A5088901110- Pluripotent Stem Cells Research
- CRISPR and Genetic Engineering
- 3D Printing in Biomedical Research
- CAR-T cell therapy research
- Developmental Biology and Gene Regulation
- Single-cell and spatial transcriptomics
- Tissue Engineering and Regenerative Medicine
- Multiple Myeloma Research and Treatments
- Protein Degradation and Inhibitors
- Neurogenesis and neuroplasticity mechanisms
- T-cell and B-cell Immunology
- Cell Image Analysis Techniques
- Gene Regulatory Network Analysis
- Genomics and Chromatin Dynamics
- Viral gastroenteritis research and epidemiology
- Immune Cell Function and Interaction
- Cellular Mechanics and Interactions
- Melanoma and MAPK Pathways
- Genetics and Neurodevelopmental Disorders
- Additive Manufacturing and 3D Printing Technologies
- Renal and related cancers
- DNA and Biological Computing
- Animal Genetics and Reproduction
- Chronic Lymphocytic Leukemia Research
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
Dana-Farber Cancer Institute
2021-2025
Dartmouth College
2023-2025
The Francis Crick Institute
2022-2024
Research Institute of Molecular Pathology
2022-2024
Vienna Biocenter
2022-2024
Institute of Molecular Biotechnology
2024
Austrian Academy of Sciences
2024
Dartmouth Hospital
2024
University of Cambridge
2014-2023
Wellcome/MRC Cambridge Stem Cell Institute
2014-2023
COVID-19 typically manifests as a respiratory illness, but several clinical reports have described gastrointestinal symptoms. This is particularly true in children whom symptoms are frequent and viral shedding outlasts clearance from the system. These observations raise question of whether virus can replicate within stomach. Here we generate gastric organoids fetal, pediatric, adult biopsies vitro models SARS-CoV-2 infection. To facilitate infection, induce reverse polarity organoids. We...
Efficacy and durability remain central shortcomings of T-cell based therapies in multiple myeloma (MM). Here, we employ blood-based transcriptional profiling to define impaired fitness as putative biomarker associated with sensitivity PD1 inhibition CAR-T refractory MM patients.
Significance We used single-cell whole-genome transcriptional profiling and protein quantification to investigate the role of OCT4 in establishing pluripotency murine embryo. Surprisingly, most pluripotency-associated factors are induced normally null early blastocysts, apart from members STAT3 signaling pathway. Coincidentally, certain trophectoderm markers but not Cdx2 , which was previously implicated repress Pou5f1 vitro. This ectopic gene activation suggests a for maintaining chromatin...
Reprogramming of a differentiated cell back to naive pluripotent identity is thought occur by several independent mechanisms. Two such mechanisms include NANOG and activated STAT3 (pSTAT3), known master regulators pluripotency acquisition [1Yang J. van Oosten A.L. Theunissen T.W. Guo G. Silva J.C. Smith A. Stat3 activation limiting for reprogramming ground state pluripotency.Cell Stem Cell. 2010; 7: 319-328Abstract Full Text PDF PubMed Scopus (187) Google Scholar, 2van Costa Y. JAK/STAT3...
Abstract Studies of mechanical signalling are typically performed by comparing cells cultured on soft and stiff hydrogel-based substrates. However, it is challenging to independently robustly control both substrate stiffness extracellular matrix tethering substrates, making a potentially confounding variable in investigations. Moreover, unstable can lead poor cell attachment weak engagement adhesions. To address this, we developed StemBond hydrogels, hydrogel which robust be varied...
In many developing tissues, the patterns of gene expression that assign cell fate are organized by graded secreted signals. Cis-regulatory elements (CREs) interpret these signals to control expression, but how this is accomplished remains poorly understood. neural tube, a gradient morphogen sonic hedgehog (Shh) progenitors. We identify two distinct ways in which CREs translate Shh into differential mouse most progenitors, common set activity integrating cell-type-specific inputs. By...
During neural tube (NT) development, the notochord induces an organizer, floorplate, which secretes Sonic Hedgehog (SHH) to pattern progenitors. Conversely, NT organoids (NTOs) from embryonic stem cells (ESCs) spontaneously form floorplates without notochord, demonstrating that can self-organize inducers. Here, we investigated floorplate self-organization in clonal mouse NTOs. Expression of marker FOXA2 was initially spatially scattered before resolving into multiple clusters, underwent...
Cis-regulatory elements (CREs) control how genes respond to external signals, but the principles governing their structure and function remain poorly understood. While differential transcription factor binding is known regulate gene expression, CREs integrate amount combination of inputs secure precise spatiotemporal profiles expression remains unclear. Here, we developed a high-throughput combinatorial screening strategy, that term NeMECiS, investigate signal-dependent synthetic (synCREs)...
A hallmark of naive pluripotency is the presence two active X chromosomes in females. It not clear whether prevention chromosome inactivation (XCI) mediated by gene networks that preserve state. Here, we show robust pluripotent stem cell (nPSC) self-renewal represses expression Xist, master regulator XCI. We found nPSCs accumulate Xist on male and both female as they become NANOG negative at onset differentiation. This accompanied appearance a repressive chromatin signature partial X-linked...
Understanding how cell identity transitions occur and whether there are multiple paths between the same beginning end states questions of wide interest. Here we show that acquisition naive pluripotency can follow transcriptionally mechanistically distinct routes. Starting from post-implantation epiblast stem cells (EpiSCs), one route advances through a mesodermal state prior to induction, whereas another transiently resembles early inner mass correspondingly gains greater developmental...
Abstract Purpose: Although remarkably effective in some patients, precision medicine typically induces only transient responses despite initial absence of resistance-conferring mutations. Using BRAF-mutated myeloma as a model for resistance to we investigated if cancer cells have the ability ensure their survival by rapidly adapting BRAF inhibitor treatment. Experimental Design: Full-length single-cell RNA (scRNA) sequencing (scRNA-seq) was conducted on 3 patients with and 1 healthy donor....
Induced pluripotency provides a tool to explore mechanisms underlying establishment, maintenance, and differentiation of naive pluripotent stem cells (nPSCs). Here, we report that self-renewal nPSCs requires minimal Sox2 expression (Sox2-low). Sox2-low do not show impaired neuroectoderm specification differentiate efficiently in vitro into all embryonic germ lineages. Strikingly, upon the removal self-renewing cues both extraembryonic cell fates vivo. This differs from previous studies which...
Abstract Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global public health emergency. COVID-19 typically manifests as illness but an increasing number of clinical reports describe gastrointestinal (GI) symptoms. This particularly true in children whom GI symptoms are frequent and viral shedding outlasts clearance from the system. By contrast, fetuses seem to be rarely affected COVID-19, although virus has...
Abstract Human cellular reprogramming to induced pluripotency is still an inefficient process, which has hindered studying the role of critical intermediate stages. Here we take advantage high efficiency in microfluidics and temporal multi-omics identify resolve distinct sub-populations their interactions. We perform secretome analysis single-cell transcriptomics show functional extrinsic pathways protein communication between re-shaping a permissive extracellular environment. pinpoint...
Abstract The neural tube (NT) has been a hallmark example of embryonic induction and patterning whereby the notochord induces an organiser, floorplate, that secretes Sonic Hedgehog (SHH) to pattern surrounding field progenitors. On other hand, NT organoids (NTOs) formed from stem cells (ESCs) undergo spontaneous floorplate formation in absence their normal inducers. Understanding how regulative organiser is central challenge biology. Here, we investigated self-organisation SHH-expressing...
In many developing tissues the patterns of gene expression that assign cell fate are organised by secreted signals functioning in a graded manner over multiple diameters. Cis Regulatory Elements (CREs) interpret these inputs to control expression. How this is accomplished remains poorly understood. neural tube, gradient morphogen Sonic hedgehog allocates progenitor identity. Here, we uncover two distinct ways which CREs translate Shh signaling into differential majority ventral progenitors...
The human developmental processes during the early post-implantation stage instruct specification and organization of lineage progenitors into a body plan. These processes, which include patterning, cell sorting, establishment three germ layers, have been classically studied in non-human model organisms only recently, through micropatterning technology, human-specific context. Micropatterning technology has unveiled mechanisms patterning layer specification; however, sorting their...
Summary Generating balanced populations of CD8 effector and memory T cells is necessary for immediate durable immunity to infections cancer. Yet, a definitive understanding differentiation remains unclear. We used CARLIN, processive lineage recording mouse model with single-cell RNA-seq TCR-seq track endogenous antigen-specific during acute viral infection. identified diverse repertoire expanded T-cell clones represented by seven transcriptional states. TCR enrichment analysis revealed...
Summary Human central nervous system (CNS) development involves complex transitions from pluripotency to regionalised neural tissues. The early phases of this process are inaccessible in humans but can potentially be modelled vitro using brain organoids, including study neurodevelopmental disorders. However, current methods based on post-implantation-like human pluripotent stem cells (hPSCs), which exhibit a hypermethylated state and show epigenetic memory retention. Here we developed 3D...
Abstract Induced pluripotency provides a tool to explore the molecular mechanisms underlying establishment, maintenance and differentiation of naïve pluripotent stem cells (nPSCs). Here, we report that self-renewal nPSCs requires minimal Sox2 expression (Sox2-low). Sox2-low do not show impaired neuroectoderm specification differentiate efficiently in vitro into all embryonic germ lineages. Strikingly, also towards trophoblast lineage both vivo . At single-cell level self-renewing exhibit...