Biology subjects

Mangold, K.

Publications and source records attributed to Mangold, K..

3 recordsLinked to original sources

bioRxiv2024

Unbiased profiling of multipotency landscapes reveals spatial modulators of clonal fate biases

The proportion of cell types varies systematically across the body, but it remains unclear how individual progenitor cells integrate positional information to establish patterns of cellular composition. In this study we profile the clonal landscape of the embryo, using single-cell lineage tracing of mouse embryos from neurulation until mid-gestation. To analyze the complex clonal patterns derived from highly multipotent progenitors, we developed clone2vec, which uses unsupervised learning to categorize individual clones into lineages based on shared transcriptional context. This revealed a body-wide gradient of clonal fate biases, in which anatomical position and clonal composition are mutually predictive. Comparison of clonal lineages revealed spatial transcription factor programs associated with dynamic cell biasing towards skeletal versus non-skeletal fates. Mosaic combinatorial perturbations targeting the Hedgehog pathway generated clones in which positional identity was mismatched with clonal composition, suggesting a potential signaling influence on somite patterning. We explore the effects of position and heterochrony on fate biases in cranial, trunk, and caudal neural crest clones. Altogether, our work demonstrates an effective practical approach for dissecting mechanisms of lineage specification.

developmental biology↗

bioRxiv2024

Microbial metabolite-guided CAR T cell engineering enhances anti-tumor immunity via epigenetic-metabolic crosstalk

The microbiome is a complex host factor and key determinant of the outcome of antibody-based and cellular immunotherapy. Its postbiotics are a blend of soluble commensal byproducts that are released into the host environment and have been associated with the regulation of immune homeostasis, particularly through impacts on epigenetics and cell signaling. In this study, we show that the postbiotic pentanoate is metabolized to citrate within the TCA cycle via both the acetyl- and succinyl-CoA entry points, a feature uniquely enabled by the chemical structure of the C5 aliphatic chain. We identified ATP-citrate lyase as the crucial factor that redirects pentanoate-derived citrate from the succinyl-CoA route to the nucleus, thereby linking metabolic output and histone acetylation. This epigenetic-metabolic crosstalk mitigated T cell exhaustion and promoted naive-like differentiation in pentanoate-programmed chimeric antigen receptor (CAR) T cells. The predictive and therapeutic potential of pentanoate was corroborated in two independent patient cohorts and three syngeneic models of CAR T adoptive therapy. Our data demonstrate that postbiotics are integrated into mitochondrial metabolism and subsequently incorporated as epigenetic imprints. This bridge between microbial and mammalian interspecies communication can ultimately impact T cell differentiation and efficacy.

immunology↗

bioRxiv2020

Neural Plate Targeting by in Utero NanoinjEction (NEPTUNE) reveals a role for Sptbn2 in neurulation and abdominal wall closure

Gene variants associated with disease are efficiently identified with whole genome sequencing or GWAS, but validation in vivo lags behind. We developed NEPTUNE (neural plate targeting by in utero nanoinjection), to rapidly and flexibly introduce gene expression-modifying viruses to the embryonic murine neural plate prior to neurulation, to target the future adult nervous system. Stable integration in >95% of cells in the brain enabled long-term gain- or loss-of-function, and conditional expression was achieved using mini-promotors for cell types of interest. Using NEPTUNE, we silenced Sptbn2, a gene associated with Spinocerebellar ataxia type 5 (SCA5) in humans. Silencing of Sptbn2 induced severe neural tube defects and embryo resorption, suggesting that SPTBN2 in-frame and missense deletions in SCA5 reflect hypomorphic or neomorphic functions, not loss of function. In conclusion, NEPTUNE offers a novel, rapid and cost-effective technique to test gene function in brain development, and can reveal loss of function phenotypes incompatible with life.

developmental biology↗