Same-section spatial metabolo-transcriptomics using Stereo-meta-seq reveals DHA-driven kidney maturation
bioRxiv (Cold Spring Harbor Laboratory)
Abstract
Abstract 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 μm or 20 μm 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 PPARα-and HNF4α-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 .
Authors 15
-
Roan H van Scheppingen Aachen Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW)
Leiden University · Leiden University Medical Center · Novo Nordisk Foundation Center for Stem Cell Medicine
Affiliation as printed
Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
-
Center for Excellence in Molecular Cell Science · University of Chinese Academy of Sciences · State Key Laboratory of Cell Biology
Affiliation as printed
State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
-
Fudan University · Children's Hospital of Fudan University
Affiliation as printed
Department of Nephrology, Children’s Hospital of Fudan University, Shanghai, China and Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai, China
-
Sytske Schep Aachen Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW)
Leiden University · Leiden University Medical Center · Novo Nordisk Foundation Center for Stem Cell Medicine
Affiliation as printed
Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
-
Ulli Winter Aachen Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW)
Leiden University · Leiden University Medical Center · Novo Nordisk Foundation Center for Stem Cell Medicine
Affiliation as printed
Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
-
Affiliation as printed
Department of Chemistry, School of Science, Westlake University, Hangzhou 310024, Zhejiang, China
School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang, China
-
Susana M. Chuva de Sousa Lopes Aachen Department of Anatomy and Embryology Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW)
Leiden University Medical Center · Novo Nordisk Foundation Center for Stem Cell Medicine
Affiliation as printed
Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands
The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
-
National University of Singapore · Duke-NUS Medical School
Affiliation as printed
Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School, Singapore 169857, Singapore
-
И. В. Сидоров Aachen Center of Proteomics and Metabolomics Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW)
Leiden University Medical Center · Novo Nordisk Foundation Center for Stem Cell Medicine
Affiliation as printed
Center of Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
-
Martin A. Giera Aachen Center of Proteomics and Metabolomics Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW)
Leiden University Medical Center · Novo Nordisk Foundation Center for Stem Cell Medicine
Affiliation as printed
Center of Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
-
Bernard M. van den Berg Aachen Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW)
Leiden University · Leiden University Medical Center · Novo Nordisk Foundation Center for Stem Cell Medicine
Affiliation as printed
Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
-
Cathelijne W. van den Berg Aachen Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW)
Leiden University · Leiden University Medical Center · Novo Nordisk Foundation Center for Stem Cell Medicine
Affiliation as printed
Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
-
Center for Excellence in Molecular Cell Science · University of Chinese Academy of Sciences · State Key Laboratory of Cell Biology
Affiliation as printed
State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
-
Ton J. Rabelink corresponding Aachen Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW)
Leiden University · Leiden University Medical Center · Novo Nordisk Foundation Center for Stem Cell Medicine
Affiliation as printed
Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
-
Fudan University · Children's Hospital of Fudan University
Affiliation as printed
Children’s Hospital of Fudan University and the Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
Cited by 0 stored of 0
No patents citing this paper on Lens.org (checked 2026-10-11).