Kasra Khalaj

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One of the biggest challenges for babies with CDH is that fetal hypoplastic lungs are immature, whereby there is an impairment of cell differentiation, especially in the epithelium.
quote · Congenital Diaphragmatic Hernia
Congenital diaphragmatic hernia is characterized by impaired fetal lung growth and maturation. This condition has unacceptably high mortality and morbidity rates.
quote · Congenital Diaphragmatic Hernia

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Kasra's statements about Congenital Diaphragmatic Hernia 48 statements

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CAPS - Administration of amniotic fluid stem cell extracellular vesicles regenerates the lung epithelium in fetal rats with CDH at translationally relevant developmental stages - Kasra Khalaj

Statement Congenital diaphragmatic hernia is characterized by impaired fetal lung growth and maturation with unacceptably high mortality and morbidity rates. Open
Quotation Congenital diaphragmatic hernia is characterized by impaired fetal lung growth and maturation. This condition has unacceptably high mortality and morbidity rates. Open
Quotation One of the biggest challenges for babies with CDH is that fetal hypoplastic lungs are immature, whereby there is an impairment of cell differentiation, especially in the epithelium. Open
Statement Fetal hypoplastic lungs in CDH are immature with impairment of cell differentiation, especially in the epithelium. Open
Statement Extracellular vesicles (EVs) are the main mediators of stem cell paracrine signaling. Open
Statement Amniotic fluid stem cell-derived EVs can rescue fetal lung growth and maturation in several models of CDH at the pseudoglandular stage (corresponding to 7-16 weeks of human gestation). Open
Statement CDH is diagnosed around 18-20 weeks of human gestation. Open
Statement The canalicular and saccular stages are translationally relevant developmental stages for CDH intervention, corresponding to when the condition can be diagnosed. Open
Statement The nitrofen model is a well-established model for studying CDH, created by administering the herbicide nitrofen to pregnant rat dams at embryonic day 9.5. Open
Statement Key epithelial populations in the fetal lung include alveolar type 1 and type 2 cells (primarily comprising the alveolus), and club, ciliated, and basal cells (mainly comprising the bronchi and bronchioles). Open
Statement Hypoplastic lungs at canalicular and saccular stages show down-regulation of alveolar type 1 and 2 cells, as well as basal and club cells compared to control. Open
Statement Treatment with amniotic fluid stem cell-derived extracellular vesicles restores primary markers of alveolar type 1 and 2 cells, basal cells, and club cells in hypoplastic lungs, indicating that cell homeostasis can be achieved. Open
Quotation Remarkably, when we treat these hypoplastic lungs with the amniotic fluid stem cell derived extracellular vesicles, we are able to restore these primary markers, as you can see in the green shaded area, thus indicating that cell homeostasis can be achieved. Open
Statement In vivo experiments have been performed using intraamniotic and tracheal administration routes for extracellular vesicles in a rat model, with promising results. Open
Statement Safety and feasibility studies of AFSCEV treatment are being investigated in collaboration with Jan De Prest in a lamb model. Open
Statement Ciliated cells were not rescued by AFSCEV treatment, which may reflect achievement of a different homeostatic cell composition rather than failure of the treatment. Open
Statement Key markers of branching morphogenesis are being effectively rescued by AFSCEV treatment. Open

EUPSA - MicroRNAs in amniotic fluid stem cellextracellular vesicles modulate lung development in experimental congenital diaphragmatic hernia - Kasra Khalaj

Quotation It is well known that hypoplastic lungs of babies with pulmonary hypoplasia secondary to CDH have impaired fetal lung growth and maturation. Open
Statement Hypoplastic lungs of babies with pulmonary hypoplasia secondary to CDH have impaired fetal lung growth and maturation Open
Statement Several treatment agents have been administered prenatally for CDH, but none have been shown to fully rescue lung development Open
Statement Extracellular vesicles are nanoparticles known to be the mediators of stem cell paracrine signaling Open
Statement AFSCEV administration rescued the number of lung branches back to normal in CDH models Open
Statement AFSCEVs improve fetal lung maturation as shown by rescuing the expression of surfactant protein C Open
Statement AFSCEVs contain microRNA 17-92 cluster, which has been reported in the literature to modulate fetal lung development Open
Statement Knockout of the microRNA 17-92 cluster can recapitulate pulmonary hypoplasia Open
Statement Autophagy has been shown to be critical for lung branching morphogenesis Open
Quotation Many refer to autophagy as a recycling mechanism of cellular tra, so to speak, and this is because it's one of the key ways that cell survival is promoted. Open
Statement Autophagy is a recycling mechanism of cellular trash and is one of the key ways that cell survival is promoted Open
Statement Autophagy is most impaired at the pseudoglandular and canalicular stages in the nitrofen model of CDH Open
Statement CDH fetal lungs show reduced levels of Beclin 1 and ATG5 (autophagy activators) and higher levels of sequestosome (autophagy adapter) at pseudoglandular and canalicular stages Open
Statement High levels of sequestosome indicate autophagy impairment Open
Statement Treatment with AFSCEVs restores autophagy key genes (Beclin 1, ATG5, sequestosome) at the pseudoglandular and canalicular stage Open
Statement AFSCEVs are taken up by virtually all cells in fetal lung explants, including the fetal lung epithelium Open
Statement Activation of autophagy by AFSCEVs is localized in the lung epithelial compartment of the fetal lung microenvironment Open
Statement Knockdown of microRNAs 17 and 20 in AFSCEVs results in increased sequestosome and down regulation of Beclin mRNA, indicating impaired autophagy Open
Statement Knockdown of microRNAs 17 and 20 results in lower levels of LC3B2 protein, which is the active isoform of the autophagy cascade Open
Quotation Well, by now I bet you're all asking, well, are these findings clinically relevant in human CDH? Open
Statement Human fetal lung explant model of pulmonary hypoplasia was established using fetal lungs from healthy terminated fetuses from 15 to 19 weeks of gestation, corresponding to late pseudoglandular and canalicular stages Open
Statement In human hypoplastic fetal lung explants, there is a reduction of Beclin 1 and ATG5 at the mRNA level Open
Statement Treatment with human AFSCEVs results in restoration of Beclin 1 and ATG5 in human hypoplastic fetal lung explants Open
Statement At the protein level in human tissue, all three autophagy markers (Beclin 1, ATG5, sequestosome) were dysregulated in the hypoplastic group, and human AFSCEVs restored all three markers back to control Open
Quotation In conclusion, we are very excited as this is the first study discovering an important mechanism in the CDH pathophysiology. Open
Statement This is the first study discovering autophagy impairment as an important mechanism in CDH pathophysiology Open
Statement Autophagy levels are restored with administration of AFSCEVs, thus partially explaining their effect on branching morphogenesis Open
Statement Autophagy can be targeted with microRNAs 17 and 20 Open
Statement Future work includes looking at ER stress, which is very closely interrelated with autophagy pathway, to see if AFSCEVs can exert an effect on this related mechanism Open
Statement Studies in oncology have shown that the quantity of extracellular vesicles released when autophagy is impaired is different Open
Statement Future functional studies will examine endogenous extracellular vesicle production in hypoplastic fetal lungs Open