Basic Study
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World J Stem Cells. May 26, 2022; 14(5): 347-361
Published online May 26, 2022. doi: 10.4252/wjsc.v14.i5.347
Soluble factors secreted by human Wharton’s jelly mesenchymal stromal/stem cells exhibit therapeutic radioprotection: A mechanistic study with integrating network biology
Dharmendra Kumar Maurya, Mayuri Bandekar, Santosh Kumar Sandur
Dharmendra Kumar Maurya, Mayuri Bandekar, Santosh Kumar Sandur, Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400085, Maharashtra, India
Dharmendra Kumar Maurya, Santosh Kumar Sandur, Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094, India
Mayuri Bandekar, University of Mumbai, Kalina, Mumbai 400098, India
Author contributions: Maurya DK contributed to conceptualization, experimentation, data analysis, and writing of the manuscript; Bandekar M contributed to experimentation; Sandur SK contributed to manuscript correction and finalization; All authors have read and approve the final manuscript.
Institutional review board statement: Ethical approval for isolation and conducting experiments using human Wharton’s jelly mesenchymal stem cells was obtained from the Institutional ethical review board at Bhabha Atomic Research Centre Hospital, Mumbai, India (project numbers IC-SCR-BARC/2018/2 and BARCHMEC/14).
Institutional animal care and use committee statement: All animal experiments were carried out according to the internationally accepted norms and principles. For conducting animal experiments, the guidelines issued by the Institutional Animal Ethics Committee of Bhabha Atomic Research Centre, Government of India, were strictly followed (BAEC/15/18).
Conflict-of-interest statement: The authors do not have a potential conflict of interest concerning the research, authorship, and/or publication of this article.
Data sharing statement: No additional data is available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised 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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Dharmendra Kumar Maurya, BSc, MSc, PhD, Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, 3-82-S, A-block, Modular Laboratory, Mumbai 400085, Maharashtra, India. dkmaurya@barc.gov.in
Received: January 28, 2022
Peer-review started: January 28, 2022
First decision: March 11, 2022
Revised: March 25, 2022
Accepted: May 8, 2022
Article in press: May 8, 2022
Published online: May 26, 2022
ARTICLE HIGHLIGHTS
Research background

Exposure to high doses of ionizing radiation is known to cause acute radiation syndrome, such as damage to hematopoietic, gastrointestinal, and neurovascular systems depending on the dose. To avoid acute radiation syndrome, regenerative therapy will be a good therapeutic option. Therefore, stem cell therapy may be one of the promising candidates to ameliorate acute radiation syndrome because of its regenerative and damage sensing potential.

Research motivation

Stem cells isolated from Wharton’s jelly of the umbilical cord are a unique source of mesenchymal stromal/stem cells (MSCs), which have been reported to be safe when administered to recipients without inducing any adverse effects or teratoma formation. Recently, we reported that human Wharton’s jelly-MSCs (hWJ-MSCs) and their conditioned medium (CM) have significant therapeutic radioprotective potential in lethally irradiated mice. These findings motivated us to identify a unique feature of hWJ-MSCs over other sources of stem cells for the understanding of its radioprotective mechanism and deciphering the role of the granulocyte-colony stimulating factor (G-CSF) present in hWJ-MSC-CM.

Research objectives

The main objective was to understand the radioprotective mechanism of soluble factors secreted by hWJ-MSCs and identification of their unique genes.

Research methods

Propidium iodide staining, endogenous spleen colony-forming assay, and survival study were carried out for radioprotection studies. Homeostasis-driven proliferation assay was performed for in vivo lymphocyte proliferation measurement. Neutralization of G-CSF with anti-G-CSF was done to investigate the role of G-CSF in therapeutic radioprotection. Analysis of RNAseq data was performed to find the unique genes of WJ-MSCs by comparing them with bone marrow mesenchymal stem cells, embryonic stem cells, and human fibroblasts. Gene enrichment analysis and protein-protein interaction network were used for pathway analysis.

Research results

Co-culture of irradiated murine splenic lymphocytes with WJ-MSCs offered significant radioprotection to lymphocytes. WJ-MSC transplantation increased the homeostasis-driven proliferation of the lymphocytes. Neutralization of WJ-MSC-CM with G-CSF antibody abolished therapeutic radioprotection. Transcriptome analysis showed that WJ-MSCs share several common genes with bone marrow MSCs and embryonic stem cells and express a high level of unique genes such as interleukin (IL)1-α, IL1-β, IL-6, CXCL3, CXCL5, CXCL8, CXCL2, CCL2, FLT-1, and IL-33. It was also observed that WJ-MSCs preferentially modulated several cellular pathways and processes that are responsible for the repair and regeneration of damaged tissues compared to other sources of stem cells. Cytokine-based network analysis showed that most of the radiosensitive tissues have a more complex network for the elevated cytokines.

Research conclusions

This study showed the role of cytokine G-CSF present in WJ-MSC-CM in eliciting therapeutic radioprotection. Systemic infusion of WJ-MSC-CM may have significant potential for treating accidental radiation exposed victims.

Research perspectives

WJ-MSC-CM holds significant therapeutic radioprotective ability and has translational potential for its use during radiation accidents.