DSP30 enhances the immunosuppressive properties of mesenchymal stromal cells and protects their suppressive potential from lipopolysaccharide effects: A potential role of adenosine.
Multipotent mesenchymal stromal cells (MSC) are imbued with an immunosuppressive phenotype that extends to several immune system cells. In this study, we evaluated how distinct Toll-like receptor (TLR) agonists impact immunosuppressive properties of bone marrow (BM)-MSC and explored the potential mechanisms involved. We show that TLR4 stimulation by lipopolysaccharide (LPS) restricted the ability of MSC to suppress the proliferation of T lymphocytes, increasing the gene expression of interleukin (IL)-1β and IL-6. In contrast, stimulation of TLR9 by DSP30 induced proliferation and the suppressive potential of BM-MSC, coinciding with reducing tumor necrosis factor (TNF)-α expression, increased expression of transforming growth factor (TGF)-β1, increased percentages of BM-MSC double positive for the ectonucleotidases CD39+CD73+ and adenosine levels. Importantly, following simultaneous stimulation with LPS and DSP30, BM-MSC's ability to suppress T lymphocyte proliferation was comparable with that of non-stimulated BM-MSC levels. Moreover, stimulation of BM-MSC with LPS reduced significantly the gene expression levels, on co-cultured T lymphocyte, of IL-10 and interferon (IFN)γ, a cytokine with potential to enhance the immunosuppression mediated by MSC and ameliorate the clinical outcome of patients with graft-versus-host disease (GVHD). Altogether, our findings reiterate the harmful effects of LPS on MSC immunosuppression, besides indicating that DSP30 could provide a protective effect against LPS circulating in the blood of GVHD patients who receive BM-MSC infusions, ensuring a more predictable immunosuppressive effect. The novel effects and potential mechanisms following the stimulation of BM-MSC by DSP30 might impact their clinical use, by allowing the derivation of optimal "licensing" protocols for obtaining therapeutically efficient MSC.
Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, São Paulo, Brazil; Centro de Terapia Celular, Fundação Hemocentro de Ribeirão Preto, São Paulo, Brazil.
Bruno
B
Sangiorgi
Centro de Terapia Celular, Fundação Hemocentro de Ribeirão Preto, São Paulo, Brazil.
Helder Teixeira
HT
De Freitas
Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, São Paulo, Brazil; Centro de Terapia Celular, Fundação Hemocentro de Ribeirão Preto, São Paulo, Brazil.
Josiane Lilian Dos Santos
JL
Schiavinato
Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, São Paulo, Brazil; Centro de Terapia Celular, Fundação Hemocentro de Ribeirão Preto, São Paulo, Brazil.
Vitor
V
Leão
Faculdade de Ceilândia, Universidade de Brasília, Brasília, Brazil.
Rodrigo
R
Haddad
Centro de Terapia Celular, Fundação Hemocentro de Ribeirão Preto, São Paulo, Brazil.
Maristela Delgado
MD
Orellana
Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, São Paulo, Brazil.
Vitor Marcel
VM
Faça
Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, São Paulo, Brazil.
Germano Aguiar
GA
Ferreira
Centro de Terapia Celular, Fundação Hemocentro de Ribeirão Preto, São Paulo, Brazil.
Dimas Tadeu
DT
Covas
Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, São Paulo, Brazil; Centro de Terapia Celular, Fundação Hemocentro de Ribeirão Preto, São Paulo, Brazil.
Marco Antônio
MA
Zago
Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, São Paulo, Brazil; Centro de Terapia Celular, Fundação Hemocentro de Ribeirão Preto, São Paulo, Brazil. Electronic address: rapane@gmail.com.
Rodrigo Alexandre
RA
Panepucci
D000241:Adenosine / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009841:Oligonucleotides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051193:Toll-Like Receptors / Q000378:metabolism
D015703:Antigens, CD; C539572:CpG-ODN DSP30; D007166:Immunosuppressive Agents; D008024:Ligands; D008070:Lipopolysaccharides; D009841:Oligonucleotides; D051193:Toll-Like Receptors; D000241:Adenosine
immunosuppression; inflammatory factors; multipotent mesenchymal stromal cells; toll-like receptors