2. Academic Validation
  3. Lysophosphatidic acid and sphingosine-1-phosphate are apical polarity cues in multiple organoid systems

Lysophosphatidic acid and sphingosine-1-phosphate are apical polarity cues in multiple organoid systems

  • Cell Rep. 2025 Jun 24;44(6):115842. doi: 10.1016/j.celrep.2025.115842.
Andrew M Tidball 1,  Jinghui Luo 2,  J Clayton Walker 2,  Charlotte Y Yang 2,  Keithan Lee 2,  Ryan C Spencer 3,  Carissa Matthews 2,  Geshan Feng 2,  Peggy P Hsu 3,  Yusoo Lee 3,  Jack Morgan 3,  Charlie J Childs 3,  Madeline K Eiken 4,  Katherine D Walton 5,  Jason R Spence 6
Affiliations

Affiliations

  • 1 Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Neuroscience Institute, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address: atidball@umich.edu.
  • 2 Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 3 Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 4 Department of Biomedical Engineering, University of Michigan Medical School and University of Michigan College of Engineering, Ann Arbor, MI, USA.
  • 5 Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 6 Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan Medical School and University of Michigan College of Engineering, Ann Arbor, MI, USA; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA.
PMID: 40503936 DOI: 10.1016/j.celrep.2025.115842
Abstract

Apicobasal polarization is crucial for tissue organization during in vivo development and in human Organoid models. Extracellular matrix (ECM) signaling typically provides a basal cue, and intestinal and lung organoids reverse polarity from apical-in to apical-out after ECM removal. However, ECM-free brain organoids maintain apical-in polarity, suggesting that media components may influence polarity. Exposing brain organoids to serum induced apical-out orientation. Lysophosphatidic acid (LPA), present in the medium of prior apical-out techniques, was identified as the causative factor. LPA-induced apical-out orientation in brain organoids occurred within 1 day, lasted at least 1 month, and was optimal at human cerebrospinal fluid LPA concentrations. Sphingosine-1-phosphate (S1P) induced similar apical-out polarization. Pharmacological studies revealed that LPA/S1P act via a G-protein coupled receptor/RhoA pathway. Finally, LPA induced apical-out polarity in patient-derived human lung and intestinal organoids, iPSC spheres, and multilineage iPSC-derived intestinal organoids. These findings indicate that LPA signaling is a critical apical polarity cue in multiple tissues.

Keywords

CP: Cell biology; CP: Stem cell research; LPAR1; Rho; apical-out; apicobasal polarity; brain organoid; cerebrospinal fluid; epithelium; phospholipid signaling; tight junctions.

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