Fibroblast Activation Protein (FAP) Is Essential for the Migration of Bone Marrow Mesenchymal Stem Cells through RhoA Activation

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Abstract

Background

The ability of human bone marrow mesenchymal stem cells (BM-MSCs) to migrate and localize specifically to injured tissues is central in developing therapeutic strategies for tissue repair and regeneration. Fibroblast activation protein (FAP) is a cell surface serine protease expressed at sites of tissue remodeling during embryonic development. It is also expressed in BM-MSCs, but not in normal tissues or cells. The function of FAP in BM-MSCs is not known.

Principal Findings

We found that depletion of FAP proteins significantly inhibited the migration of BM-MSCs in a transwell chemotaxis assay. Such impaired migration ability of BM-MSCs could be rescued by re-expressing FAP in these cells. We then demonstrated that depletion of FAP activated intracellular RhoA GTPase. Consistently, inhibition of RhoA activity using a RhoA inhibitor rescued its migration ability. Inhibition of FAP activity with an FAP-specific inhibitor did not affect the activation of RhoA or the migration of BM-MSCs. Furthermore, the inflammatory cytokines interleukin-1beta (IL-1β) and transforming growth factor-beta (TGF-β) upregulated FAP expression, which coincided with better BM-MSC migration.

Conclusions

Our results indicate FAP plays an important role in the migration of BM-MSCs through modulation of RhoA GTPase activity. The peptidase activity of FAP is not essential for such migration. Cytokines IL-1β and TGF-β upregulate the expression level of FAP and thus enhance BM-MSC migration.

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Most cited references 56

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Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha.

Matthew Kraman, Paul J Bambrough, James Arnold … (2010)

The stromal microenvironment of tumors, which is a mixture of hematopoietic and mesenchymal cells, suppresses immune control of tumor growth. A stromal cell type that was first identified in human cancers expresses fibroblast activation protein-α (FAP). We created a transgenic mouse in which FAP-expressing cells can be ablated. Depletion of FAP-expressing cells, which made up only 2% of all tumor cells in established Lewis lung carcinomas, caused rapid hypoxic necrosis of both cancer and stromal cells in immunogenic tumors by a process involving interferon-γ and tumor necrosis factor-α. Depleting FAP-expressing cells in a subcutaneous model of pancreatic ductal adenocarcinoma also permitted immunological control of growth. Therefore, FAP-expressing cells are a nonredundant, immune-suppressive component of the tumor microenvironment.

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Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone.

E Horwitz, P L Gordon, W. K. K. Koo … (2002)

Treatment with isolated allogeneic mesenchymal cells has the potential to enhance the therapeutic effects of conventional bone marrow transplantation in patients with genetic disorders affecting mesenchymal tissues, including bone, cartilage, and muscle. To demonstrate the feasibility of mesenchymal cell therapy and to gain insight into the transplant biology of these cells, we used gene-marked, donor marrow-derived mesenchymal cells to treat six children who had undergone standard bone marrow transplantation for severe osteogenesis imperfecta. Each child received two infusions of the allogeneic cells. Five of six patients showed engraftment in one or more sites, including bone, skin, and marrow stroma, and had an acceleration of growth velocity during the first 6 mo postinfusion. This improvement ranged from 60% to 94% (median, 70%) of the predicted median values for age- and sex-matched unaffected children, compared with 0% to 40% (median, 20%) over the 6 mo immediately preceding the infusions. There was no clinically significant toxicity except for an urticarial rash in one patient just after the second infusion. Failure to detect engraftment of cells expressing the neomycin phosphotransferase marker gene suggested the potential for immune attack against therapeutic cells expressing a foreign protein. Thus, allogeneic mesenchymal cells offer feasible posttransplantation therapy for osteogenesis imperfecta and likely other disorders originating in mesenchymal precursors.

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Adhesion signaling - crosstalk between integrins, Src and Rho.

Stephan Huveneers, Erik Danen (2009)

Interactions between cells and the extracellular matrix coordinate signaling pathways that control various aspects of cellular behavior. Integrins sense the physical properties of the extracellular matrix and organize the cytoskeleton accordingly. In turn, this modulates signaling pathways that are triggered by various other transmembrane receptors and augments the cellular response to growth factors. Over the past years, it has become clear that there is extensive crosstalk between integrins, Src-family kinases and Rho-family GTPases at the heart of such adhesion signaling. In this Commentary, we discuss recent advances in our understanding of the dynamic regulation of the molecular connections between these three protein families. We also discuss how this signaling network can regulate a range of cellular processes that are important for normal tissue function and disease, including cell adhesion, spreading, migration and mechanotransduction.

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Author and article information

Contributors

Eva Mezey: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 13 February 2014

Volume: 9

Issue: 2

Electronic Location Identifier: e88772

Affiliations

[1 ]Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan, Republic of China

[2 ]Vaccine Research and Development Center, National Health Research Institutes, Miaoli, Taiwan, Republic of China

[3 ]Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan, Republic of China

[4 ]Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, Republic of China

National Institutes of Health, United States of America

Author notes

* E-mail: 970304@ 123456nhri.org.tw (K-MC); xchen@ 123456nhri.org.tw (XC)

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: KMC XC SCH. Performed the experiments: KMC YRC. Analyzed the data: KMC SCH YRC. Contributed reagents/materials/analysis tools: MYL WTJ RHC. Wrote the paper: KMC XC.

Article

Publisher ID: PONE-D-13-44775

DOI: 10.1371/journal.pone.0088772

PMC ID: 3923824

PubMed ID: 24551161

SO-VID: 3922adf4-7700-40c8-bc15-ea45ea805e6c

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 1 November 2013

Date accepted : 15 January 2014

Page count

Pages: 11

Funding

The work was supported by (NRPGMNRPGM-98LC009), National Science Council (NSC 98-3112-B-400-013), Taiwan and National Health Research Institutes, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Fibroblast Activation Protein (FAP) Is Essential for the Migration of Bone Marrow Mesenchymal Stem Cells through RhoA Activation

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Abstract

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Principal Findings

Conclusions

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PLOS Climate

Most cited references 56

Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha.

Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone.

Adhesion signaling - crosstalk between integrins, Src and Rho.

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