Single-cell analysis of lizard blastema fibroblasts reveals phagocyte-dependent activation of Hedgehog-responsive chondrogenesis

Single-cell analysis of lizard blastema fibroblasts reveals phagocyte-dependent activation of Hedgehog-responsive chondrogenesis

Lizards cannot naturally regenerate limbs but are the closest known relatives of mammals capable of epimorphic tail regrowth. However, the mechanisms regulating lizard blastema formation and chondrogenesis remain unclear. Here, single-cell RNA sequencing analysis of regenerating lizard tails identif...

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Bibliographic Details
Published in:Nature communications Vol. 14; no. 1; p. 4489
Main Authors: Vonk, Ariel C., Zhao, Xiaofan, Pan, Zheyu, Hudnall, Megan L., Oakes, Conrad G., Lopez, Gabriela A., Hasel-Kolossa, Sarah C., Kuncz, Alexander W. C., Sengelmann, Sasha B., Gamble, Darian J., Lozito, Thomas P.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 10-08-2023
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Cartilage
Chondrogenesis
Electrons
Fibroblasts
Gene sequencing
Hedgehog protein
Humanities and Social Sciences
Limbs
Lizards
Mammals
multidisciplinary
Phagocytes
Populations
Regrowth
Saururaceae
Science
Science (multidisciplinary)
Sequence analysis
Squamata
Tails
Trajectory analysis
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Summary:Lizards cannot naturally regenerate limbs but are the closest known relatives of mammals capable of epimorphic tail regrowth. However, the mechanisms regulating lizard blastema formation and chondrogenesis remain unclear. Here, single-cell RNA sequencing analysis of regenerating lizard tails identifies fibroblast and phagocyte populations linked to cartilage formation. Pseudotime trajectory analyses suggest spp1 + -activated fibroblasts as blastema cell sources, with subsets exhibiting sulf1 expression and chondrogenic potential. Tail blastema, but not limb, fibroblasts express sulf1 and form cartilage under Hedgehog signaling regulation. Depletion of phagocytes inhibits blastema formation, but treatment with pericytic phagocyte-conditioned media rescues blastema chondrogenesis and cartilage formation in amputated limbs. The results indicate a hierarchy of phagocyte-induced fibroblast gene activations during lizard blastema formation, culminating in sulf1 + pro-chondrogenic populations singularly responsive to Hedgehog signaling. These properties distinguish lizard blastema cells from homeostatic and injury-stimulated fibroblasts and indicate potential actionable targets for inducing regeneration in other species, including humans. Lizards are the closest known relatives of mammals capable of epimorphic tail regrowth. Here, single-cell analysis of regenerating lizard tails reveals a phagocyte-induced fibroblast population contributing to blastema formation and chondrogenesis.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-40206-z