Konstantinos-Dionysios Alysandratos's research while affiliated with Boston Medical Center and other places

Publications (28)

Article
Full-text available
Type 2 alveolar epithelial cells (AT2s), facultative progenitor cells of the lung alveolus, play a vital role in the biology of the distal lung. In vitro model systems that incorporate human cells, recapitulate the biology of primary AT2s, and interface with the outside environment could serve as useful tools to elucidate functional characteristics...
Preprint
The alveolar epithelial type 2 cell (AEC2) is the facultative progenitor of lung alveoli tasked to maintain distal lung homeostasis. AEC2 dysfunction has been implicated in the pathogenesis of a number of pulmonary diseases, including idiopathic pulmonary fibrosis (IPF), highlighting the importance of human in vitro models of the alveolar epitheliu...
Article
Full-text available
Next generation sequencing has revealed the presence of numerous RNA viruses in animal reservoir hosts, including many closely related to known human pathogens. Despite their zoonotic potential, most of these viruses remain understudied due to not yet being cultured. While reverse genetic systems can facilitate virus rescue, this is often hindered...
Article
Full-text available
FOXA pioneer transcription factors (TFs) associate with primed enhancers in endodermal organ precursors. Using a human stem cell model of pancreas differentiation, we here discover that only a subset of pancreatic enhancers is FOXA-primed, whereas the majority is unprimed and engages FOXA upon lineage induction. Primed enhancers are enriched for si...
Article
Full-text available
Article Patient-specific iPSCs carrying an SFTPC mutation reveal the intrinsic alveolar epithelial dysfunction at the inception of interstitial lung disease Graphical abstract Highlights d Patient-specific iAEC2s serve as a human preclinical platform for modeling ILD d Patient-derived iAEC2s expressing mutant SFTPC I73T have diminished progenitor c...
Preprint
Full-text available
Next generation sequencing has revealed the presence of many RNA viruses in animal reservoir hosts, including many closely related to known human pathogens. Despite their zoonotic potential, many of these viruses remain understudied due to not yet being cultured. While reverse genetic systems can facilitate virus rescue, this is often hindered by m...
Preprint
Full-text available
SARS-CoV-2 emerged in China at the end of 2019 and caused the global pandemic of COVID-19, a disease with high morbidity and mortality. While our understanding of this novel virus is rapidly increasing, gaps remain in our understanding of how SARS-CoV-2 can effectively suppress host cell antiviral responses. Recent work on other viruses has demonst...
Preprint
Full-text available
The incompletely understood pathogenesis of pulmonary fibrosis (PF) and lack of reliable preclinical disease models have limited development of effective therapies. An emerging literature now implicates alveolar epithelial type 2 cell (AEC2) dysfunction as an initiating pathogenic event in the onset of a variety of PF syndromes, including adult idi...
Article
The mammalian lung epithelium is composed of a wide array of specialized cells that have adapted to survive environmental exposure and perform the tasks necessary for respiration. Although the majority of these cells are remarkably quiescent during adult lung homeostasis, a growing body of literature has demonstrated the capacity of these epithelia...
Article
A hallmark of severe COVID-19 pneumonia is SARS-CoV-2 infection of the facultative progenitors of lung alveoli, the alveolar epithelial type 2 cells (AT2s). However, inability to access these cells from patients, particularly at early stages of disease, limits an understanding of disease inception. Here, we present an in vitro human model that simu...
Preprint
Full-text available
FOXA pioneer transcription factors (TFs) displace nucleosomes and prime chromatin across enhancers of different endodermal organs in multipotent precursors before lineage induction. Here, we examined patterns and mechanisms of FOXA target site engagement using human pluripotent stem cell models of endodermal organ development. Unexpectedly, we find...
Preprint
Full-text available
The most severe and fatal infections with SARS-CoV-2 result in the acute respiratory distress syndrome, a clinical phenotype of coronavirus disease 2019 (COVID-19) that is associated with virions targeting the epithelium of the distal lung, particularly the facultative progenitors of this tissue, alveolar epithelial type 2 cells (AT2s). Little is k...
Article
Alveolar epithelial type II cells (AEC2s) are the facultative progenitors of lung alveoli and serve as the surfactant-producing cells of air-breathing organisms. Although primary human AEC2s are difficult to maintain stably in cell cultures, recent advances have facilitated the derivation of AEC2-like cells from human pluripotent stem cells (hPSCs)...
Data
Table S3. Table of All Genes Upregulated (by ANOVA with FDR-Adjusted p < 0.05; Variance > 3) in Clusters from Analysis in Figure 5. This List of Genes Is Represented in the Heatmap in Figure 5C, Related to Figure 5
Data
Table S4. Searchable Table of Analyzed Single-Cell RNA-Seq Data Showing Genes Differentially Expressed (FDR-Adjusted p < 0.1 by Negative Binomial Exact Test) in Each Cell Cluster, Related to Figure 6
Data
Table S2. Searchable Table of Analyzed Microarray Results with Statistical Analysis by One-Way ANOVA Comparing All Five Array Samples and Moderated Pairwise Student's t Tests to Compare Each Pair of Individual Samples for Each Gene, Related to Figure 3
Data
Table S1. Table of All p Values Obtained by ANOVA with Tukey's Multiple Comparisons Test for Figures 2H, 4B, and 7G, Related to Figures 2, 4, and 7
Data
Table S5. List of Cell-Cycle Genes Included versus Excluded from Analysis of Single-Cell RNA-Seq Data to Test the Effect on Cell Clustering, Related to Figure 6
Article
Full-text available
Lung epithelial lineages have been difficult to maintain in pure form in vitro, and lineage-specific reporters have proven invaluable for monitoring their emergence from cultured pluripotent stem cells (PSCs). However, reporter constructs for tracking proximal airway lineages generated from PSCs have not been previously available, limiting the char...
Article
The in vitro directed differentiation of pluripotent stem cells (PSCs) through stimulation of developmental signaling pathways can generate mature somatic cell types for basic laboratory studies or regenerative therapies. However, there has been significant uncertainty regarding how to separately derive lung vs. thyroid epithelial lineages, since t...
Article
Full-text available
Objective: We examined associations between body weight and plasma 25-hydroxyvitamin D concentration (25OHD) in prediabetes and sought to estimate the impact of adiposity on these associations. Methods: The study was conducted in the placebo (n = 1082) and intensive lifestyle (n = 1079) groups of the Diabetes Prevention Program (DPP), a multicen...

Citations

... Although rLLOV is able to infect known target cells of EBOV, including human primary macrophages, the inflammatory response in human macrophages, a hallmark of Ebola virus disease, is not induced by rLLOV. This suggests that LLOV might be able to infect humans, but the infection might not lead to disease, similar to the nonpathogenic Reston virus 21 . Public health preparedness to filovirus zoonoses is highly related to the ecological attributes of wildlife hosts. ...
... show that HHEX drives pancreatic differentiation by cooperating with FOXA1, FOXA2 and GATA4, TFs with pioneer factor activity and pivotal for both pancreas and liver development [15][16][17][18][19][20]26 . In the absence of HHEX, these shared TFs become unrestrained and activate liver and duodenum lineages instead. ...
... To develop an ALI culture system for human alveolar epithelial cells, we generated iAT2s (14, 21) from a human iPSC line carrying a tdTomato-encoding cassette targeted to the SFTPC locus (SPC2; refs. 15,22). We established 3D cultures of self-renewing iAT2 spheres that could be serially passaged to provide a stable source of human AT2-like cells (18,22). ...
... Image analysis is considered an effective and high-throughput readout. Self-organization is one of the characteristics of organoids, and changes in organoid morphology have been reported in several disease modeling studies (Chen et al. 2017;Alysandratos et al. 2021a). Human PSCs can be easily gene-edited, and it is possible to generate injury marker reporter cell lines. ...
... The pseudostratified human airway epithelium is composed of several subsets of cells, including secretory goblet and club cells, ciliated cells, basal cells and more rare cell types such as tuft cells, neuroendocrine cells and recently identified ionocytes, each responsible for a specific function (figure 1a) [27]. Mucus produced by goblet cells trap and neutralise noxious particles that can subsequently be cleared by ciliary movement of the ciliated cells. ...
... AT2 cells are progenitor cells of the lung epithelium and precursor cells of AT1 and can, therefore, regulate lung epithelial cell homeostasis via self-renewal and differentiation, maintain alveolar tension by secreting pulmonary surfactant, and support efficient gas exchange at the lung-blood interface (28). After mild inflammatory stimulation or viral infection, AT2 cells can present antigens to T cells to initiate T cell responses (29) and maintain alveolar function by increasing citrate synthase expression, upregulating the expression of the mitochondrial biogenesis-related gene PPARGC1A (PGC-1a), and promoting mitochondrial apoptosis and other approaches for maintaining alveolar function (30). However, our current study showed that the AT2 count significantly decreased in the lung tissue of patients with COVID-19. ...
... Alveolar type II epithelial cells (AT2) promote the biosynthesis of lung surfactant. SARS-CoV-2 attacks the AT2 cells, causing defective functionality of these cells, which may cause exhaustion of pulmonary surfactant, raise the alveolar surface tension, and finally lead to alveolar collapse [21,22]. Hence, the wetting properties of NaCl may provide a benefit in reducing surface tensions, thus improving airway compliance. ...
... Figure 1 illustrates the general procedure of this ML model. The classification of different cell types is a key step in an important regulator of gene expression [12,39]. An accurate classification requires a better characterization of geometric structures of Hi-C data. ...
... The gold standard to create large cell numbers of human progenitors for such models is directed differentiation from human pluripotent stem cell (PSC) populations. These directed differentiation protocols are capable of recapitulating much of the diversity within a target organ by exposing the PSCs to a specific sequence of chemical signals designed to mimic developmental cues characterized from in vivo human and mouse studies [1][2][3][4][5][6][7][8][9][10][11]. While this approach has enabled great progress, in many tissues, challenges remain, such as the poor yield of specific cell populations, variability in the proportion of each cell population produced, and a lack of maturity beyond fetal levels. ...