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

Ariel C. Vonk, Xiaofan Zhao, Zheyu Pan, Megan L. Hudnall, Conrad G. Oakes, Gabriela A. Lopez, Sarah C. Hasel-Kolossa, Alexander W. C. Kuncz, Sasha B. Sengelmann, Darian J. Gamble and Thomas P. Lozito ()
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Ariel C. Vonk: University of Southern California
Xiaofan Zhao: University of Southern California
Zheyu Pan: University of Southern California
Megan L. Hudnall: University of Southern California
Conrad G. Oakes: University of Southern California
Gabriela A. Lopez: University of Southern California
Sarah C. Hasel-Kolossa: University of Southern California
Alexander W. C. Kuncz: University of Southern California
Sasha B. Sengelmann: University of Southern California
Darian J. Gamble: University of Southern California
Thomas P. Lozito: University of Southern California

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-40206-z

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