TY - JOUR
T1 - Fibroblast inflammatory priming determines regenerative versus fibrotic skin repair in reindeer
AU - Sinha, Sarthak
AU - Sparks, Holly D.
AU - Labit, Elodie
AU - Robbins, Hayley N.
AU - Gowing, Kevin
AU - Jaffer, Arzina
AU - Kutluberk, Eren
AU - Arora, Rohit
AU - Raredon, Micha Sam Brickman
AU - Cao, Leslie
AU - Swanson, Scott
AU - Jiang, Peng
AU - Hee, Olivia
AU - Pope, Hannah
AU - Workentine, Matt
AU - Todkar, Kiran
AU - Sharma, Nilesh
AU - Bharadia, Shyla
AU - Chockalingam, Keerthana
AU - de Almeida, Luiz G.N.
AU - Adam, Mike
AU - Niklason, Laura
AU - Potter, S. Steven
AU - Seifert, Ashley W.
AU - Dufour, Antoine
AU - Gabriel, Vincent
AU - Rosin, Nicole L.
AU - Stewart, Ron
AU - Muench, Greg
AU - McCorkell, Robert
AU - Matyas, John
AU - Biernaskie, Jeff
N1 - Publisher Copyright:
© 2022 The Author(s)
PY - 2022/12/8
Y1 - 2022/12/8
N2 - Adult mammalian skin wounds heal by forming fibrotic scars. We report that full-thickness injuries of reindeer antler skin (velvet) regenerate, whereas back skin forms fibrotic scar. Single-cell multi-omics reveal that uninjured velvet fibroblasts resemble human fetal fibroblasts, whereas back skin fibroblasts express inflammatory mediators mimicking pro-fibrotic adult human and rodent fibroblasts. Consequently, injury elicits site-specific immune responses: back skin fibroblasts amplify myeloid infiltration and maturation during repair, whereas velvet fibroblasts adopt an immunosuppressive phenotype that restricts leukocyte recruitment and hastens immune resolution. Ectopic transplantation of velvet to scar-forming back skin is initially regenerative, but progressively transitions to a fibrotic phenotype akin to the scarless fetal-to-scar-forming transition reported in humans. Skin regeneration is diminished by intensifying, or enhanced by neutralizing, these pathologic fibroblast-immune interactions. Reindeer represent a powerful comparative model for interrogating divergent wound healing outcomes, and our results nominate decoupling of fibroblast-immune interactions as a promising approach to mitigate scar.
AB - Adult mammalian skin wounds heal by forming fibrotic scars. We report that full-thickness injuries of reindeer antler skin (velvet) regenerate, whereas back skin forms fibrotic scar. Single-cell multi-omics reveal that uninjured velvet fibroblasts resemble human fetal fibroblasts, whereas back skin fibroblasts express inflammatory mediators mimicking pro-fibrotic adult human and rodent fibroblasts. Consequently, injury elicits site-specific immune responses: back skin fibroblasts amplify myeloid infiltration and maturation during repair, whereas velvet fibroblasts adopt an immunosuppressive phenotype that restricts leukocyte recruitment and hastens immune resolution. Ectopic transplantation of velvet to scar-forming back skin is initially regenerative, but progressively transitions to a fibrotic phenotype akin to the scarless fetal-to-scar-forming transition reported in humans. Skin regeneration is diminished by intensifying, or enhanced by neutralizing, these pathologic fibroblast-immune interactions. Reindeer represent a powerful comparative model for interrogating divergent wound healing outcomes, and our results nominate decoupling of fibroblast-immune interactions as a promising approach to mitigate scar.
KW - fetal human fibroblast
KW - fibroblast
KW - immune modulation
KW - inflammation
KW - inflammatory priming
KW - myeloid cell maturation
KW - reindeer
KW - scar
KW - skin regeneration
KW - stromal-immune crosstalk
KW - wound healing
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U2 - 10.1016/j.cell.2022.11.004
DO - 10.1016/j.cell.2022.11.004
M3 - Article
C2 - 36493752
AN - SCOPUS:85143856512
SN - 0092-8674
VL - 185
SP - 4717-4736.e25
JO - Cell
JF - Cell
IS - 25
ER -