Combination therapy of menstrual derived mesenchymal stem cells and antibiotics ameliorates survival in sepsis

Abstract

IntroductionSepsis is a clinical syndrome associated with a severe systemic inflammation induced by infection. Although different anti-microbial drugs have been used as treatments, morbidity and mortality rates remain high. Mesenchymal stem cells (MSCs) derived from the bone marrow have demonstrated a partial protective effect in sepsis. Menstrual derived MSCs (MenSCs) emerge as an attractive candidate because they present important advantages over other sources, including improved proliferation rates and paracrine response under specific stress conditions. Here, we evaluate their therapeutic effect in a polymicrobial severe sepsis model.MethodsThe antimicrobial activity of MenSCs was determined in vitro through direct and indirect bacterial growth assays and the measurement of the expression levels of different antimicrobial peptides (AMPs) by quantitative reverse transcription-polymerase chain reaction. The therapeutic effect of MenSCs was determined in the cecal ligation and puncture (CLP) mouse model. Mice were then treated with antibiotics (AB) or MenSCs alone or in combination. The survival rates and histological and biochemical parameters were evaluated, and the systemic levels of pro- and anti-inflammatory cytokines as well as the response of specific lymphocyte subsets were determined by flow cytometry.ResultsMenSCs exerted an important antimicrobial effect in vitro, mediated by a higher expression of the AMP-hepcidin. In the CLP mouse model, MenSCs in synergy with AB (a) improved the survival rate (95 %) in comparison with saline (6 %), AB (73 %), and MenSCs alone (48 %) groups; (b) enhanced bacterial clearance in the peritoneal fluids and blood; (c) reduced organ injuries evaluated by lower concentrations of the liver enzymes alanine aminotransferase and aspartate aminotransferase; and (d) modulated the inflammatory response through reduction of pro- and anti-inflammatory cytokines without significant loss of T and B lymphocytes.ConclusionsWe conclude that MenSCs in combination with AB enhance survival in CLP-induced sepsis by acting on multiples targets. MenSCs thus constitute a feasible approach for the future clinical treatment of sepsis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0192-0) contains supplementary material, which is available to authorized users.

Prostate tumor-induced angiogenesis is blocked by exosomes derived from menstrual stem cells through the inhibition of reactive oxygen species

“…Consistently with previous reports [29, 31, 32, 37], MenSCs express CD105, CD44, CD73, CD90 and HLA-ABC, but showed negative expression for CD45, CD34, CD14 and HLA-DR (Figure S1 A). Also, mesodermal lineage induction showed positive specific staining for fat, bone and cartilage differentiation (Figure S1 B).…”

“…Menstrual fluids and bone marrow were obtained after informed consents following institutional guidelines from four healthy donors aged 24-38 years-old and two hip-operated patients aged 60-68 years-old, respectively [29, 31]. MSCs were isolated, cultured, and characterized as described previously [29, 31, 32], and cryopreserved at low passage (< 5) until use. Human umbilical vein endothelial cells (HUVEC), human pancreas adenocarcinoma MIA PaCa-2, human pancreas carcinoma PANC-1, metastatic human breast cancer MD-MB-231, metastatic human breast cancer MCF-7, metastatic human prostate adenocarcinoma PC3, metastatic human prostate carcinoma DU 145, metastatic human prostate carcinoma LNCaP and metastatic human prostate cancer VCaP cell lines were obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA).…”

Antimicrobial Activity of Mesenchymal Stem Cells: Current Status and New Perspectives of Antimicrobial Peptide-Based Therapies

“…On the other hand, current data suggest that MSCs exert strong antimicrobial effects through indirect and direct mechanisms (16–26). Indirectly, across their role in the host immune response against pathogens, especially in the dynamic coordination of the pro- and anti-inflammatory elements of the immune system (22, 27–29) or increasing the activity of phagocytes (18, 21, 25, 30, 31); and directly, by the secretion of antimicrobial peptides and proteins (AMPs) (19, 20, 23, 24, 26), and also by the expression of molecules such as indoleamine 2,3-dioxygenase (IDO) (16) and interleukin (IL)-17 (32). In fact, MSCs have been reportedly responsible of the bacterial clearance in preclinical models of sepsis (17–20, 22, 25), acute respiratory distress syndrome (ARDS) (21, 26), and cystic fibrosis infection (23).…”

“…These molecules have selective activity against a wide range of organisms including bacteria, yeasts, fungi, viruses, and even cancer cells (34). So far, MSCs have been found to constitutively express four AMPs: cathelicidin LL-37 (19, 23), human β-defensin-2 (hBD-2) (24), hepcidin (20), and lipocalin-2 (Lcn2) (26), which can be further modulated during infection and inflammation. In fact, it has been demonstrated that, in MSCs, a bacterial preconditioning induces an upregulation of LL-37, hBD-2, and hepcidin (19, 20, 24), while their preconditioning with inflammatory stimuli evoke increasing levels of LL-37 and Lcn2 (23, 26).…”

“…So far, MSCs have been found to constitutively express four AMPs: cathelicidin LL-37 (19, 23), human β-defensin-2 (hBD-2) (24), hepcidin (20), and lipocalin-2 (Lcn2) (26), which can be further modulated during infection and inflammation. In fact, it has been demonstrated that, in MSCs, a bacterial preconditioning induces an upregulation of LL-37, hBD-2, and hepcidin (19, 20, 24), while their preconditioning with inflammatory stimuli evoke increasing levels of LL-37 and Lcn2 (23, 26). In different preclinical models, MSCs-derived AMPs have demonstrated to be part of the bacterial clearance effect observed with MSCs treatment, revealing that MSCs can directly enhance the innate immune response to bacterial infection (19, 20, 23, 24, 26).…”