Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Dec 26, 2020; 12(12): 1652-1666
Published online Dec 26, 2020. doi: 10.4252/wjsc.v12.i12.1652
Umbilical cord-derived mesenchymal stem cells preconditioned with isorhamnetin: potential therapy for burn wounds
Shazmeen Aslam, Irfan Khan, Fatima Jameel, Midhat Batool Zaidi, Asmat Salim
Shazmeen Aslam, Irfan Khan, Fatima Jameel, Midhat Batool Zaidi, Asmat Salim, Stem Cell Laboratory, Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 74700, Sindh, Pakistan
Author contributions: Aslam S performed all experiments, analyzed the data and wrote the first draft of the manuscript; Khan I and Salim A conceived the idea, designed the experiments, and assisted in data analysis; Salim A wrote the final manuscript; Jameel F assisted in the in vivo models and wrote part of the manuscript; Zaidi MB assisted in the in vitro studies and image analysis; all authors approved the final version of the article.
Institutional review board statement: The study was reviewed and approved by the Independent Ethics Committee of International Center for Chemical and Biological Sciences, University of Karachi (ICCBS/IEC-036-HT-2018/Protocol/1.0).
Institutional animal care and use committee statement: The study was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of the International Center for Chemical and Biological Sciences, University of Karachi (Animal study protocol number: 2018-0018).
Conflict-of-interest statement: The authors have nothing to disclose.
Data sharing statement: Informed consent regarding the experiments in the current study was received from all participants. No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Asmat Salim, PhD, Professor, Stem Cell Laboratory, Dr. Panjwani Center for Molecular Medicine and Drug Research, ICCBS, University of Karachi, University Road, Karachi 74700, Sindh, Pakistan. asmat.salim@iccs.edu
Received: July 30, 2020
Peer-review started: July 30, 2020
First decision: September 17, 2020
Revised: October 1, 2020
Accepted: October 26, 2020
Article in press: October 26, 2020
Published online: December 26, 2020
Processing time: 149 Days and 18.5 Hours
Abstract
BACKGROUND

Impaired wound healing can be associated with different pathological states. Burn wounds are the most common and detrimental injuries and remain a major health issue worldwide. Mesenchymal stem cells (MSCs) possess the ability to regenerate tissues by secreting factors involved in promoting cell migration, proliferation and differentiation, while suppressing immune reactions. Preconditioning of MSCs with small molecules having cytoprotective properties can enhance the potential of these cells for their use in cell-based therapeutics.

AIM

To enhance the therapeutic potential of MSCs by preconditioning them with isorhamnetin for second degree burn wounds in rats.

METHODS

Human umbilical cord MSCs (hU-MSCs) were isolated and characterized by surface markers, CD105, vimentin and CD90. For preconditioning, hU-MSCs were treated with isorhamnetin after selection of the optimized concentration (5 µmol/L) by cytotoxicity analysis. The migration potential of these MSCs was analyzed by the in vitro scratch assay. The healing potential of normal, and preconditioned hU-MSCs was compared by transplanting these MSCs in a rat model of a second degree burn wound. Normal, and preconditioned MSCs (IH + MSCs) were transplanted after 72 h of burn injury and observed for 2 wk. Histological and gene expression analyses were performed on day 7 and 14 after cell transplantation to determine complete wound healing.

RESULTS

The scratch assay analysis showed a significant reduction in the scratch area in the case of IH + MSCs compared to the normal untreated MSCs at 24 h, while complete closure of the scratch area was observed at 48 h. Histological analysis showed reduced inflammation, completely remodeled epidermis and dermis without scar formation and regeneration of hair follicles in the group that received IH + MSCs. Gene expression analysis was time dependent and more pronounced in the case of IH + MSCs. Interleukin (IL)-1β, IL-6 and Bcl-2 associated X genes showed significant downregulation, while transforming growth factor β, vascular endothelial growth factor, Bcl-2 and matrix metallopeptidase 9 showed significant upregulation compared to the burn wound, showing increased angiogenesis and reduced inflammation and apoptosis.

CONCLUSION

Preconditioning of hU-MSCs with isorhamnetin decreases wound progression by reducing inflammation, and improving tissue architecture and wound healing. The study outcome is expected to lead to an improved cell-based therapeutic approach for burn wounds.

Keywords: Burn wound, Isorhamnetin, Mesenchymal stem cells, Preconditioning, Wound healing, Small molecule

Core Tip: In this study, we propose an improved cell-based therapeutic approach using a cytoprotective chemical compound, isorhamnetin to precondition human umbilical cord mesenchymal stem cells (MSCs) for second degree burn wounds. The findings of this study suggest that transplantation of preconditioned MSCs in the rat burn wound model decreases wound progression by the downregulation of inflammatory cytokines and restoration of tissue architecture. The study outcome may lead to an effective cell-based treatment strategy for burn wounds to accelerate wound healing and promote skin regeneration.