Integrative small and long RNA omics analysis of human healing and nonhealing wounds discovers cooperating microRNAs as therapeutic targets

  1. Zhuang Liu
  2. Letian Zhang
  3. Maria A Toma
  4. Dongqing Li
  5. Xiaowei Bian
  6. Irena Pastar
  7. Marjana Tomic-Canic
  8. Pehr Sommar  Is a corresponding author
  9. Ning Xu Landén  Is a corresponding author
  1. Karolinska Institute, Sweden
  2. Chinese Academy of Medical Sciences and Peking Union Medical College, China
  3. University of Miami, United States
  4. Karolinska University Hospital, Sweden

Abstract

MicroRNAs (miR), as important epigenetic control factors, reportedly regulate wound repair. However, our insufficient knowledge of clinically relevant miRs hinders their potential therapeutic use. For this, we performed paired small RNA and long RNA sequencing and integrative omics analysis in human tissue samples, including matched skin and acute wounds collected at each healing stage and chronic non-healing venous ulcers (VU). On the basis of the findings, we developed a compendium (https://www.xulandenlab.com/humanwounds-mirna-mrna), which will be an open, comprehensive resource to broadly aid wound healing research. With this first clinical, wound-centric resource of miRs and mRNAs, we identified 17 pathologically relevant miRs that exhibited abnormal VU expression and displayed their targets enriched explicitly in the VU gene signature. Intermeshing regulatory networks controlled by these miRs revealed their high cooperativity in contributing to chronic wound pathology characterized by persistent inflammation and proliferative phase initiation failure. Furthermore, we demonstrated that miR-34a, miR-424, and miR-516, upregulated in VU, cooperatively suppressed keratinocyte migration and growth while promoting inflammatory response. By combining miR expression patterns with their specific target gene expression context, we identified miRs highly relevant to VU pathology. Our study opens the possibility of developing innovative wound treatment that targets pathologically relevant cooperating miRs to attain higher therapeutic efficacy and specificity.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE174661 and GSE196773.The analyzed dataset is presented with an online R Shiny app and can be accessed through a browsable web portal (https://www.xulandenlab.com/humanwounds-mirna-mrna).The analysis source code is available at https://github.com/Zhuang-Bio/miRNAprofiling.Source data files have been provided by excel files for figures 1c, 1d, 1e, 2a, 2b, 2c, 2d, 2e, 4a, 4b, 5b-j, 6k, 8, 9 and figure supplements 2-2, 2-4c, 6, 7a, b lower panels.

The following data sets were generated

Article and author information

Author details

  1. Zhuang Liu

    Department of Medicine, Karolinska Institute, Stockholm, Sweden
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8938-0086
  2. Letian Zhang

    Department of Medicine, Karolinska Institute, Stockholm, Sweden
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0987-0905
  3. Maria A Toma

    Department of Medicine, Karolinska Institute, Stockholm, Sweden
    Competing interests
    No competing interests declared.
  4. Dongqing Li

    Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
    Competing interests
    No competing interests declared.
  5. Xiaowei Bian

    Department of Medicine, Karolinska Institute, Stockholm, Sweden
    Competing interests
    No competing interests declared.
  6. Irena Pastar

    Department of Dermatology and Cutaneous Surgery, University of Miami, Miami, United States
    Competing interests
    Irena Pastar, is on the Board of Directors for the Wound Healing Society. Irena Pastar received payment for speaking at the Symposium of Advanced Wound Care and Wound Healing Society 2022 meeting, and the World Union of the Wound Healing Societies 2022. The author has no other competing interests to declare..
  7. Marjana Tomic-Canic

    Department of Dermatology and Cutaneous Surgery, University of Miami, Miami, United States
    Competing interests
    Marjana Tomic-Canic, received grants from NIH/NIDDK [U01DK119085], NIH/NINR [R01NR015649], NIH/NIDDK [U24DK115255] and NIH/NIDDK [R41DK127900] for research unrelated to the topic of the manuscript. Marjana Tomic-Canic received payment for attending, speaking and moderating at the Symposium of Advanced Wound Care and Wound Healing Society 2022 meeting, and for attending the World Union of the Wound Healing Societies 2022. Marjana Tomic-Canic participates on the Scientific Advisory Board of Molnlycke. The patent No. 63/335,306 Theraputic Compositions" is pending. The author has no other competing interests to declare.".
  8. Pehr Sommar

    Department of Plastic and Reconstructive Surgery, Karolinska University Hospital, Stockholm, Sweden
    For correspondence
    pehr.sommar@regionstockholm.se
    Competing interests
    No competing interests declared.
  9. Ning Xu Landén

    Department of Medicine, Karolinska Institute, Solna, Sweden
    For correspondence
    ning.xu@ki.se
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4868-3798

Funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Brian S Kim MD, Icahn School of Medicine at Mount Sinai, United States

Ethics

Human subjects: Written informed consent was obtained from all the donors to collect and use the tissue samples.The study was approved by the Stockholm Regional Ethics Committee and conducted according to the Declaration of Helsinki's principles.

Version history

  1. Preprint posted: December 17, 2021 (view preprint)
  2. Received: May 16, 2022
  3. Accepted: July 19, 2022
  4. Accepted Manuscript published: August 9, 2022 (version 1)
  5. Version of Record published: August 12, 2022 (version 2)

Copyright

© 2022, Liu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Zhuang Liu
  2. Letian Zhang
  3. Maria A Toma
  4. Dongqing Li
  5. Xiaowei Bian
  6. Irena Pastar
  7. Marjana Tomic-Canic
  8. Pehr Sommar
  9. Ning Xu Landén
(2022)
Integrative small and long RNA omics analysis of human healing and nonhealing wounds discovers cooperating microRNAs as therapeutic targets
eLife 11:e80322.
https://doi.org/10.7554/eLife.80322

Share this article

https://doi.org/10.7554/eLife.80322

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