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The secretome of mesenchymal stem cells and oxidative stress: challenges and opportunities in cell-free regenerative medicine

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Abstract

Over the last decade, mesenchymal stem cells (MSCs) have been considered a suitable source for cell-based therapy, especially in regenerative medicine. First, the efficacy and functions of MSCs in clinical applications have been attributed to their differentiation ability, called homing and differentiation. However, it has recently been confirmed that MSCs mostly exert their therapeutic effects through soluble paracrine bioactive factors and extracellular vesicles, especially secretome. These secreted components play critical roles in modulating immune responses, improving the survival, and increasing the regeneration of damaged tissues. The secretome content of MSCs is variable under different conditions. Oxidative stress (OS) is one of these conditions that is highly important in MSC therapy and regenerative medicine. High levels of reactive oxygen species (ROS) are produced during isolation, cell culture, and transplantation lead to OS, which induces cell death and apoptosis and limits the efficacy of their regeneration capability. In turn, the preconditioning of MSCs in OS conditions contributes to the secretion of several proteins, cytokines, growth factors, and exosomes, which can improve the antioxidant potential of MSCs against OS. This potential of MSC secretome has turned it into a new promising cell-free tissue regeneration strategy.

This review provides a view of MSC secretome under OS conditions, focusing on different secretome contents of MSCs and thier possible therapeutic potential against cell therapy.

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Data availability

Input data for the analyses are available from the corresponding authors on request.

Abbreviations

MSCs:

Mesenchymal stem cells

OS:

Oxidative stress

ROS:

Reactive oxygen species

IGF:

Insulin-like growth factor

PEDF:

Pigment epithelium-derived factor

VEGF:

Vascular endothelial growth factor

IGF-1:

Insulin-like growth factor-1

BMP-2:

Bone morphogenic protein-2

BMP-4:

Bone morphogenic protein-4

M-CSF:

Monocyte colony stimulating factor

RANKL:

Receptor activator of nuclear factor kappa-B ligand

G-CSF:

Granulocyte colony stimulating factor

SDF-1:

Stromal-cell-derived factor 1

LIF:

Leukemia inhibitory factor

VE-cadherin:

Vein endothelial cadherin

CNS:

Central nervous system

NGF:

Nerve growth factor

BDNF:

Brain derived neurotrophic factor

GDNF:

Glial derived neurotrophic factor

NT-3:

Neurotrophin-3

FGF-2:

Fibroblast growth factor-2

EPO:

Erythropoietin

CNTF:

Ciliary neurotrophic factor

PNS:

Peripheral nervous system

bFGF:

Basic fibroblast growth factor

SDF-1α:

Stromal cell-derived factor 1 α

MCP-1:

Monocyte chemotactic protein-1

STC-1:

Stanniocalcin-1

MHC-I:

Major histocompatibility complex I

PGE2:

Prostaglandin E2

TGF-β:

Transforming growth factor beta

IDO:

Indoleamine-pyrrole 2,3-dioxygenase

GVHD:

Graft versus host disease

Nrf2:

Erythroid 2-related factor

HIF:

Hypoxia-inducible factor

CAT:

Catalase

SOD:

Superoxide dismutase

GSH:

Glutathione

GPx:

Glutathione peroxidase

TrxR:

Thioredoxin reductase

AD-MSC:

Adipose tissue-derived MSCs

Ang-1:

Aangiogenin-1

HGF:

Hepatocyte growth factor

PDGF:

Platelet-derived growth factor

iPSCs:

Induced pluripotent stem cells

DPSCs:

Include dental pulp stem cells

CDPSCs:

Dental pulp's inferior duct' stem cells

EVs:

extracellular vesicles

MVs:

Micro vesicles

ILVs:

Intraluminal vesicles

MVBs:

Multi-vesicular bodies

PRDX1:

Peroxiredoxin 1

TXN1:

Thioredoxin 1

ApoD:

Apolipoprotein D

RPE:

Retinal pigment cells

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Funding

This work was supported by a grant from Tabriz University of Medical Sciences, Deputy for Research and Technology, grant number: (63680)- IR. TBZMED. REC. 1399. 036.

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  1. Bahareh Rahimi and Mohammad Panahi have contributed equally to this article.

Authors and Affiliations

  1. Student Research Committee, Iran University of Medical Sciences, Tehran, Iran

    Bahareh Rahimi

  2. Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

    Mohammad Panahi

  3. Student Research Committee, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

    Mohammad Panahi

  4. Department of Medical Biotechnology, Faculty of Allied Medical Sciences, Iran University of Medical Sciences, Hemmat Highway, Tehran, Iran

    Bahareh Rahimi, Neda Saraygord-Afshari & Davod Jafari

  5. Department of Plant and Animal Biology, University of Esfahan, Esfahan, Iran

    Neda Taheri

  6. Department of Biochemistry, Faculty of Sciences, Ege University, Izmir, Turkey

    Merve Bilici

  7. Drug Applied Research Center and Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Golgasht Street, 5166/15731, Tabriz, Iran

    Effat Alizadeh

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BR and MP contributed equally and shared the first co-authorship. They wrote all sections of the manuscript. DJ wrote some sections of the original draft and revised the manuscript critically for important intellectual content. MB worked on the literature research and original draft preparation. EA contributed to the conceptualization, literature research, writing the discussion and conclusion, and editing, reviewing, and organizing the final draft.

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Rahimi, B., Panahi, M., Saraygord-Afshari, N. et al. The secretome of mesenchymal stem cells and oxidative stress: challenges and opportunities in cell-free regenerative medicine. Mol Biol Rep 48, 5607–5619 (2021). https://doi.org/10.1007/s11033-021-06360-7

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