Biology subjects

Obed, M.

Publications and source records attributed to Obed, M..

3 recordsLinked to original sources

bioRxiv2024

Amniotic fluid stem cell extracellular vesicles promote lung development via TGF-beta modulation in a fetal rat model of oligohydramnios

Oligohydramnios (decreased amniotic fluid volume for gestational age) is a severe condition associated with high morbidity and mortality mainly due to fetal pulmonary hypoplasia. Currently, there are limited treatment options to promote fetal lung development. Administration of stem cells and their derivates have shown promising regenerative properties for several fetal and neonatal diseases related to arrested lung development. Herein, we first characterized pulmonary hypoplasia secondary to oligohydramnios in a surgical rat model. Experimental induction of oligohydramnios led to impaired lung growth, branching morphogenesis (fewer airspaces with decreased Fgf10, Nrp1, Ctnnb1 expression), proximal/distal progenitor cell patterning (decreased Sox2 and Sox9 expression), and TGF-{beta} signaling. We then tested antenatal administration of extracellular vesicles derived from amniotic fluid stem cells (AFSC- EVs). In oligohydramnios lungs, AFSC-EV administration improved lung branching morphogenesis and airway progenitor cell patterning at least in part through the release of miR-93-5p. Our experiments suggest that AFSC-EV miR-93-5p blocked SMAD 7, resulting in upregulation of pSMAD2/3 and restoration of TGF-{beta} signaling. Conversely, oligohydramnios lungs treated with antagomir 93-5p transfected AFSC- EVs had decreased branching morphogenesis and TGF-{beta} signaling. This is the first study reporting that antenatal administration of stem cell derivatives could be a potential therapy to rescue lung development in fetuses with oligohydramnios. HighlightsO_LIPulmonary hypoplasia secondary to oligohydramnios in fetal rats is characterized by impaired TGF-{beta} signaling. C_LIO_LIAFSC-EV administration improves fetal lung branching morphogenesis and airway progenitor cell patterning. C_LIO_LIAFSC-EV effects are mediated at least in part via modulation of TGF-{beta} signaling by the release of miR-93-5p from AFSC-EVs. C_LI

developmental biology↗

bioRxiv2023

Fetal lung vascular development is disrupted by mechanical compression and rescued by administration of amniotic fluid stem cell extracellular vesicles via regulation of the Hippo signaling pathway.

Postnatal pulmonary hypertension is the biggest treatment challenge and major determinant for poor outcome in infants with congenital diaphragmatic hernia (CDH). CDH lungs are hypoplastic and exhibit vascular remodeling, whose pathogenesis remains poorly understood. Using a novel micro-static compression system, herein we found that mechanical compression induces vascular remodeling and downregulation of key angiogenic markers in rat and human fetal lung models, with similar features observed in CDH fetal lung autopsy samples. These fetal lung vascular changes are reversed back to normal upon administration of extracellular vesicles derived from amniotic fluid stem cells (AFSC-EVs), a regenerative approach previously shown to restore lung branching morphogenesis and epithelial differentiation in CDH models. Exploring pathways that are dysregulated in CDH lungs and involved in mechanotransduction, we found that compressed fetal lungs had altered expression of Hippo signaling factors that was restored upon AFSC-EV administration. We found that AFSC-EV cargo contains some miRNAs involved in lung vascular development and Hippo pathway, indicating that AFSC-EV regenerative effects is associated with the delivery of specific miRNAs. This study uncovers the role of mechanical compression that herniated organs exert on CDH fetal lungs and proposes a new cell-free strategy to restore normal fetal lung vascular development.

developmental biology↗

bioRxiv2022

Administration of amniotic fluid stem cell extracellular vesicles promotes development of fetal hypoplastic lungs by immunomodulating lung macrophages

Congenital diaphragmatic hernia (CDH) is a devastating condition characterized by incomplete closure of the diaphragm and herniation of abdominal organs into the chest. As a result, fetuses have pulmonary hypoplasia, whose severity is the main determinant of poor outcome. The pathogenesis of pulmonary hypoplasia secondary to CDH is at least in part explained by lack or dysregulation of miRNAs that are known to regulate lung developmental processes. Herein, we report that intra-amniotic administration of extracellular vesicles derived from amniotic fluid stem cells (AFSC-EVs) rescues lung growth and maturation in a fetal rat model of CDH. To understand which fetal lung cells and biological pathways are affected by AFSC-EVs, we conducted whole lung single nucleus RNA-sequencing. We discovered that CDH lungs have a multilineage inflammatory signature with macrophage enrichment, and confirmed these findings in autopsy samples of lungs from human fetuses with CDH. Transcriptomic analysis of CDH fetal rat lungs also showed that AFSC-EV treatment reduced macrophage density and inflammation to normal levels. Analyzing the miRNAs contained in the AFSC-EV cargo with validated mRNA targets, we found that the downregulated genes in AFSC-EV treated CDH lungs were involved in inflammatory response and immune system processes. This study reports a single cell atlas of normal and hypoplastic CDH fetal rat lungs and provides evidence that AFSC-EVs restore lung development by addressing multiple pathophysiological aspects of CDH. One Sentence SummaryAmniotic fluid stem cell extracellular vesicle treatment for fetal lung macrophage modulation

developmental biology↗