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Fernandez, R.

Publications and source records attributed to Fernandez, R..

At least 55 records · Page 3Linked to original sources

Reference genome of the ant Lasius platythorax

Ants are a highly diversified insect family of the order Hymenoptera, with many fascinating characteristics such as eusociality, chemical communication, farming, or social parasitism. Moreover, ants frequent a wide variety of habitats from dry deserts, grasslands, and savannas to cold temperate forests. The ability of ants to inhabit such diverse habitat ranges demonstrates their adaptability and ecological resilience. However, little is known about the genetic underpinnings of this vast array of traits and their adaptive potential. Here, we generated a high-quality genome assembly for the ant species Lasius platythorax using long-read PacBio HiFi in combination with chromatin conformation capture (Hi-C) sequencing. We successfully assembled the genome into 15 chromosome-level scaffolds ranging from 7.9 to 19.2 Mb and encompassing 204.6 Mb out of 235.3 Mb (total assembly), and a BUSCO score of 86% (Hymenoptera_odb10). Comparative genomics between the two sister species will provide insights into the genomic basis of trait differentiation.

genomics↗

Fundamental parameters governing the transmission of conjugative plasmids

Because their ability to spread infectiously, conjugative plasmids represent a major route for the propagation of antibiotic resistances. In the wild, there are hundreds of different plasmids, but their distribution, prevalence and host range are extremely variable. To understand the reasons behind these ecological differences, we need to obtain precise models for plasmid transmission dynamics. Here, we show that the dynamics of plasmid transmission follow a simple ecological model known as Hollings Type II Functional Response. Plasmid transmission dynamics can be faithfully captured using two parameters: the searching rate (the pace at which a donor bacterium encounters a suitable recipient) and the handling time (the time required for a donor to transfer the plasmid). By analyzing the dynamics of different plasmid prototypes, we show that these parameters are characteristic of the plasmid transfer machinery. Quantifying the dynamics of plasmid spread may shed light on the epidemiology of antibiotic resistance genes.

microbiology↗

Polygenic Risk Score Associates with Atherosclerotic Plaque Characteristics at Autopsy

BackgroundPolygenic risk scores (PRS) for coronary artery disease (CAD) potentially improve cardiovascular risk prediction. However, their relationship with histopathologic features of CAD has never been examined systematically. MethodsFrom 4,327 subjects referred to CVPath by the State of Maryland Office Chief Medical Examiner (OCME) for sudden death between 1994 and 2015, 2,455 cases were randomly selected for genotyping. We generated PRS from 291 known CAD risk loci. Detailed histopathologic examination of the coronary arteries was performed in all subjects. The primary study outcome measurements were histopathologic plaque features determining severity of atherosclerosis, including %stenosis, calcification, thin-cap fibroatheromas (TCFA), and thrombotic CAD. ResultsAfter exclusion of cases with insufficient DNA sample quality or with missing data, 954 cases (mean age 48.8{+/-}14.7; 75.7% men) remained in the final study cohort. Subjects in the highest PRS quintile exhibited more severe atherosclerosis compared to subjects in the lowest quintile, with greater %stenosis (80.3%{+/-}27.0% vs. 50.4%{+/-}38.7%; adjusted p<0.001) and a higher frequency of calcification (69.6% vs. 35.8%; adjusted p=0.004) and TCFAs (26.7% vs. 9.5%; adjusted p=0.007). Even after adjustment for traditional CAD risk factors subjects within the highest PRS quintile had higher odds of severe atherosclerosis (i.e., [&ge;]75% stenosis; adjusted OR 3.77; 95%CI 2.10-6.78; p<0.001) and plaque rupture (adjusted OR 4.05; 95%CI 2.26-7.24; p<0.001). Moreover, subjects within the highest quintile had higher odds of CAD-associated cause of death, especially among those aged 50 years and younger (adjusted OR 4.08; 95%CI 2.01-8.30; p<0.001). No associations were observed with plaque erosion. ConclusionsThis is the first autopsy study investigating associations between PRS and atherosclerosis severity at the histopathologic level in subjects with sudden death. Our pathological analysis suggests PRS correlates with plaque burden and features of advanced atherosclerosis and may be useful as a method for CAD risk stratification, especially in younger subjects. HighlightsO_LIIn this autopsy study including 954 subjects within the CVPath Sudden Death Registry, high PRS correlated with plaque burden and atherosclerosis severity. C_LIO_LIThe PRS showed differential associations with plaque rupture and plaque erosion, suggesting different etiologies to these two causes of thrombotic CAD. C_LIO_LIPRS may be useful for risk stratification, particularly in the young. Further examination of individual risk loci and their association with plaque morphology may help understand molecular mechanisms of atherosclerosis, potentially revealing new therapy targets of CAD. C_LI Graphic AbstractA polygenic risk score, generated from 291 known CAD risk loci, was assessed in 954 subjects within the CVPath Sudden Death Registry. Histopathologic examination of the coronary arteries was performed in all subjects. Subjects in the highest PRS quintile exhibited more severe atherosclerosis as compared to subjects in the lowest quintile, with a greater plaque burden, more calcification, and a higher frequency of plaque rupture.

genetics↗

Contextualising samples: Supporting reference genomes for European biodiversity through sample and associated metadata collection

The European Reference Genome Atlas (ERGA) consortium aims to generate a reference genome catalogue for all of Europes eukaryotic biodiversity. The biological material underlying this mission, the specimens and their derived samples, are provided through ERGAs pan- European network. To demonstrate the communitys capability and capacity to realise ERGAs ambitious mission, the ERGA Pilot project was initiated. In support of the ERGA Pilot effort to generate reference genomes for European biodiversity, the ERGA Sampling and Sample Processing committee (SSP) was formed by volunteer experts from ERGAs member base. SSP aims to aid participating researchers through i) establishing standards for and collecting of sample/ specimen metadata; ii) prioritisation of species for genome sequencing; and iii) development of taxon-specific collection guidelines including logistics support. SSP serves as the entry point for sample providers to the ERGA genomic resource production infrastructure and guarantees that ERGAs high-quality standards are upheld throughout sample collection and processing. With the volume of researchers, projects, consortia, and organisations with interests in genomics resources expanding, this manuscript shares important experiences and lessons learned during the development of standardised operational procedures and sample provider support. The manuscript details our experiences in incorporating the FAIR and CARE principles, species prioritisation, and workflow development, which could be useful to individuals as well as other initiatives.

genomics↗

The genome sequence of the Montseny horsehair worm, Gordionus montsenyensis sp. nov., a key resource to investigate Ecdysozoa evolution

Nematomorpha, also known as Gordiacea or Gordian worms, are a phylum of parasitic organisms that belong to the Ecdysozoa, a clade of invertebrate animals characterized by molting. They are one of the less scientifically studied animal phyla, and many aspects of their biology and evolution are still unknown, partially due to the lack of genomic resources for this phylum. As part of the European Reference Genome Atlas pilot effort to generate reference genomes for European biodiversity, we present the taxonomic description and chromosome-level genome assembly of a newly described species of Nematomorpha (Gordionus montsenyensis Schmidt-Rhaesa & Fernandez sp. nov.). The final assembly has a total length of 288 Mb in 396 scaffolds with an N50 of 64.4 Mb, 97% of which is scaffolded into 5 pseudochromosomes. The circular mitochondrial genome was also assembled into a 15-kilobases sequence. Gene annotation predicted 10,320 protein-coding genes in the nuclear genome. In this study, we contribute a key genomic resource to not only explore the evolution of Ecdysozoa, but also to further our understanding on the genomic basis of parasitic lifestyles. In addition, we describe a species new to science from this enigmatic animal phyla.

evolutionary biology↗

SARS-CoV-2 accessory proteins involvement in inflammatory and profibrotic processes through IL11 signaling

SARS-CoV-2, the cause of the COVID19 pandemic, possesses eleven accessory proteins encoded in its genome. Their roles during infection are still not completely understood. Transcriptomic analysis revealed that both WNT5A and IL11 were significantly up-regulated in A549 cells expressing individual accessory proteins ORF6, ORF8, ORF9b or ORF9c from SARS-CoV-2 (Wuhan-Hu-1 isolate). IL11 signaling-related genes were also differentially expressed. Bioinformatics analysis disclosed that both WNT5A and IL11 were involved in pulmonary fibrosis idiopathic disease. Functional assays confirmed their association with profibrotic cell responses. Subsequently, data comparison with lung cell lines infected with SARS-CoV-2 or lung biopsies from patients with COVID19 evidenced altered gene expression that matched those obtained in this study. Our results show ORF6, ORF8, ORF9b and ORF9c involvement in inflammatory and profibrotic responses. Thus, these accessory proteins could be targeted by new therapies against COVID19 disease. Research topic(s)Viral diseases, COVID19 insights

immunology↗

Highly dynamic evolution of the chemosensory gene repertoire driven by gene gain and expansion across subterranean beetles

Chemical cues in subterranean habitats differ highly from those on the surface due to the contrasting environmental conditions, such as absolute darkness, high humidity or food scarcity. Subterranean animals underwent changes to their sensory systems to facilitate the perception of essential stimuli for underground lifestyles. Despite representing unique systems to understand biological adaptation, the genomic basis of chemosensation across cave-dwelling species remains unexplored from a macroevolutionary perspective. Here, we explore the evolution of chemoreception in three beetle tribes that underwent at least six independent transitions to the underground, through a phylogenomics spyglass. Our findings suggest that the chemosensory gene repertoire varies dramatically between species. Overall, no parallel changes in the net rate of evolution of chemosensory gene families were detected prior, during, or after the habitat shift among subterranean lineages. Contrarily, we found evidence of lineage-specific changes within surface and subterranean lineages. However, our results reveal key duplications and losses shared between some of the lineages transitioning to the underground, including the loss of sugar receptors and gene duplications of the highly conserved ionotropic receptors IR25a and IR8a, involved in thermal and humidity sensing among other olfactory roles in insects. These duplications were detected both in independent subterranean lineages and their surface relatives, suggesting parallel evolution of these genes across lineages giving rise to cave-dwelling species. Overall, our results shed light on the genomic basis of chemoreception in subterranean beetles and contribute to our understanding of the genomic underpinnings of adaptation to the subterranean lifestyle at a macroevolutionary scale.

evolutionary biology↗

The neuropeptidergic connectome of C. elegans

SummaryEfforts are currently ongoing to map synaptic wiring diagrams or connectomes in order to understand the neural basis of brain function. However, chemical synapses represent only one type of functionally important neuronal connection; in particular, extrasynaptic, "wireless" signaling by neuropeptides is widespread and plays essential roles in all nervous systems. By integrating single-cell anatomical and gene expression datasets with a biochemical analysis of receptor-ligand interactions, we have generated a draft connectome of neuropeptide signaling in the C. elegans nervous system. This connectome is characterized by a high connection density, extended signaling cascades, autocrine foci, and a decentralized topology, with a large, highly interconnected core containing three constituent communities sharing similar patterns of input connectivity. Intriguingly, several of the most important nodes in this connectome are little-studied neurons that are specialized for peptidergic neuromodulation. We anticipate that the C. elegans neuropeptidergic connectome will serve as a prototype to understand basic organizational principles of neuroendocrine signaling networks.

neuroscience↗

Parallel duplication and loss of aquaporin-coding genes during the 'out of the sea' transition paved the way for animal terrestrialization

One of the most important physiological challenges animals had to overcome during terrestrialization (i.e., the transition from sea to land) is water loss, which alters their osmotic and hydric homeostasis. Aquaporins are a superfamily of membrane water transporters heavily involved in osmoregulatory processes. Their diversity and evolutionary dynamics in most animal lineages remain unknown, hampering our understanding of their role in marine-terrestrial transitions. Here, we interrogated aquaporin gene repertoire evolution across the main terrestrial animal lineages. We annotated aquaporin-coding genes in genomic data from 458 species from 7 animal phyla where terrestrialization episodes occurred. We then explored aquaporin gene evolutionary dynamics to assess differences between terrestrial and aquatic species through phylogenomics and phylogenetic comparative methods. Our results revealed parallel aquaporin-coding gene duplications in aquaporins during the transition from marine to non-marine environments (e.g., brackish, freshwater and terrestrial), rather than from aquatic to terrestrial ones, with some notable duplications in ancient lineages. Contrarily, we also recovered a significantly lower number of superaquaporin genes in terrestrial arthropods, suggesting that more efficient oxygen homeostasis in land arthropods might be linked to a reduction in this type of aquaporins. Our results thus indicate that aquaporin-coding gene duplication and loss might have been one of the key steps towards the evolution of osmoregulation across animals, facilitating the out of the sea transition and ultimately the colonisation of land.

evolutionary biology↗

PhenoTrack3D: an automatic high-throughput phenotyping pipeline to track maize organs over time

BackgroundHigh-throughput phenotyping platforms allow the study of the form and function of a large number of genotypes subjected to different growing conditions (GxE). A number of image acquisition and processing pipelines have been developed to automate this process, for micro-plots in the field and for individual plants in controlled conditions. Capturing shoot development requires extracting from images both the evolution of the 3D plant architecture as a whole, and a temporal tracking of the growth of its organs. ResultsWe propose PhenoTrack3D, a new pipeline to extract a 3D+t reconstruction of maize at organ level from plant images. It allows the study of plant architecture and individual organ development over time during the entire growth cycle. PhenoTrack3D improves a former method limited to 3D reconstruction at a single time point [Artzet et al., 2019] by (i) a novel stem detection method based on deep-learning and (ii) a new and original multiple sequence alignment method to perform the temporal tracking of ligulated leaves. Our method exploits both the consistent geometry of ligulated leaves over time and the unambiguous topology of the stem axis. Growing leaves are tracked afterwards with a distance-based approach. This pipeline is validated on a challenging dataset of 60 maize hybrids imaged daily from emergence to maturity in the PhenoArch platform (ca. 250,000 images). Stem tip was precisely detected over time (RMSE < 2.1cm). 97.7% and 85.3% of ligulated and growing leaves respectively were assigned to the correct rank after tracking, on 30 plants x 43 dates. The pipeline allowed to extract various development and architecture traits at organ level, with good correlation to manual observations overall, on random subsets of 10 to 355 plants. ConclusionsWe developed a novel phenotyping method based on sequence alignment and deep-learning. It allows to characterise automatically and at a high-throughput the development of maize architecture at organ level. It has been validated for hundreds of plants during the entire development cycle, showing its applicability to the GxE analyses of large maize datasets.

plant biology↗

MATEdb, a data repository of high-quality metazoan transcriptome assemblies to accelerate phylogenomic studies

AO_SCPLOWBSTRACTC_SCPLOWWith the advent of high throughput sequencing, the amount of genomic data available for animals (Metazoa) species has bloomed over the last decade, especially from transcriptomes due to lower sequencing costs and easier assembling process compared to genomes. Transcriptomic data sets have proven useful for phylogenomic studies, such as inference of phylogenetic interrelationships (e.g., species tree reconstruction) and comparative genomics analyses (e.g., gene repertoire evolutionary dynamics). However, these data sets are often analyzed following different analytical pipelines, particularly including different software versions, leading to potential methodological biases when analyzed jointly in a comparative framework. Moreover, these analyses are computationally expensive and not affordable for a large part of the scientific community. More importantly, assembled transcriptomes are usually not deposited in public databases. Furthermore, the quality of these data sets is hardly ever taken into consideration, potentially impacting subsequent analyses such as orthology and phylogenetic or gene repertoire evolution inference. To alleviate these issues, we present Metazoan Assemblies from Transcriptomic Ensembles (MATEdb), a curated database of 335 high-quality transcriptome assemblies from different animal phyla analyzed following the same pipeline. The repository is composed, for each species, of (1) a de novo transcriptome assembly, (2) its candidate coding regions within transcripts (both at the level of nucleotide and amino acid sequences), (3) the coding regions filtered using their contamination profile (i.e., only metazoan content), (4) the longest isoform of the amino acid candidate coding regions, (5) the gene content completeness score as assessed against the BUSCO database, and (6) an orthology-based gene annotation. We complement the repository with gene annotations from high-quality genomes, which are often not straightforward to obtain from individual sequencing projects, totalling 423 high-quality genomic and transcriptomic data sets. We invite the community to provide suggestions for new data sets and new annotation features to be included in subsequent versions, that will be analyzed following the same pipeline and be permanently stored in public repositories. We believe that MATEdb will accelerate research on animal phylogenomics while saving thousands of hours of computational work in a plea for open and collaborative science.

evolutionary biology↗

High-throughput and automatic structural and developmental root phenotyping on Arabidopsis seedlings

BackgroundHigh-throughput phenotyping is crucial for the genetic and molecular understanding of adaptive root system development. In recent years, imaging automata have been developed to acquire the root system architecture of many genotypes grown in Petri dishes to explore the Genetic x Environment (GxE) interaction. There is now an increasing interest in understanding the dynamics of the adaptive responses, such as the organ apparition or the growth rate. However, due to the increasing complexity of root architectures in development, the accurate description of the topology, geometry, and dynamics of a growing root system remains a challenge. ResultsWe designed a high-throughput phenotyping method, combining an imaging device and an automatic analysis pipeline based on registration and topological tracking, capable of accurately describing the topology and geometry of observed root systems in 2D+t. The method was tested on a challenging Arabidopsis seedling dataset, including numerous root occlusions and crossovers. Static phenes are estimated with high accuracy (R2 = 0.996 and 0, 923 for primary and second-order roots length, respectively). These performances are similar to state-of-the-art results obtained on root systems of equal or lower complexity. In addition, our pipeline estimates dynamic phenes accurately between two successive observations (R2 = 0. 938 for lateral root growth). ConclusionsWe designed a novel method of root tracking that accurately and automatically measures both static and dynamic RSA parameters from a novel high-throughput root phenotyping platform. It has been used to characterize developing patterns of root systems grown under various environmental conditions. It provides a solid basis to explore the GxE interaction controlling the dynamics of root system architecture adaptive responses. In future work, our approach will be adapted to a wider range of imaging configurations and species.

plant biology↗

An end-to-end workflow based on multimodal 3D imaging and machine learning for non-destructive diagnosis of grapevine trunk diseases

Quantifying healthy and degraded inner tissues in plants is of great interest in agronomy, for example, to assess plant health and quality and monitor physiological traits or diseases. However, detecting functional and degraded plant tissues in-vivo without harming the plant is extremely challenging. New solutions are needed in ligneous and perennial species, for which the sustainability of plantations is crucial. To tackle this challenge, we developed a novel approach based on multimodal 3D imaging and Artificial Intelligence (AI)-based image processing that allowed a noninvasive diagnosis of inner tissues in living plants. The method was successfully applied to the grapevine (Vitis vinifera L.) in vineyards where sustainability was threatened by trunk diseases, while the sanitary status of vines cannot be ascertained without injuring the plants. By combining MRI and X-ray CT 3D imaging with an automatic voxel classification, we could discriminate intact, degraded, and white rot tissues with a mean global accuracy of over 91%. Each imaging modality contribution to tissue detection was evaluated, and we identified quantitative structural and physiological markers characterizing wood degradation steps. The combined study of inner tissue distribution versus external foliar symptom history demonstrated that white rot and intact tissue contents are key measurements in evaluating vines sanitary status. We finally proposed a model for an accurate trunk disease diagnosis in grapevine. This work opens new routes for precision agriculture and in-situ monitoring of wood quality and plant health across plant species.

plant biology↗

Widespread employment of conserved C. elegans homeobox genes in neuronal identity specification

Homeobox genes are prominent regulators of neuronal identity, but the extent to which their function has been probed in animal nervous systems remains limited. In the nematode Caenorhabditis elegans, each individual neuron class is defined by the expression of unique combinations of homeobox genes, prompting the question of whether each neuron class indeed requires a homeobox gene for its proper identity specification. We present here progress in addressing this question by extending previous mutant analysis of homeobox gene family members and describing multiple examples of homeobox gene function in different parts of the C. elegans nervous system. To probe homeobox function, we make use of a number of reporter gene tools, including a novel multicolor reporter transgene, NeuroPAL, which permits simultaneous monitoring of the execution of multiple differentiation programs throughout the entire nervous system. Using these tools, we add to the previous characterization of homeobox gene function by identifying neuronal differentiation defects for 12 homeobox genes in 20 distinct neuron classes that are mostly unrelated by location, function and lineage history. 10 of these 20 neuron classes had no homeobox gene function ascribed to them before, while in the other 10 neuron classes, we extend the combinatorial code of transcription factors required for specifying terminal differentiation programs. Furthermore, we demonstrate that in a particular lineage, homeotic identity transformations occur upon loss of a homeobox gene and we show that these transformations are the result of changes in homeobox codes. Combining the present with past analysis, 111 of the 118 neuron classes of C. elegans are now known to require a homeobox gene for proper execution of terminal differentiation programs. Such broad deployment indicates that homeobox function in neuronal identity specification may be an ancestral feature of animal nervous systems.

neuroscience↗

Acoustic array biochip combined with allele-specific PCR for multiple cancer mutation analysis in tissue and liquid biopsy

Regular screening of cancerous point mutations is of importance to cancer management and treatment selection. Although excellent techniques like next generation sequencing and droplet digital PCR are available, these are still lacking in speed, simplicity and cost-effectiveness. Here a new approach is presented where allele-specific PCR (AS-PCR) is combined with a novel High Fundamental Frequency Quartz Crystal Microbalance (HFF-QCM) array biosensor for the amplification and detection, respectively, of cancer point mutations. For the proof-of-concept, the method was applied to the screening of the BRAF V600E and KRAS G12D mutations in spiked-in and clinical samples. Regarding the BRAF target, an analytical sensitivity of 0.01%, i.e., detection of 1 mutant copy of genomic DNA in an excess of 104 wild type molecules, was demonstrated; moreover, quantitative results during KRAS detection were obtained when an optimized assay was employed with a sensitivity of 0.05%. The assays were validated using tissue and plasma samples obtained from melanoma, colorectal and lung cancer patients. Results are in full agreement with Sanger sequencing and droplet digital PCR, demonstrating efficient detection of BRAF and KRAS mutations in samples having an allele frequency below 1%. The high sensitivity and technology-readiness level of the methodology, together with the ability for multiple sample analysis (24 array biochip), cost-effectiveness and compatibility with routine work-flow, hold promise for the implementation of this AS-PCR/acoustic methodology in clinical oncology as a tool for tissue and liquid biopsy.

biophysics↗

Single-synapse analyses of Alzheimers disease implicate pathologic tau, DJ1, CD47, and ApoE

Synaptic molecular characterization is limited for Alzheimers disease (AD). We used mass cytometry to quantify 38 probes in approximately 17 million single synaptic events from human brains without pathologic change or with pure AD or Lewy body disease (LBD), non-human primates (NHP), and PS/APP mice. Synaptic molecular integrity in humans and NHP was similar. Although not detected in human synapses, A{beta} was in PS/APP mice synaptic events. Clustering and pattern identification of human synapses showed expected disease-specific differences, like increased hippocampal pathologic tau in AD and reduced caudate dopamine transporter in LBD, and revealed novel findings including increased hippocampal CD47 and lowered DJ1 in AD and higher ApoE in AD dementia. Our results were independently supported by multiplex ion beam imaging of intact tissue.

neuroscience↗

Smelling in the dark: phylogenomic insights on the chemosensory system of a subterranean beetle

The chemosensory system has experienced relevant changes in subterranean animals, facilitating the orientation into darkness via the perception of specific chemical signals critical to survive in this particular environment. However, the genomic basis of chemoreception in cave-dwelling fauna is largely unexplored. We generated de novo transcriptomes for antennae and body samples of the troglobitic beetle Speonomus longicornis (whose characters suggest an extreme adaptation to the deep subterranean) in order to interrogate the evolutionary origin and diversification of the chemosensory gene repertoire across coleopterans through a phylogenomic approach. Our results suggested a diminished diversity of odorant and gustatory gene repertoires compared to polyphagous epigean beetles. Moreover, S. longicornis showed a large diversity of odorant-binding proteins, suggesting an important role of these proteins in capturing airborne chemical cues. We identified a gene duplication in the ionotropic co-receptor I R25a, a highly conserved single-copy gene in protostomes involved in thermal and humidity sensing. In addition, no homologous genes to sugar receptors or the ionotropic receptor IR41a were detected. Our findings suggest that the chemosensory gene repertoire of this cave beetle may have been reshaped by the low complexity of chemical signals of this particular environment, and that gene duplication and loss may have played an important role in the evolution of genes involved in chemoreception. Altogether, our results shed light on the genomic basis of chemoreception in a cave-dwelling invertebrate and pave the road towards understanding the genomic underpinnings of adaptation to the subterranean lifestyle at a deeper level.

evolutionary biology↗

Orthotopic Transplantation and Engraftment of Human Induced Pluripotent Stem Cell-Derived Alveolar Progenitor Cells into Murine Lungs

Humanized mice possessing human cells, tissues, or organ systems provide an unparalleled platform for preclinical studies in oncology, immunology, and infectious diseases. While the lungs are a vital organ subject to a wide variety of pathologies, exemplified by the ongoing COVID-19 pandemic, discrete differences in murine and human lungs can obfuscate interpretation of murine models of lung disease. Here we provide proof-of-concept methodology for the potential humanization of murine lungs via orthotopic transplantation of human NKX2.1+ progenitor cells and alveolar type 2 cells derived from induced pluripotent stem cells. We show that these cells engraft readily into highly immunocompromised mice after pharmacological injury with bleomycin, which presumably generates "space" for human cells to access denuded basement membrane and engraft. Transplanted cells stably retain their pulmonary lineage restriction and persist as superficially differentiated alveolar type 2 and type 1 cells. Future work should focus on strategies to promote xenorepopulation of most / all of the murine lung with human cells while retaining appropriate regio-specific epithelial differentiation and normal physiological function.

developmental biology↗