Mesenchymal Stromal Cells Affect Disease Outcomes via Macrophage Polarization

Mesenchymal stromal cells (MSCs) are multipotent and self-renewable cells that reside in almost all postnatal tissues. In recent years, many studies have reported the effect of MSCs on the innate and adaptive immune systems. MSCs regulate the proliferation, activation, and effector function of T lymphocytes, professional antigen presenting cells (dendritic cells, macrophages, and B lymphocytes), and NK cells via direct cell-to-cell contact or production of soluble factors including indoleamine 2,3-dioxygenase, prostaglandin E2, tumor necrosis factor-stimulated gene/protein 6, nitric oxide, and IL-10. MSCs are also able to reprogram macrophages from a proinflammatory M1 phenotype toward an anti-inflammatory M2 phenotype capable of regulating immune response. Because of their capacity for differentiation and immunomodulation, MSCs have been used in many preclinical and clinical studies as possible new therapeutic agents for the treatment of autoimmune, degenerative, and inflammatory diseases. In this review, we discuss the central role of MSCs in macrophage polarization and outcomes of diseases such as wound healing, brain/spinal cord injuries, and diseases of heart, lung, and kidney in animal models

Mesenchymal stem cell-derived extracellular vesicles affect disease outcomes via transfer of microRNAs

Abstract Mesenchymal stem cells (MSCs) are adult stromal cells with the capacity to differentiate into multiple types of cells. MSCs represent an attractive option in regenerative medicine due to their multifaceted abilities for tissue repair, immunosuppression, and anti-inflammation. Recent studies demonstrate that MSCs exert their effects via paracrine activity, which is at least partially mediated by extracellular vesicles (EVs). MSC-derived EVs (MSC-EVs) could mimic the function of parental MSCs by transferring their components such as DNA, proteins/peptides, mRNA, microRNA (miRNA), lipids, and organelles to recipient cells. In this review, we aim to summarize the mechanism and role of miRNA transfer in mediating the effects of MSC-EVs in the models of human diseases. The first three sections of the review discuss the sorting of miRNAs into EVs, uptake of EVs by target cells, and functional transfer of miRNAs via EVs. Then, we describe the composition of miRNAs in MSC-EVs. Next, we provide the existing evidence that MSC-EVs affect the outcomes of renal, liver, heart, and brain diseases by transferring their miRNA contents. In conclusion, EV-mediated miRNA transfer plays an important role in disease-modulating capacity of MSCs

miR-10a in Peripheral Blood Mononuclear Cells Is a Biomarker for Sepsis and Has Anti-Inflammatory Function

Background. Recent literature has reported the use of circulating microRNAs (miRNAs) as biomarkers for sepsis. Immune cells play an essential role in the pathophysiology of sepsis. The aim of this prospective study was to identify miRNAs in peripheral blood mononuclear cells (PBMC) that could differentiate between sepsis and infection based on Sepsis-3 definition. Methods. A total of 62 patients (41 with sepsis and 21 with infection suffering from pneumonia but without sepsis) and 20 healthy controls were enrolled into the study. PBMC at admission were examined for a panel of 4 miRNAs (miR-10a, miR-17, miR-27a, and miR-125b), which have been documented to participate in inflammatory response in immune cells, via qRT-PCR. Data were validated in a mouse model of sepsis induced via cecal ligation and puncture (CLP) and THP-1 monocytes. Results. miR-10a levels in PBMC at admission were significantly lower in sepsis patients compared with patients with infection and healthy controls. miR-10a levels were negatively correlated with disease severity scores as well as levels for c-reactive protein and procalcitonin. In addition, low miR-10a expression had a diagnostic value for sepsis and a prognostic value for 28-day mortality in receiving operating characteristic analysis. Compared with infection patients and healthy controls, PBMC from sepsis patients also had higher levels of mitogen-activated kinase kinase kinase 7 (MAP3K7), a known target protein of miR-10a and an activator of the NF-κB pathway. In the mouse model of CLP-induced sepsis, miR-10a levels in PBMC were significantly decreased as early as 8 h after CLP. Overexpression of miR-10a in THP-1 cells significantly reduced the expression of MAP3K7 and proinflammatory cytokines including IL-6, TNF-α, and MCP-1. Conclusions. PBMC miR-10a levels are decreased in sepsis and negatively correlated with the disease severity. Levels of miR-10a could distinguish between sepsis and infection and predict 28-day mortality. miR-10a plays an anti-inflammatory role in the pathogenesis of sepsis

Human adipose-derived mesenchymal stem cells alleviate obliterative bronchiolitis in a murine model via IDO

Abstract Background Long-term survival of lung transplantation is hindered by the development of obliterative bronchiolitis (OB). Adipose-derived stem cells (ASCs) were documented to have more potent immunosuppressive ability than mesenchymal stem cells (MSCs) from bone marrow and placenta. The goal of our study is to evaluate the effect of repeated administration of ASCs on OB and the involvement of indoleamine 2,3-dioxygenase (IDO) mediating the protective effect of ASCs in a heterotopic tracheal transplantation (HTT) model. Methods For studies in vitro, ASCs were treated with interferon-γ (IFN-γ). For in vivo study, tracheas from BALB/c or C57BL/6 donors were transplanted into C57BL/6 recipients to create a HTT model. On days 0, 1, 3, 5, 8, 12, 15, 20 and 25 post-transplant, the allogeneic recipient mice were administered intravenously with phosphate buffered saline, 1 × 106 human ASCs, or 1 × 106 human ASCs plus 1-methyltryptophan (1-MT), an IDO inhibitor. On days 3, 7, 14 and 28, serum, trachea and spleen samples were harvested for analysis. Results ASCs homed to heterotopic tracheal grafts after infusion. Multiple doses of ASCs significantly increased tracheal IDO levels in allografts. There were significant increases in graft and serum IFN-γ levels in allografts compared with isografts. IFN-γ elevated IDO expression and activity in ASCs in vitro. ASCs alleviated OB in allografts as evidenced by reduced epithelial loss, epithelial apoptosis, and intraluminal obstruction. The effects of ASCs on OB were blocked by 1-MT. 1-MT also blocked the alterations in pro and anti-inflammatory cytokines as well as CD3+ T cell infiltration induced by ASCs. ASCs induced not only splenic levels of CD4+CD25+Foxp3+ regulatory T cells (Treg) but also IL-10 and TGF-β-producing Treg. Furthermore, IDO inhibition abolished the changes of splenic Treg induced by ASCs. In addition, Treg reduction by cyclophosphamide treatment did not alter the effects of ASCs on tracheal IDO expression in allografts confirming Treg induction is downstream of IDO. Conclusions Repeated doses of ASCs are capable of ameliorating OB. ASCs act at least in part via elevating IDO expression. ASCs promote the generation of Treg and suppress T cell infiltration via an IDO-dependent mechanism

Factor Analysis of Genetic Parameters for Body Conformation Traits in Dual-Purpose Simmental Cattle

In this study, we estimated the genetic parameters for 6 composite traits and 27 body conformation traits of 1016 dual-purpose Simmental cattle reared in northwestern China from 2010 to 2019 using a linear animal mixed model. To integrate these traits, a variety of methods were used as follows: (1) genetic parameters estimates for composite and individual body conformation traits based on the pedigree relationship matrix (A) and combined genomic-pedigree relationship matrix (H); (2) factor analysis to explore the relationships among body conformation traits; and (3) genetic parameters of factor scores estimated using A and H, and the correlations of EBVs of the factor scores and EBVs of the composite traits. Heritability estimates of the composite traits using A and H were low to medium (0.07–0.47). The 24 common latent factors explained 96.13% of the total variance. Among factors with eigenvalues ≥ 1, F1 was mainly related to body frame, muscularity, and rump; F2 was related to feet and legs; F3, F4, F5, and F6 were related to teat placement, teat size, udder size, and udder conformation; and F7 was related to body frame. Single-trait analysis of factor scores yielded heritability estimates that were low to moderate (0.008–0.43 based on A and 0.04–0.43 based on H). Spearman and Pearson correlations, derived from the best linear unbiased prediction analysis of composite traits and factor scores, showed a similar pattern. Thus, incorporating factor analysis into the morphological evaluation to simplify the assessment of body conformation traits may improve the genetics of dual-purpose Simmental cattle

High‐Performance Industrial‐Grade CsPbBr3 Single Crystal by Solid–Liquid Interface Engineering

Abstract All‐inorganic metal halide perovskite CsPbBr3 crystal is regarded as an attractive alternative to high purity Ge and CdZnTe for room temperature γ‐ray detection. However, high γ‐ray resolution is only observable in small CsPbBr3 crystal; more practical and deployable large crystal exhibits very low, and even no detection efficiency, thereby thwarting prospects for cost‐effective room temperature γ‐ray detection. The poor performance of large crystal is attributed to the unexpected secondary phase inclusion during crystal growth, which traps the generated carriers. Here, the solid–liquid interface during crystal growth is engineered by optimizing the temperature gradient and growth velocity. This minimizes the unfavorable formation of the secondary phase, leading to industrial‐grade crystals with a diameter of 30 mm. This excellent‐quality crystal exhibits remarkably high carrier mobility of 35.4 cm2 V−1 s−1 and resolves the peak of 137Cs@ 662 keV γ‐ray at an energy resolution of 9.91%. These values are the highest among previously reported large crystals

Mesenchymal Stem Cell-Educated Macrophages Ameliorate LPS-Induced Systemic Response

Both bone marrow and adipose-derived mesenchymal stem cells (ASCs) have immunomodulatory effects. The goal of this study was to determine whether ASCs-educated macrophages could directly ameliorate LPS-induced systemic response in a mouse model. Mouse peritoneal macrophages were cocultured with ASCs in a Transwell system for 2 days to educate macrophages. Mice were divided into 5 groups: control, LPS, LPS + ASCs, LPS + untreated macrophages, and LPS + educated macrophages. Educated macrophages decreased lung inflammation, weight loss, pulmonary edema, and inflammatory cytokine response. In vitro, ASCs increased expression of M2 macrophages independent of direct cell-to-cell contact when macrophages were treated with LPS or serum from patients with acute respiratory distress syndrome (ARDS). When macrophages were cultured with serum from ARDS patients who were treated with ASCs or placebo in our previous clinical trial, there was no difference in M2 macrophage levels before and after ASCs treatment indicating a suboptimal response to the treatment protocol. ASCs also reduced the levels of LPS-induced proinflammatory cytokines in vitro which were mimicked by IL-10 and blocked by antibodies for IL-10 and IL-10 receptor supporting the notion that educated macrophages exert their anti-inflammatory effects via IL-10-dependent mechanisms

Additional file 1: Figure S1. of Adipose-derived mesenchymal stem cells modulate CD14++CD16+ expression on monocytes from sepsis patients in vitro via prostaglandin E2

Cytokines and COX-2/PGE2 levels in freshly isolated monocytes. Monocytes were isolated and cultured for 24 h from sepsis patients (n = 6) and healthy volunteers (n = 6). Levels of TNF-α, IL-6, IL-1β, and PGE2 (A) in the culture supernatant were determined via ELISA. COX-2 levels in cell lysates were determined via Western blot (B). *p < 0.05, **p < 0.01. (PPTX 161 kb