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Cited by 1,238Mesenchymal stem cell researchImmune Response and InflammationImmunotherapy and Immune Responses

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

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Waterman, Ruth S., Tomchuck, Suzanne L., Henkle, Sarah L., Betancourt, Aline M.·2010·PLoS ONE
DOI 10.1371/journal.pone.0010088PMC PMC2859930
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Abstract

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 T-lymphocyte 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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Authors
Waterman, R. S., Tomchuck, S. L., Henkle, S. L., & Betancourt, A. M.
Affiliations
Tulane University (US)
Corresponding author
Betancourt, Aline M.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2010-04-26
Volume
5
Issue
4
Pages
e10088
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0010088
PMC
PMC2859930
OpenAlex
W2073024911
Cited by
1,238
References
2
Citations by year
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FWCI
21.14
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • U.S. Department of Defense (OC073102)
  • National Institutes of Health (1P20RR20152-01)
  • National Center for Research Resources (1P20RR20152-01, P20RR020152)
Topics
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
mesenchymal stem cells, Toll-like receptors, TLR3, TLR4, immunomodulation, pro-inflammatory mediators, T cell activation, peripheral blood mononuclear cells, damage-associated molecular patterns, stem cell therapy
MeSH terms
Cell Movement, Humans, Immune System, Immunity, Inflammation, Monocytes, Phenotype, Coculture Techniques, Toll-Like Receptors, Toll-Like Receptor 3, Toll-Like Receptor 4, Mesenchymal Stem Cells

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