A toolkit for mapping cell identities in relation to neighbours reveals Notch-dependent heterogeneity within neuromesodermal progenitor populations

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 3, 2024

Abstract Patterning of cell fates is central to embryonic development, tissue homeostasis, and disease. Quantitative analysis patterning reveals the logic by which cell-cell interactions orchestrate changes in fate. However, it challenging quantify when graded identity occur over complex 4D trajectories, or where different states are intermingled. Furthermore, comparing patterns across multiple individual embryos, tissues, organoids difficult because these often vary shape size. Here we present a toolkit computational approaches tackle problems. These strategies based on measuring properties each relation its neighbours patterning, using landmarks order compare between embryos. We use this characterise identities within caudal lateral epiblast E8.5 revealing local emergence early mesoderm cells that sensitive inhibition Notch activity.

Language: Английский

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Cellular signalling protrusions enable dynamic distant contacts in spinal cord neurogenesis

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 12, 2024

Abstract In the developing mouse ventral spinal cord, HES5, a transcription factor downstream of Notch signalling, is expressed as evenly spaced clusters high HES5-expressing neural progenitor cells along dorsoventral axis. While signalling requires direct membrane contact for its activation, we have previously shown mathematically that needs to extend beyond neighbouring HES5 pattern emerge. However, presence cellular structures could enable such long-distance was unclear. Here, report protrusions are present all apicobasal axis individual cells. Through live imaging, show these dynamically and retract reaching lengths up ∼20μm, enough adjacent The ligand DLL1 found colocalise with protrusions, further supporting idea can be transduced at distance. effect on tested by reducing density using CDC42 inhibitor ML141, leading tendency decrease distance between cell clusters. this not significant leaves an open question about their role in fine-grained organisation neurogenesis.

Language: Английский

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De novo-designed minibinders expand the synthetic biology sensing repertoire

Published: Oct. 30, 2024

Synthetic and chimeric receptors capable of recognizing responding to user-defined antigens have enabled “smart” therapeutics based on engineered cells. These cell engineering tools depend antigen sensors which are most often derived from antibodies. Advances in the de novo design proteins protein binders with potential target epitopes unique properties faster production timelines compared Building upon our previous work combining a -designed minibinder Spike SARS-CoV-2 synthetic receptor synNotch (SARSNotch), we investigated whether minibinders can be readily adapted diversity tools. We show that LCB1 easily generalizes next-generation proteolytic SNIPR performs similarly previously reported SARSNotch. LCB1-SNIPR successfully enables detection live SARS-CoV-2, an improvement over SARSNotch only detect cell-expressed Spike. To test generalizability diverse applications, tested as sensor for (CAR). LCB1-CAR CD8+ T cells cytotoxically Spike-expressing further demonstrate two other directed against clinically relevant epidermal growth factor able drive CAR-dependent cytotoxicity efficacy similar or better than existing antibody-based CAR. Our findings suggest represent novel class dramatically expand sensing repertoire

Language: Английский

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Engineering an αCD206-synNotch Receptor: Insights into the Development of Novel Synthetic Receptors

ACS Synthetic Biology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 18, 2024

Immune cells play a pivotal role in the establishment, growth, and progression of tumors at primary metastatic sites. Macrophages, particular, critical suppressing immune responses promoting an anti-inflammatory environment through both direct indirect cell-cell interactions. However, our understanding mechanisms underlying such interactions is limited due to lack reliable tools for studying transient between cancer macrophages within tumor microenvironment. Recent advances mammalian synthetic biology have introduced wide range receptors that been used diverse biosensing applications. One receptor synNotch receptor, which can be tailored sense specific ligands displayed on surface target cells. With this study, we aimed developing novel αCD206-synNotch targeting CD206

Language: Английский

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Control of spatio-temporal patterning via cell growth in a multicellular synthetic gene circuit

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Nov. 19, 2024

A major goal in synthetic development is to build gene regulatory circuits that control patterning. In natural development, an interplay between mechanical and chemical communication shapes the dynamics of multicellular circuits. For circuits, how non-genetic properties growth environment impact circuit behavior remains poorly explored. Here, we first describe occurrence mechano-chemical coupling Notch (synNotch) patterning circuits: high cell density decreases synNotch-gated expression different cellular systems vitro. We then construct, both vitro silico, a synNotch-based signal propagation whose outcome can be regulated by density. Spatial temporal outcomes this predicted controlled via modulation proliferation, initial density, and/or spatial distribution Our work demonstrates growth, providing means for programming outcomes. Here authors discover elevated dampens SynNotch signaling, enabling design density-dependent synNotch where are programmed proliferation time space.

Language: Английский

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