Pure Agarose, 16 500-100) made from sterilized 24-mm polydimethylsiloxane (PDMS) molds.…”

Section: Compression Testingmentioning

confidence: 99%

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Human induced pluripotent stem cell-derived lung organoids in an ex vivo model of the congenital diaphragmatic hernia fetal lung

Kunisaki

Jiang

Biancotti

et al. 2020

Stem Cells Translational Medicine

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Three-dimensional lung organoids (LOs) derived from pluripotent stem cells have the potential to enhance our understanding of disease mechanisms and to enable novel therapeutic approaches in neonates with pulmonary disorders. We established a reproducible ex vivo model of lung development using transgene-free human induced pluripotent stem cells generated from fetuses and infants with Bochdalek congenital diaphragmatic hernia (CDH), a polygenic disorder associated with fetal lung compression and pulmonary hypoplasia at birth. Molecular and cellular comparisons of CDH LOs revealed impaired generation of NKX2.1 + progenitors, type II alveolar epithelial cells, and PDGFRα + myofibroblasts. We then subjected these LOs to disease relevant mechanical cues through ex vivo compression and observed significant changes in genes associated with pulmonary progenitors, alveolar epithelial cells, and mesenchymal fibroblasts. Collectively, these data suggest both primary cellintrinsic and secondary mechanical causes of CDH lung hypoplasia and support the use of this stem cell-based approach for disease modeling in CDH.

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Section: Discussionmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Compression Testingmentioning

confidence: 99%

See 2 more Smart Citations

Human induced pluripotent stem cell-derived lung organoids in an ex vivo model of the congenital diaphragmatic hernia fetal lung

Kunisaki

Jiang

Biancotti

et al. 2020

Stem Cells Translational Medicine

Self Cite

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“…Fox et al reported an ex vivo lung compression microdevice that can replicate high compressive forces on lung explants, and using this model they showed that mechanical stress worsened the expression of surfactant protein. 101…”

Section: Lamb and Rabbit Models: Toward Clinical Translationmentioning

confidence: 99%

Congenital Diaphragmatic Hernia: State of the Art in Translating Experimental Research to the Bedside

et al. 2019

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Congenital diaphragmatic hernia (CDH) is a devastating disease that still carries a high mortality and morbidity rate. Poor outcomes for fetuses and infants with CDH are mainly related to pulmonary hypoplasia (PH) and pulmonary vascular remodeling that leads to pulmonary hypertension (PHTN). Over the last five decades, research efforts have focused on modeling CDH not only to study the pathophysiology of the diaphragmatic defect, pulmonary hypoplasia, and pulmonary hypertension, but also to identify therapies that would promote lung growth and maturation, and correct vascular remodeling. As CDH is a multifactorial condition whose etiology remains unknown, there is not a single model of CDH, rather several ones that replicate different aspects of this disease. While small animals like the mouse and the rat have mainly been used to uncover biological pathways underlying the diaphragmatic defect and poor lung growth, larger animals like the lamb and the rabbit models have been instrumental for pursuing medical and surgical interventions. Overall, the use of animal models has indeed advanced our knowledge on CDH and helped us test innovative therapeutic options. For example, the lamb model of CDH has been the paradigm for testing fetal surgical procedures, including tracheal occlusion, which has been translated to clinical use. In this review, we outline the induction protocols of CDH in animals with the use of chemicals, dietary changes, genetic alterations, and surgical maneuvers, and we describe the studies that have translated experimental results to the bedside.

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Assessment of the nitrofen model of congenital diaphragmatic hernia and of the dysregulated factors involved in pulmonary hypoplasia

Montalva

Zani

2018

Pediatr Surg Int

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Fetal lung transcriptome patterns in an ex vivo compression model of diaphragmatic hernia

Cited by 12 publications

References 37 publications

Human induced pluripotent stem cell-derived lung organoids in an ex vivo model of the congenital diaphragmatic hernia fetal lung

Human induced pluripotent stem cell-derived lung organoids in an ex vivo model of the congenital diaphragmatic hernia fetal lung

Congenital Diaphragmatic Hernia: State of the Art in Translating Experimental Research to the Bedside

Assessment of the nitrofen model of congenital diaphragmatic hernia and of the dysregulated factors involved in pulmonary hypoplasia

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