Chimpanzee and pig-tailed macaque iPSCs: Improved culture and generation of primate cross-species embryos.

As our closest living relatives, non-human primates uniquely enable explorations of human health, disease, development, and evolution. Considerable effort has thus been devoted to generating induced pluripotent stem cells (iPSCs) from multiple non-human primate species. Here, we establish improved culture methods for chimpanzee (Pan troglodytes) and pig-tailed macaque (Macaca nemestrina) iPSCs.

Autotaxin loss accelerates intestinal inflammation by suppressing TLR4-mediated immune responses.

Autotaxin (ATX) converts lysophosphatidylcholine and sphingosyl-phosphorylcholine into lysophosphatidic acid and sphingosine 1-phosphate, respectively. Despite the pivotal function of ATX in lipid metabolism, mechanisms by which ATX regulates immune and inflammatory disorders remain elusive. Here, using myeloid cell lineage-restricted Atx knockout mice, we show that Atx deficiency disrupts membrane microdomains and lipid rafts, resulting in the inhibition of Toll-like receptor 4 (TLR4) complex formation and the suppression of adaptor recruitment, thereby inhibiting TLR4-mediated responses in macrophages.

Alteration in ventricular pressure stimulates cardiac repair and remodeling.

The mammalian heart undergoes complex structural and functional remodeling to compensate for stresses such as pressure overload. While studies suggest that, at best, the adult mammalian heart is capable of very limited regeneration arising from the proliferation of existing cardiomyocytes, how myocardial stress affects endogenous cardiac regeneration or repair is unknown. To define the relationship between left ventricular afterload and cardiac repair, we induced left ventricle pressure overload in adult mice by constriction of the ascending aorta (AAC).

Human-Induced Pluripotent Stem Cell Model of Trastuzumab-Induced Cardiac Dysfunction in Patients With Breast Cancer.

Background: Molecular targeted chemotherapies have been shown to significantly improve the outcomes of patients who have cancer, but they often cause cardiovascular side effects that limit their use and impair patients' quality of life. Cardiac dysfunction induced by these therapies, especially trastuzumab, shows a distinct cardiotoxic clinical phenotype in comparison to the cardiotoxicity induced by conventional chemotherapies.

Methods: We used the human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) platform to determine the underlying cellular mechanisms in trastuzumab-induced cardiac dysfunction.

A Premature Termination Codon Mutation in MYBPC3 Causes Hypertrophic Cardiomyopathy via Chronic Activation of Nonsense-Mediated Decay.

Background: Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in myosin-binding protein C3 ( MYBPC3) resulting in a premature termination codon (PTC). The underlying mechanisms of how PTC mutations in MYBPC3 lead to the onset and progression of HCM are poorly understood. This study's aim was to investigate the molecular mechanisms underlying the pathogenesis of HCM associated with MYBPC3 PTC mutations by utilizing human isogenic induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).

Pluripotent Stem Cell-Derived Cardiomyocytes as a Platform for Cell Therapy Applications: Progress and Hurdles for Clinical Translation.

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. Regenerative therapy has been applied to restore lost cardiac muscle and cardiac performance. Induced pluripotent stem cells (iPSCs) can provide an unlimited source of cardiomyocytes and therefore play a key role in cardiac regeneration.

Modeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond.

The advent of human induced pluripotent stem cells (iPSCs) presents unprecedented opportunities to model human diseases. Differentiated cells derived from iPSCs in two-dimensional (2D) monolayers have proven to be a relatively simple tool for exploring disease pathogenesis and underlying mechanisms. In this Spotlight article, we discuss the progress and limitations of the current 2D iPSC disease-modeling platform, as well as recent advancements in the development of human iPSC models that mimic tissues and organs at the three-dimensional (3D) level.

The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids.

CD4 T cells are tightly regulated by microbiota in the intestine, but whether intestinal T cells interface with host-derived metabolites is less clear. Here, we show that CD4 T effector (Teff) cells upregulated the xenobiotic transporter, Mdr1, in the ileum to maintain homeostasis in the presence of bile acids. Whereas wild-type Teff cells upregulated Mdr1 in the ileum, those lacking Mdr1 displayed mucosal dysfunction and induced Crohn's disease-like ileitis following transfer into Rag1 hosts.

Circulating cathelicidin levels correlate with mucosal disease activity in ulcerative colitis, risk of intestinal stricture in Crohn's disease, and clinical prognosis in inflammatory bowel disease.

Background: Cathelicidin (LL-37) is an antimicrobial peptide known to be associated with various autoimmune diseases. We attempt to determine if cathelicidin can accurately reflect IBD disease activity. We hypothesize that serum cathelicidin correlates with mucosal disease activity, stricture, and clinical prognosis of IBD patients.

Informatics-Based Discovery of Disease-Associated Immune Profiles.

Advances in flow and mass cytometry are enabling ultra-high resolution immune profiling in mice and humans on an unprecedented scale. However, the resulting high-content datasets challenge traditional views of cytometry data, which are both limited in scope and biased by pre-existing hypotheses. Computational solutions are now emerging (e.

Identification of Circulating MicroRNA Signatures in Crohn's Disease Using the Nanostring nCounter Technology.

Background: Current clinical indices, such as Harvey-Bradshaw index, are often inadequate for the assessment of disease activity in Crohn's disease (CD). Alternative methods including imaging modalities and laboratory markers, such as C-reactive protein (CRP), are routinely applied to assess disease activity. However, laboratory markers poorly reflect the actual disease activity.

Optimization of human mesenchymal stem cell manufacturing: the effects of animal/xeno-free media.

Due to their immunosuppressive properties, mesenchymal stem cells (MSC) have been evaluated for the treatment of immunological diseases. However, the animal-derived growth supplements utilized for MSC manufacturing may lead to clinical complications. Characterization of alternative media formulations is imperative for MSC therapeutic application.

Assessment of Circulating MicroRNAs for the Diagnosis and Disease Activity Evaluation in Patients with Ulcerative Colitis by Using the Nanostring Technology.

Background: Clinical decision and patient care management in inflammatory bowel diseases is largely based on the assessment of clinical symptoms, while the biomarkers currently in use poorly reflect the actual disease activity. Therefore, the identification of novel biomarkers will serve an unmet clinical need for IBD screening and patient management. We examined the utility of circulating microRNAs for diagnosis and disease activity monitoring in patients with ulcerative colitis (UC).

MicroRNA214 Is Associated With Progression of Ulcerative Colitis, and Inhibition Reduces Development of Colitis and Colitis-Associated Cancer in Mice.

Background & Aims: Persistent activation of the inflammatory response contributes to the development of inflammatory bowel diseases, which increase the risk of colorectal cancer. We aimed to identify microRNAs that regulate inflammation during the development of ulcerative colitis (UC) and progression to colitis-associated colon cancer (CAC).

Methods: We performed a quantitative polymerase chain reaction analysis to measure microRNAs in 401 colon specimens from patients with UC, Crohn's disease, irritable bowel syndrome, sporadic colorectal cancer, or CAC, as well as subjects without these disorders (controls); levels were correlated with clinical features and disease activity of patients.

A microRNA signature in pediatric ulcerative colitis: deregulation of the miR-4284/CXCL5 pathway in the intestinal epithelium.

Background: Twenty to 25% of the patients with inflammatory bowel disease (IBD) present the disease before the age of 18 to 20, with worse extent and severity, compared with adult-onset IBD. We sought to identify the differential expression of microRNAs in pediatric ulcerative colitis (UC) and their association with different clinical phenotypes.

Methods: MicroRNA expression analysis was performed in colonic tissues derived from pediatric patients with UC and controls without IBD.

Neurotensin--regulated miR-133α is involved in proinflammatory signalling in human colonic epithelial cells and in experimental colitis.

Objective: Neurotensin (NT) mediates colonic inflammation through its receptor neurotensin receptor 1 (NTR1). NT stimulates miR-133α expression in colonic epithelial cells. We investigated the role of miR-133α in NT-associated colonic inflammation in vitro and in vivo.

FLT3 activation improves post-myocardial infarction remodeling involving a cytoprotective effect on cardiomyocytes.

Objectives: The goal of this study was to define the role of FMS-like tyrosine kinase 3 (FLT3) in the heart.

Background: FLT3 is a prominent target of receptor tyrosine kinase inhibitors (TKIs) used for anticancer therapy. TKIs can cause cardiomyopathy but understanding of the mechanisms is incomplete, partly because the roles of specific TKI target receptors in the heart are still obscure.

Methods to study the proliferation and differentiation of cardiac side population (CSP) cells.

Investigation of cardiac progenitor cell proliferation and differentiation is essential for both the basic understanding of progenitor cell biology as well as the development of cellular therapeutics for tissue regeneration. Herein, we describe techniques used for the analysis of CSP cell proliferation, cell cycle status, and cardiomyogenic differentiation.

Stem cell therapy in inflammatory bowel disease: which, when and how?

Purpose Of Review: Stem cell therapy has emerged as a promising therapeutic strategy for inflammatory bowel diseases (IBDs). Currently, stem cell therapy is not part of the standard of care and is usually only performed as a part of clinical trials. In this review, clinical results, proposed underlying mechanisms, and future research directions will be discussed.

Anti-TNF antibodies in inflammatory bowel disease: do we finally know how it works?

Tumor necrosis factor (TNF) is a central pro-inflammatory cytokine that regulates the expression of numerous signaling pathways implicated in the progression of the immunological reaction. Unraveling the importance of TNF on the pathogenesis of inflammatory bowel disease (IBD) promoted anti-TNF antibodies as novel therapeutic agents. Initially, the main hypothesis behind the clinical application of anti-TNF antagonists in the clinic was that they exert their effects solely through neutralization of TNF.

Dissecting the molecular relationship among various cardiogenic progenitor cells.

Rationale: Multiple progenitors derived from the heart and bone marrow (BM) have been used for cardiac repair. Despite this, not much is known about the molecular identity and relationship among these progenitors. To develop a robust stem cell therapy for the heart, it is critical to understand the molecular identity of the multiple cardiogenic progenitor cells.

ATP-binding cassette G-subfamily transporter 2 regulates cell cycle progression and asymmetric division in mouse cardiac side population progenitor cells.

Rationale: After cardiac injury, cardiac progenitor cells are acutely reduced and are replenished in part by regulated self-renewal and proliferation, which occurs through symmetric and asymmetric cellular division. Understanding the molecular cues controlling progenitor cell self-renewal and lineage commitment is critical for harnessing these cells for therapeutic regeneration. We previously have found that the cell surface ATP-binding cassette G-subfamily transporter 2 (Abcg2) influences the proliferation of cardiac side population (CSP) progenitor cells, but through unclear mechanisms.