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
  • 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: [email protected].
  • 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.
Products