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

By Ruth S. Waterman, Suzanne L. Tomchuck, Sarah L. Henkle, Aline M. Betancourt. PLoS ONE, 2010

1,209 citations recorded by the source corpus.

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.

Subfields: Genetics, Immunology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/a773a30c4a06d23001791193e31ef6d40b9d7af8

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. A. Keating
2. J. Karp
3. W. Fibbe
4. Maria Ester Bernardo

In Immunology

1. W. Fibbe
2. A. Keating
3. Maria Ester Bernardo

In Pulmonary and Respiratory Medicine

1. W. Fibbe
2. Maria Ester Bernardo

Citations in the corpus

• Harnessing the Mesenchymal Stem Cell Secretome for the Treatment of Cardiovascular Disease (2012, background): “…MSCs bound to nano-structured materials have yielded significant hemodynamic functional preservation within an infarcted heart model (Webber et al., 2010), and the transplantation of cells such as CPCs with immobilized IGF-1 on nano-fibers exhibited dual effects from IGF-1mediated…”
• Mesenchymal stromal cells: new directions. (2012, background): “On the basis of the divergent patterns of TLR3 versus TLR4 ligation in a short-term assay with respect to cytokine and chemokine secretion, cell migration capabilities, TGF-b secretion, and expression of the downstream effectors, SMAD3/SMAD7, Waterman et al. (2010) proposed a novel paradigm for MSC ”
• Mesenchymal stromal cells: sensors and switchers of inflammation. (2013, positive): “The switch toward MSC1 or MSC2 type may also depend on MSC stimulation through Toll-like receptors (TLRs) expressed on their surface (Waterman et al., 2010).”
• Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia (2020, neutral): “Aging and Disease • Volume 11, Number 2, April 2020 218 or double-stranded RNA from virus [18,19], like the HCoV-19.”