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Role of mesenchymal stem cell-derived fibrinolytic factor in tissue regeneration and cancer progression

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Abstract

Tissue regeneration during wound healing or cancer growth and progression depends on the establishment of a cellular microenvironment. Mesenchymal stem cells (MSC) are part of this cellular microenvironment, where they functionally modulate cell homing, angiogenesis, and immune modulation. MSC recruitment involves detachment of these cells from their niche, and finally MSC migration into their preferred niches; the wounded area, the tumor bed, and the BM, just to name a few. During this recruitment phase, focal proteolysis disrupts the extracellular matrix (ECM) architecture, breaks cell–matrix interactions with receptors, and integrins, and causes the release of bioactive fragments from ECM molecules. MSC produce a broad array of proteases, promoting remodeling of the surrounding ECM through proteolytic mechanisms. The fibrinolytic system, with its main player plasmin, plays a crucial role in cell migration, growth factor bioavailability, and the regulation of other protease systems during inflammation, tissue regeneration, and cancer. Key components of the fibrinolytic cascade, including the urokinase plasminogen activator receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1), are expressed in MSC. This review will introduce general functional properties of the fibrinolytic system, which go beyond its known function of fibrin clot dissolution (fibrinolysis). We will focus on the role of the fibrinolytic system for MSC biology, summarizing our current understanding of the role of the fibrinolytic system for MSC recruitment and the functional consequences for tissue regeneration and cancer. Aspects of MSC origin, maintenance, and the mechanisms by which these cells contribute to altered protease activity in the microenvironment under normal and pathological conditions will also be discussed.

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Abbreviations

MSC:

Mesenchymal stem cells

ECM:

Extracellular matrix

BM:

Bone marrow

IL:

Interleukin

VEGF-A:

Vascular endothelial growth factor-A (VEGF-A)

MMP:

Matrix metalloproteinase

uPAR:

Urokinase-type plasminogen activator receptor

PAI-1:

Plasminogen activator inhibitor-1

uPA:

Urokinase-type plasminogen activator

CD:

Cluster of differentiation

FGF-2:

Fibroblast growth factor-2

TGF-β:

Transforming growth factor-β

tPA:

Tissue-type plasminogen activator

HSC:

Hematopoietic stem cell

MCP-1:

Monocyte chemoattractant protein-1

suPAR:

Soluble uPAR

PA:

Plasminogen activator

HIF-1α:

Hypoxia inducible factor α

HGF:

Hepatocyte growth factor

CRC:

Colorectal cancer

HER 2:

Human epidermal growth factor receptor 2

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Acknowledgments

We thank Stephanie C Napier for proofreading of the manuscript. This work was supported in part by grants from the Japan Society for the Promotion of Science and Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (K.H.) Grant-in-Aid for Scientific Research on Priority Areas from the MEXT (K.H.), Mitsubishi Pharma Research Foundation (K.H), Naito Grant (B.H.), Grant-in-Aid for Scientific Research on Innovative Areas from the MEXT (B.H.), Program for Improvement of the Research Environment for Young Researchers funded by the Special Coordination Funds for Promoting Science and Technology of the MEXT, Japan (B.H.).

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Authors and Affiliations

  1. Division of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan

    Beate Heissig, Douaa Dhahri, Salita Eiamboonsert & Yousef Salama

  2. Division of Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan

    Hiroshi Shimazu, Shinya Munakata & Koichi Hattori

  3. Center for Genome and Regenerative Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

    Koichi Hattori

  4. Atopy (Allergy) Center, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

    Beate Heissig

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  1. Beate Heissig
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Correspondence to Beate Heissig.

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Heissig, B., Dhahri, D., Eiamboonsert, S. et al. Role of mesenchymal stem cell-derived fibrinolytic factor in tissue regeneration and cancer progression. Cell. Mol. Life Sci. 72, 4759–4770 (2015). https://doi.org/10.1007/s00018-015-2035-7

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  • DOI: https://doi.org/10.1007/s00018-015-2035-7

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