Fibroblast inflammatory priming determines regenerative versus fibrotic skin repair in reindeer

Sarthak Sinha; Holly D. Sparks; Elodie Labit; Hayley N. Robbins; Kevin Gowing; Arzina Jaffer; Eren Kutluberk; Rohit Arora; Micha Sam Brickman Raredon; Leslie Cao; Scott Swanson; Peng Jiang; Olivia Hee; Hannah Pope; Matt Workentine; Kiran Todkar; Nilesh Sharma; Shyla Bharadia; Keerthana Chockalingam; Luiz G.N. de Almeida; Mike Adam; Laura Niklason; S. Steven Potter; Ashley W. Seifert; Antoine Dufour; Vincent Gabriel; Nicole L. Rosin; Ron Stewart; Greg Muench; Robert McCorkell; John Matyas; Jeff Biernaskie

doi:10.1016/j.cell.2022.11.004

Fibroblast inflammatory priming determines regenerative versus fibrotic skin repair in reindeer

Sarthak Sinha, Holly D. Sparks, Elodie Labit, Hayley N. Robbins, Kevin Gowing, Arzina Jaffer, Eren Kutluberk, Rohit Arora, Micha Sam Brickman Raredon, Leslie Cao, Scott Swanson, Peng Jiang, Olivia Hee, Hannah Pope, Matt Workentine, Kiran Todkar, Nilesh Sharma, Shyla Bharadia, Keerthana Chockalingam, Luiz G.N. de AlmeidaMike Adam, Laura Niklason, S. Steven Potter, Ashley W. Seifert, Antoine Dufour, Vincent Gabriel, Nicole L. Rosin, Ron Stewart, Greg Muench, Robert McCorkell, John Matyas, Jeff Biernaskie

Research output: Contribution to journal › Article › peer-review

115 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	4717-4736.e25
Journal	Cell
Volume	185
Issue number	25
DOIs	https://doi.org/10.1016/j.cell.2022.11.004
State	Published - Dec 8 2022

Bibliographical note

Publisher Copyright:
© 2022 The Author(s)

Funding

We wish to thank Barbara Smith, Cynddae McGowan, Victoria Dunkley, Dr. Dean Brown, and Lauren Carvell for their expert assistance with animal handling and care. We also thank the following for their assistance: Min Cheng for bulk RNA extraction, Jessica Yoon for FACS, John Steill and Dillon Herbst for data archival, Dragana Ponjevic for histology, and the Centre for Health Genomics and Informatics (University of Calgary) for next-generation sequencing and high-performance computing. This work was funded by the National Science and Engineering Research Council ( RGPIN/04825-2017 to J.B. and RGPIN/04992-2014 to J.M.), the Calgary Firefighters Burn Treatment Society (J.B.), NIAMS - R01AR070313 (A.W.S.), the National Center for Advancing Translational Sciences , National Institutes of Health ( UL1TR001998 ; A.W.S./S.S.P.), and a grant from Marv Conney (R.S.). We wish to thank Barbara Smith, Cynddae McGowan, Victoria Dunkley, Dr. Dean Brown, and Lauren Carvell for their expert assistance with animal handling and care. We also thank the following for their assistance: Min Cheng for bulk RNA extraction, Jessica Yoon for FACS, John Steill and Dillon Herbst for data archival, Dragana Ponjevic for histology, and the Centre for Health Genomics and Informatics (University of Calgary) for next-generation sequencing and high-performance computing. This work was funded by the National Science and Engineering Research Council (RGPIN/04825-2017 to J.B. and RGPIN/04992-2014 to J.M.), the Calgary Firefighters Burn Treatment Society (J.B.), NIAMS-R01AR070313 (A.W.S.), the National Center for Advancing Translational Sciences, National Institutes of Health (UL1TR001998; A.W.S./S.S.P.), and a grant from Marv Conney (R.S.). Conceptualization, S. Sinha, H.D.S. J.M. and J.B.; reindeer experiments and husbandry, S. Sinha, H.D.S. H.N.R. K.G. O.H. H.P. N.L.R. G.M. R.M. J.M. and J.B.; rodent experiments, E.L. and E.K.; laboratory experiments, H.D.S. H.N.R. K.G. E.L. N.S. S.B. K.T. O.H. H.P. N.L.R. and J.M.; bioinformatics, S. Sinha, A.J. R.A. L.C. K.C. M.W. M.S.B.R. and L.N.; bulk RNA-seq, S. Swanson, P.J. and R.S. cross-species comparisons, M.A. S.S.P. and A.W.S.; manuscript editing and review, S. Sinha, H.D.S. N.L.R. J.M. A.W.S. and J.B.; manuscript writing, S. Sinha, H.D.S. and J.B. The authors declare no competing interests. We support inclusive, diverse and equitable conduct of research.

Funders	Funder number
Barbara Smith
Cynddae McGowan
Marv Conney
National Institutes of Health (NIH)	UL1TR001998
National Institutes of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases	R01AR070313
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Center for Advancing Translational Sciences (NCATS)
Natural Sciences and Engineering Research Council of Canada	RGPIN/04825-2017, RGPIN/04992-2014
Natural Sciences and Engineering Research Council of Canada
Calgary Firefighters Burn Treatment Society	NIAMS-R01AR070313
Calgary Firefighters Burn Treatment Society

Keywords

fetal human fibroblast
fibroblast
immune modulation
inflammation
inflammatory priming
myeloid cell maturation
reindeer
scar
skin regeneration
stromal-immune crosstalk
wound healing

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.cell.2022.11.004

Cite this

Sinha, S., Sparks, H. D., Labit, E., Robbins, H. N., Gowing, K., Jaffer, A., Kutluberk, E., Arora, R., Raredon, M. S. B., Cao, L., Swanson, S., Jiang, P., Hee, O., Pope, H., Workentine, M., Todkar, K., Sharma, N., Bharadia, S., Chockalingam, K., ... Biernaskie, J. (2022). Fibroblast inflammatory priming determines regenerative versus fibrotic skin repair in reindeer. Cell, 185(25), 4717-4736.e25. https://doi.org/10.1016/j.cell.2022.11.004

@article{bc0da2cfc3364cb79e960e1dbcaccf2e,

title = "Fibroblast inflammatory priming determines regenerative versus fibrotic skin repair in reindeer",

abstract = "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.",

keywords = "fetal human fibroblast, fibroblast, immune modulation, inflammation, inflammatory priming, myeloid cell maturation, reindeer, scar, skin regeneration, stromal-immune crosstalk, wound healing",

author = "Sarthak Sinha and Sparks, \{Holly D.\} and Elodie Labit and Robbins, \{Hayley N.\} and Kevin Gowing and Arzina Jaffer and Eren Kutluberk and Rohit Arora and Raredon, \{Micha Sam Brickman\} and Leslie Cao and Scott Swanson and Peng Jiang and Olivia Hee and Hannah Pope and Matt Workentine and Kiran Todkar and Nilesh Sharma and Shyla Bharadia and Keerthana Chockalingam and \{de Almeida\}, \{Luiz G.N.\} and Mike Adam and Laura Niklason and Potter, \{S. Steven\} and Seifert, \{Ashley W.\} and Antoine Dufour and Vincent Gabriel and Rosin, \{Nicole L.\} and Ron Stewart and Greg Muench and Robert McCorkell and John Matyas and Jeff Biernaskie",

note = "Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = dec,

day = "8",

doi = "10.1016/j.cell.2022.11.004",

language = "English",

volume = "185",

pages = "4717--4736.e25",

number = "25",

}

Sinha, S, Sparks, HD, Labit, E, Robbins, HN, Gowing, K, Jaffer, A, Kutluberk, E, Arora, R, Raredon, MSB, Cao, L, Swanson, S, Jiang, P, Hee, O, Pope, H, Workentine, M, Todkar, K, Sharma, N, Bharadia, S, Chockalingam, K, de Almeida, LGN, Adam, M, Niklason, L, Potter, SS, Seifert, AW, Dufour, A, Gabriel, V, Rosin, NL, Stewart, R, Muench, G, McCorkell, R, Matyas, J & Biernaskie, J 2022, 'Fibroblast inflammatory priming determines regenerative versus fibrotic skin repair in reindeer', Cell, vol. 185, no. 25, pp. 4717-4736.e25. https://doi.org/10.1016/j.cell.2022.11.004

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

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

UR - https://www.scopus.com/pages/publications/85143856512

UR - https://www.scopus.com/inward/citedby.url?scp=85143856512&partnerID=8YFLogxK

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 -

Fibroblast inflammatory priming determines regenerative versus fibrotic skin repair in reindeer

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this