A New Mesenchymal Stem Cell (MSC) Paradigm: Polarization into a Pro-Inflammatory MSC1 or an Immunosuppressive MSC2 Phenotype

被引:929
作者
Waterman, Ruth S. [1 ]
Tomchuck, Suzanne L. [2 ]
Henkle, Sarah L. [2 ]
Betancourt, Aline M. [2 ]
机构
[1] Tulane Univ, Dept Anesthesiol, New Orleans, LA 70118 USA
[2] Tulane Univ, Dept Microbiol & Immunol, Tulane Canc Ctr, Tulane Ctr Gene Therapy, New Orleans, LA 70118 USA
来源
PLOS ONE | 2010年 / 5卷 / 04期
基金
美国国家卫生研究院;
关键词
TOLL-LIKE RECEPTORS; MARROW STROMAL CELLS; SUPPRESS T-LYMPHOCYTE; STEM/PROGENITOR CELLS; GENE-EXPRESSION; TGF-BETA; RESPONSES; MODULATION; MACROPHAGES; INHIBIT;
D O I
10.1371/journal.pone.0010088
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background: Our laboratory and others reported that the stimulation of specific Toll-like receptors (TLRs) affects the immune modulating responses of human multipotent mesenchymal stromal cells (hMSCs). Toll-like receptors recognize "danger" signals, and their activation leads to profound cellular and systemic responses that mobilize innate and adaptive host immune cells. The danger signals that trigger TLRs are released following most tissue pathologies. Since danger signals recruit immune cells to sites of injury, we reasoned that hMSCs might be recruited in a similar way. Indeed, we found that hMSCs express several TLRs (e. g., TLR3 and TLR4), and that their migration, invasion, and secretion of immune modulating factors is drastically affected by specific TLR-agonist engagement. In particular, we noted diverse consequences on the hMSCs following stimulation of TLR3 when compared to TLR4 by our low-level, short-term TLR-priming protocol. Principal Findings: Here we extend our studies on the effect on immune modulation by specific TLR-priming of hMSCs, and based on our findings, propose a new paradigm for hMSCs that takes its cue from the monocyte literature. Specifically, that hMSCs can be polarized by downstream TLR signaling into two homogenously acting phenotypes we classify here as MSC1 and MSC2. This concept came from our observations that TLR4-primed hMSCs, or MSC1, mostly elaborate pro-inflammatory mediators, while TLR3-primed hMSCs, or MSC2, express mostly immunosuppressive ones. Additionally, allogeneic co-cultures of TLR-primed MSCs with peripheral blood mononuclear cells (PBMCs) predictably lead to suppressed Tlymphocyte activation following MSC2 co-culture, and permissive T-lymphocyte activation in co-culture with MSC1. Significance: Our study provides an explanation to some of the conflicting reports on the net effect of TLR stimulation and its downstream consequences on the immune modulating properties of stem cells. We further suggest that MSC polarization provides a convenient way to render these heterogeneous preparations of cells more uniform while introducing a new facet to study, as well as provides an important aspect to consider for the improvement of current stem cell-based therapies.
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页数:14
相关论文
共 57 条
[1]   Immunomodulation by mesenchymal stem cells - A potential therapeutic strategy for type 1 diabetes [J].
Abdi, Reza ;
Fiorina, Paolo ;
Adra, Chaker N. ;
Atkinson, Mark ;
Sayegh, Mohamed H. .
DIABETES, 2008, 57 (07) :1759-1767
[2]   Human mesenchymal stem cells modulate allogeneic immune cell responses [J].
Aggarwal, S ;
Pittenger, MF .
BLOOD, 2005, 105 (04) :1815-1822
[3]   Assessment of the tissue distribution of transplanted human endothelial progenitor cells by radioactive labeling [J].
Aicher, A ;
Brenner, W ;
Zuhayra, M ;
Badorff, C ;
Massoudi, S ;
Assmus, B ;
Eckey, T ;
Henze, E ;
Zeiher, AM ;
Dimmeler, S .
CIRCULATION, 2003, 107 (16) :2134-2139
[4]   Toll-like receptors and their signaling mechanisms [J].
Akira, S ;
Sato, S .
SCANDINAVIAN JOURNAL OF INFECTIOUS DISEASES, 2003, 35 (09) :555-562
[5]   Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness [J].
Beyth, S ;
Borovsky, Z ;
Mevorach, D ;
Liebergall, M ;
Gazit, Z ;
Aslan, H ;
Galun, E ;
Rachmilewitz, J .
BLOOD, 2005, 105 (05) :2214-2219
[6]   Cross-talk between the Notch and TGF-β signaling pathways mediated by interaction of the Notch intracellular domain with Smad3 [J].
Blokzijl, A ;
Dahlqvist, C ;
Reissmann, E ;
Falk, A ;
Moliner, A ;
Lendahl, U ;
Ibáñez, CF .
JOURNAL OF CELL BIOLOGY, 2003, 163 (04) :723-728
[7]  
Caplan A I, 1995, Connect Tissue Res, V31, pS9, DOI 10.3109/03008209509116826
[8]   Role of toll-like receptors on human adipose-derived stromal cells [J].
Cho, Hyun Hwa ;
Bae, Yong Chan ;
Jung, Jin Sup .
STEM CELLS, 2006, 24 (12) :2744-2752
[9]   Ovarian cancers overexpress the antimicrobial protein hCAP-18 and its derivative LL-37 increases ovarian cancer cell proliferation and invasion [J].
Coffelt, Seth B. ;
Waterman, Ruth S. ;
Florez, Luisa ;
zu Bentrup, Kerstin Honer ;
Zwezdaryk, Kevin J. ;
Tomchuck, Suzanne L. ;
LaMarca, Heather L. ;
Danka, Elizabeth S. ;
Morris, Cindy A. ;
Scandurro, Aline B. .
INTERNATIONAL JOURNAL OF CANCER, 2008, 122 (05) :1030-1039
[10]   Leucine Leucine-37 Uses Formyl Peptide Receptor-Like 1 to Activate Signal Transduction Pathways, Stimulate Oncogenic Gene Expression, and Enhance the Invasiveness of Ovarian Cancer Cells [J].
Coffelt, Seth B. ;
Tomchuck, Suzanne L. ;
Zwezdaryk, Kevin J. ;
Danka, Elizabeth S. ;
Scandurro, Aline B. .
MOLECULAR CANCER RESEARCH, 2009, 7 (06) :907-915