Interrogation of RDEB Epidermal Allografts after BMT Reveals Coexpression of Collagen VII and Keratin 15 with Proinflammatory Immune Cells and Fibroblasts

Julia A Riedl; Megan J Riddle; Lily H Xia; Cindy R Eide; Christina Boull; Christen L. Ebens; Jakub Tolar

doi:10.1016/j.jid.2022.01.034

Interrogation of RDEB Epidermal Allografts after BMT Reveals Coexpression of Collagen VII and Keratin 15 with Proinflammatory Immune Cells and Fibroblasts

Julia A Riedl, Megan J Riddle, Lily H Xia, Cindy R Eide, Christina Boull, Christen L. Ebens, Jakub Tolar

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

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a devastating genodermatosis characterized by dysfunctional collagen VII protein resulting in epithelial blistering of the skin, mucosa, and gastrointestinal tract. There is no cure for RDEB, but improvement of clinical phenotype has been achieved with bone marrow transplantation and subsequent epidermal allografting from the bone marrow transplant donor. Epidermal allografting of these patients has decreased wound surface area for up to 3 years after treatment. This study aimed to determine the phenotype of the epidermal allograft cells responsible for durable persistence of wound healing and skin integrity. We found that epidermal allografts provide basal keratinocytes coexpressing collagen VII and basal stem cell marker keratin 15. Characterization of RDEB full-thickness skin biopsies with single-cell RNA sequencing uncovered proinflammatory immune and fibroblast phenotypes potentially driven by the local environment of RDEB skin. This is further highlighted by the presence of a myofibroblast population, which has not been described in healthy control human skin. Finally, we found inflammatory fibroblasts expressing profibrotic gene POSTN, which may have implications in the development of squamous cell carcinoma, a common, lethal complication of RDEB that lacks curative treatment. In conclusion, this study provides insights into and targets for future RDEB studies and treatments.

Original language	English (US)
Pages (from-to)	2424-2434
Number of pages	11
Journal	Journal of Investigative Dermatology
Volume	142
Issue number	9
DOIs	https://doi.org/10.1016/j.jid.2022.01.034
State	Published - Sep 2022

Bibliographical note

Funding Information:
This research was conducted with funding support from the National Institutes of Health (NIH) grant National Heart, Lung, and Blood Institute of the NIH R01 AR063070 . We thank F. Knipping, A. Herman, University of Minnesota Supercomputing Institute, T. Starr, and Z. Sachs for their guidance with single-cell RNA-sequencing analyses. We thank E. Stanley and J. Daniels at the University of Minnesota Genome Core for completing all the 10x Genomics library preparations and sequencing. Finally, we thank Carpe Scientia for the critical review of the manuscript.

Funding Information:
This research was conducted with funding support from the National Institutes of Health (NIH) grant National Heart, Lung, and Blood Institute of the NIH R01 AR063070. We thank F. Knipping, A. Herman, University of Minnesota Supercomputing Institute, T. Starr, and Z. Sachs for their guidance with single-cell RNA-sequencing analyses. We thank E. Stanley and J. Daniels at the University of Minnesota Genome Core for completing all the 10x Genomics library preparations and sequencing. Finally, we thank Carpe Scientia for the critical review of the manuscript. Conceptualization: JAR, CE, CLE, LX, JT; Data Curation: JAR, MR; Formal Analysis: JAR, MR; Funding Acquisition: JT; Methodology: JAR, CE, CLE, JT; Resources: CB, JT; Software: JAR; Supervision: CE, JT; Visualization: JAR, MR; Writing - Original Draft Preparation: JAR, CLE, JT; Writing - Review and Editing: JAR, MR, LX, CE, CB, CLE, JT, The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2022 The Authors

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Journal Article
Research Support, N.I.H., Extramural

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10.1016/j.jid.2022.01.034

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title = "Interrogation of RDEB Epidermal Allografts after BMT Reveals Coexpression of Collagen VII and Keratin 15 with Proinflammatory Immune Cells and Fibroblasts",

abstract = "Recessive dystrophic epidermolysis bullosa (RDEB) is a devastating genodermatosis characterized by dysfunctional collagen VII protein resulting in epithelial blistering of the skin, mucosa, and gastrointestinal tract. There is no cure for RDEB, but improvement of clinical phenotype has been achieved with bone marrow transplantation and subsequent epidermal allografting from the bone marrow transplant donor. Epidermal allografting of these patients has decreased wound surface area for up to 3 years after treatment. This study aimed to determine the phenotype of the epidermal allograft cells responsible for durable persistence of wound healing and skin integrity. We found that epidermal allografts provide basal keratinocytes coexpressing collagen VII and basal stem cell marker keratin 15. Characterization of RDEB full-thickness skin biopsies with single-cell RNA sequencing uncovered proinflammatory immune and fibroblast phenotypes potentially driven by the local environment of RDEB skin. This is further highlighted by the presence of a myofibroblast population, which has not been described in healthy control human skin. Finally, we found inflammatory fibroblasts expressing profibrotic gene POSTN, which may have implications in the development of squamous cell carcinoma, a common, lethal complication of RDEB that lacks curative treatment. In conclusion, this study provides insights into and targets for future RDEB studies and treatments.",

author = "Riedl, {Julia A} and Riddle, {Megan J} and Xia, {Lily H} and Eide, {Cindy R} and Christina Boull and Ebens, {Christen L.} and Jakub Tolar",

note = "Funding Information: This research was conducted with funding support from the National Institutes of Health (NIH) grant National Heart, Lung, and Blood Institute of the NIH R01 AR063070 . We thank F. Knipping, A. Herman, University of Minnesota Supercomputing Institute, T. Starr, and Z. Sachs for their guidance with single-cell RNA-sequencing analyses. We thank E. Stanley and J. Daniels at the University of Minnesota Genome Core for completing all the 10x Genomics library preparations and sequencing. Finally, we thank Carpe Scientia for the critical review of the manuscript. Funding Information: This research was conducted with funding support from the National Institutes of Health (NIH) grant National Heart, Lung, and Blood Institute of the NIH R01 AR063070. We thank F. Knipping, A. Herman, University of Minnesota Supercomputing Institute, T. Starr, and Z. Sachs for their guidance with single-cell RNA-sequencing analyses. We thank E. Stanley and J. Daniels at the University of Minnesota Genome Core for completing all the 10x Genomics library preparations and sequencing. Finally, we thank Carpe Scientia for the critical review of the manuscript. Conceptualization: JAR, CE, CLE, LX, JT; Data Curation: JAR, MR; Formal Analysis: JAR, MR; Funding Acquisition: JT; Methodology: JAR, CE, CLE, JT; Resources: CB, JT; Software: JAR; Supervision: CE, JT; Visualization: JAR, MR; Writing - Original Draft Preparation: JAR, CLE, JT; Writing - Review and Editing: JAR, MR, LX, CE, CB, CLE, JT, The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = sep,

doi = "10.1016/j.jid.2022.01.034",

language = "English (US)",

volume = "142",

pages = "2424--2434",

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AU - Riedl, Julia A

AU - Riddle, Megan J

AU - Xia, Lily H

AU - Eide, Cindy R

AU - Boull, Christina

AU - Ebens, Christen L.

AU - Tolar, Jakub

N1 - Funding Information: This research was conducted with funding support from the National Institutes of Health (NIH) grant National Heart, Lung, and Blood Institute of the NIH R01 AR063070 . We thank F. Knipping, A. Herman, University of Minnesota Supercomputing Institute, T. Starr, and Z. Sachs for their guidance with single-cell RNA-sequencing analyses. We thank E. Stanley and J. Daniels at the University of Minnesota Genome Core for completing all the 10x Genomics library preparations and sequencing. Finally, we thank Carpe Scientia for the critical review of the manuscript. Funding Information: This research was conducted with funding support from the National Institutes of Health (NIH) grant National Heart, Lung, and Blood Institute of the NIH R01 AR063070. We thank F. Knipping, A. Herman, University of Minnesota Supercomputing Institute, T. Starr, and Z. Sachs for their guidance with single-cell RNA-sequencing analyses. We thank E. Stanley and J. Daniels at the University of Minnesota Genome Core for completing all the 10x Genomics library preparations and sequencing. Finally, we thank Carpe Scientia for the critical review of the manuscript. Conceptualization: JAR, CE, CLE, LX, JT; Data Curation: JAR, MR; Formal Analysis: JAR, MR; Funding Acquisition: JT; Methodology: JAR, CE, CLE, JT; Resources: CB, JT; Software: JAR; Supervision: CE, JT; Visualization: JAR, MR; Writing - Original Draft Preparation: JAR, CLE, JT; Writing - Review and Editing: JAR, MR, LX, CE, CB, CLE, JT, The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: © 2022 The Authors

PY - 2022/9

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N2 - Recessive dystrophic epidermolysis bullosa (RDEB) is a devastating genodermatosis characterized by dysfunctional collagen VII protein resulting in epithelial blistering of the skin, mucosa, and gastrointestinal tract. There is no cure for RDEB, but improvement of clinical phenotype has been achieved with bone marrow transplantation and subsequent epidermal allografting from the bone marrow transplant donor. Epidermal allografting of these patients has decreased wound surface area for up to 3 years after treatment. This study aimed to determine the phenotype of the epidermal allograft cells responsible for durable persistence of wound healing and skin integrity. We found that epidermal allografts provide basal keratinocytes coexpressing collagen VII and basal stem cell marker keratin 15. Characterization of RDEB full-thickness skin biopsies with single-cell RNA sequencing uncovered proinflammatory immune and fibroblast phenotypes potentially driven by the local environment of RDEB skin. This is further highlighted by the presence of a myofibroblast population, which has not been described in healthy control human skin. Finally, we found inflammatory fibroblasts expressing profibrotic gene POSTN, which may have implications in the development of squamous cell carcinoma, a common, lethal complication of RDEB that lacks curative treatment. In conclusion, this study provides insights into and targets for future RDEB studies and treatments.

AB - Recessive dystrophic epidermolysis bullosa (RDEB) is a devastating genodermatosis characterized by dysfunctional collagen VII protein resulting in epithelial blistering of the skin, mucosa, and gastrointestinal tract. There is no cure for RDEB, but improvement of clinical phenotype has been achieved with bone marrow transplantation and subsequent epidermal allografting from the bone marrow transplant donor. Epidermal allografting of these patients has decreased wound surface area for up to 3 years after treatment. This study aimed to determine the phenotype of the epidermal allograft cells responsible for durable persistence of wound healing and skin integrity. We found that epidermal allografts provide basal keratinocytes coexpressing collagen VII and basal stem cell marker keratin 15. Characterization of RDEB full-thickness skin biopsies with single-cell RNA sequencing uncovered proinflammatory immune and fibroblast phenotypes potentially driven by the local environment of RDEB skin. This is further highlighted by the presence of a myofibroblast population, which has not been described in healthy control human skin. Finally, we found inflammatory fibroblasts expressing profibrotic gene POSTN, which may have implications in the development of squamous cell carcinoma, a common, lethal complication of RDEB that lacks curative treatment. In conclusion, this study provides insights into and targets for future RDEB studies and treatments.

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Interrogation of RDEB Epidermal Allografts after BMT Reveals Coexpression of Collagen VII and Keratin 15 with Proinflammatory Immune Cells and Fibroblasts

Abstract

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