Berg, B. | bioRxiv Science

bioRxiv2026

Same-section spatial metabolo-transcriptomics using Stereo-meta-seq reveals DHA-driven kidney maturation

A central unresolved question in developmental biology is whether local metabolites merely accompany, or actively instruct, tissue maturation. Addressing this question requires direct spatial coupling of metabolic states with genome-wide transcriptional programs in situ at high spatial resolution, which existing approaches do not readily achieve. Here, we introduce Stereo-meta-seq, a workflow that integrates quantitative MALDI-MSI with Stereo-seq spatial transcriptomics within a single tissue section. A conductive adapter was designed to overcome the electrical incompatibility of non-conductive Stereo-seq chips with vacuum MALDI platforms, improving efficiency of MSI detection that preserves RNA integrity. MALDI laser-ablation marks are retained in downstream Stereo-seq data and serve as intrinsic fiducials for direct co-registration at 10 m or 20 m resolution, enabling fine grained spatial metabolite-transcript integration. Applying Stereo-meta-seq to human kidney development, we uncover selective enrichment of docosahexaenoic acid (DHA) in maturing proximal tubules. Functional studies in human kidney organoids demonstrate that DHA activates PPAR-and HNF4-driven transcriptional programs and promotes proximal tubule maturation in vitro and after transplantation in vivo. These findings identify lipid metabolism as an instructive regulator of human nephrogenesis and establish Stereo-meta-seq as a practical platform for dissecting metabolite-gene coupling and tissue heterogeneity in situ.

Cell Biology↗

bioRxiv2025

Astral architecture can enhance mechanical strength of cytoskeletal networks by modulating percolation thresholds

A repeated pattern in cytoskeletal architecture is the aster, in which a number of F-actin filaments emerge star-shaped from a central node. Aster-based structures occur in cytoplasmic actin, the early stages of the cytokinetic ring in yeast, and in the context of biomimetic materials engineering. In this work, we use computational simulation to show that there is an optimal number of filaments per aster that maximizes rigidity, even at a fixed density of F-actin. This nonlinear dependence holds for both the shear and extensional moduli. At physiological parameters, the maximum corresponds approximately to the same filaments-per-aster observed in recent super-resolution images of cortical F-actin. Furthermore, we find that increasing filaments-per-aster leads to dramatic increases in the sample-to-sample variability in network rigidity. We explain both effects using percolation theory, wherein the probability that a given network is productively connected exhibits a sharp dependence on parameters. The dependence of network rigidity on this nanoscale architectural feature may suggest a mechanism by which cells tune the physical properties of their actin networks locally and rapidly (since no new F-actin must be assembled) and may inform efforts to create adaptive synthetic metamaterials inspired by actin networks.

biophysics↗