Neuroendocrine cells orchestrate regeneration through Desert hedgehog signaling

Affiliations

¹ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
² Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
³ Gladstone Institutes, University of California, San Francisco, San Francisco, CA 94158, USA.
⁴ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁵ Atropos Health, Palo Alto, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁶ Gladstone Institutes, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁸ Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁹ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Internal Medicine, Division of Pulmonary, Allergy and Critical Care, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹⁰ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Departments of Urology, Developmental Biology, and (by courtesy) Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: pbeachy@stanford.edu.

PMID: 40494346
PMCID: PMC12232213 (available on 2026-06-09)
DOI: 10.1016/j.cell.2025.05.012

Neuroendocrine cells orchestrate regeneration through Desert hedgehog signaling

William Kong et al. Cell. 2025.

. 2025 Sep 4;188(18):5020-5038.e20.

doi: 10.1016/j.cell.2025.05.012. Epub 2025 Jun 9.

Authors

Affiliations

¹ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
² Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
³ Gladstone Institutes, University of California, San Francisco, San Francisco, CA 94158, USA.
⁴ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁵ Atropos Health, Palo Alto, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁶ Gladstone Institutes, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁸ Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁹ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Internal Medicine, Division of Pulmonary, Allergy and Critical Care, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹⁰ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Departments of Urology, Developmental Biology, and (by courtesy) Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: pbeachy@stanford.edu.

PMID: 40494346
PMCID: PMC12232213 (available on 2026-06-09)
DOI: 10.1016/j.cell.2025.05.012

Abstract

Understanding the mechanisms underlying mammalian regeneration may enable development of novel regenerative therapies. We present a mechanism wherein Desert hedgehog (Dhh), secreted from epithelial neuroendocrine cells, elicits a regenerative/protective response from mesenchymal cells. In mammalian airway, this mesenchymal response strikingly amplifies the initial signal from rare neuroendocrine cells to activate the entire tissue for survival and regeneration upon injury from SO₂ gas inhalation or following influenza or SARS-CoV-2 infection. Similar epithelial-mesenchymal feedback (EMF) signaling directed by Dhh from neuroendocrine β cells likewise protects mouse pancreatic islets from streptozotocin (STZ) injury. A role for EMF signaling in human pancreatic islets is suggested by higher incidence of diabetes in patients treated with Hedgehog pathway inhibitors. Remarkably, EMF augmentation by small-molecule Hedgehog pathway agonism protects against STZ injury of pancreatic β cells and shields against airway injury from SO₂ and influenza infection, with potential protective/therapeutic utility in chemical or infectious airway injury and in diabetes.

Keywords: Desert hedgehog; Hedgehog agonist; Hedgehog inhibitor; SARS-CoV-2; airway inhalation injury; diabetes; influenza; neuroendocrine cells; pancreatic islets of Langerhans; regeneration.

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Conflict of interest statement

Declaration of interests S.G. is a founder, shareholder, and employee of Atropos Health.

References

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Neuroendocrine cells orchestrate regeneration through Desert hedgehog signaling

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Neuroendocrine cells orchestrate regeneration through Desert hedgehog signaling

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