The LIT score can effectively differentiate surgical NEC from nonsurgical NEC infants and nonsurvivors of NEC from survivors at the onset of clinical presentation. Frontline neonatologists and surgeons may, therefore, target NEC infants who are most in need of close monitoring and those who may benefit from early surgical intervention.

Transforming growth factor-β (TGF-β) signaling triggers diverse biological actions in inflammatory diseases. In tissue fibrosis, it acts as a key pathogenic regulator for promoting immunoregulation via controlling the activation, proliferation, and apoptosis of immunocytes. In cancer, it plays a critical role in tumor microenvironment (TME) for accelerating invasion, metastasis, angiogenesis, and immunosuppression. Increasing evidence suggest a pleiotropic nature of TGF-β signaling as a critical pathway for generating fibrotic TME, which contains numerous cancer-associated fibroblasts (CAFs), extracellular matrix proteins, and remodeling enzymes. Its pathogenic roles and working mechanisms in tumorigenesis are still largely unclear. Importantly, recent studies successfully demonstrated the clinical implications of fibrotic TME in cancer. This review systematically summarized the latest updates and discoveries of TGF-β signaling in the fibrotic TME.

The molecular evidence suggests that NEC and SIP are likely 2 different diseases caused by distinct etiology and pathophysiology. This first comprehensive database on differential gene expression profiles of human NEC and SIP tissues could lead to development of disease-specific diagnostic and prognostic biomarkers and new therapeutic strategies for improving outcomes.

Cancer-associated fibroblasts (CAFs) are important in tumor microenvironment (TME) driven cancer progression. However, CAFs are heterogeneous and still largely underdefined, better understanding their origins will identify new therapeutic strategies for cancer. Here, the authors discovered a new role of macrophage-myofibroblast transition (MMT) in cancer for de novo generating protumoral CAFs by resolving the transcriptome dynamics of tumor-associated macrophages (TAM) with single-cell resolution. MMT cells (MMTs) are observed in non-small-cell lung carcinoma (NSCLC) associated with CAF abundance and patient mortality. By fate-mapping study, RNA velocity, and pseudotime analysis, existence of novel macrophage-lineage-derived CAF subset in the TME of Lewis lung carcinoma (LLC) model is confirmed, which is directly transited via MMT from M2-TAM in vivo and bone-marrow-derived macrophages (BMDM) in vitro. Adoptive transfer of BMDM-derived MMTs markedly promote CAF formation in LLC-bearing mice. Mechanistically, a Smad3-centric regulatory network is upregulated in the MMTs of NSCLC, where chromatin immunoprecipitation sequencing(ChIP-seq) detects a significant enrichment of Smad3 binding on fibroblast differentiation genes in the macrophage-lineage cells in LLC-tumor. More importantly, macrophage-specific deletion and pharmaceutical inhibition of Smad3 effectively block MMT, therefore, suppressing the CAF formation and cancer progression in vivo. Thus, MMT may represent a novel therapeutic target of CAF for cancer immunotherapy.

The stromal cell-derived factor-1 (SDF-1)/ chemokine C-X-C receptor 4 (CXCR4) axis plays a critical role in homing and engraftment of hematopoietic stem/progenitor cells (HSCs) during bone marrow transplantation. To investigate the transcriptional regulation provided by this axis, we performed the first differential transcriptome profiling of human cord blood CD34 ؉ cells in response to short-term exposure to SDF-1 and identified a panel of genes with putative homing functions. We demonstrated that CD9, a member of the tetraspanin family of proteins, was expressed in CD34 ؉ CD38 ؊/lo and CD34 ؉ CD38 ؉ cells. CD9 levels were enhanced by SDF-1, which simultaneously down-regulated CXCR4 membrane expression. Using specific inhibitors and activators, we demonstrated that CD9 expression was modulated via CXCR4, G-protein, protein kinase C, phospholipase C, extracellular signalregulated kinase, and Janus kinase 2 signals. Pretreatment of CD34 ؉ cells with the anti-CD9 monoclonal antibody ALB6 significantly inhibited SDF-1-mediated transendothelial migration and calcium mobilization, whereas adhesion to fibronectin IntroductionHoming of hematopoietic stem/progenitor cells (HSCs) to their bone marrow niches is crucial to successful transplantation. This multistep process starts with rolling and tethering of HSCs to bone marrow sinusoidal endothelial cells, followed by migration through the endothelium and extracellular matrix barrier to engage their bone marrow niches. 1,2 The molecular mechanism controlling HSC homing is still not fully understood. Experimental evidence suggests that it requires the orchestrated action of chemokines, 3,4 adhesion molecules, 5,6 and proteolytic enzymes. 7,8 Signaling provided by the interaction of stromal cell-derived factor-1 (SDF-1) with its receptor, chemokine CXC receptor 4 (CXCR4), plays essential roles in regulating HSC homing. Mice lacking SDF-1 or CXCR4 are severely defective in seeding of stem cells in the bone marrow and in the establishment of B-lymphopoiesis and myelopoiesis during development. [9][10][11] In vitro, SDF-1 induces chemotactic and transendothelial migration, 12 adhesion to extracellular matrix proteins under static or shear stress conditions, 5 actin polymerization, 13 and calcium flux 12 in human CD34 ϩ cells. Moreover, homing and engraftment of transplanted CD34 ϩ cells in NOD/ SCID (nonobese diabetic/severe combined immune-deficient) mice are greatly impaired by neutralization of CXCR4 or desensitization by high doses of SDF-1. 3,14 However, CXCR4 Ϫ/Ϫ fetal liver cells are capable (albeit at a lower level) of engraftment in the bone marrow of wild-type mice, 15,16 suggesting that HSC homing and repopulation might not be exclusively controlled by the SDF-1/CXCR4 axis.We previously demonstrated that a short exposure of human cord blood-derived CD34 ϩ cells to a peptide analog of SDF-1 enhances their engraftment in the NOD/SCID mice model. 17 Similarly, others have reported that homing of human or murine HSCs could be significantly improved by pretreatment wit...

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SummaryEpigenomic changes and stem cell deterioration are two hallmarks of aging. Accumulating evidence suggest that senescence of mesenchymal stromal cells (MSCs) perpetuates aging or age-related diseases. Here we report that two H3K9 demethylases, KDM3A and KDM4C, regulate heterochromatin reorganization via transcriptionally activating condensin components NCAPD2 and NCAPG2 during MSC senescence. Suppression of KDM3A or KDM4C by either genetic or biochemical approach leads to robust DNA damage response and aggravates cellular senescence, whereas overexpression of KDM3A/KDM4C or NCAPD2 promotes heterochromatin reorganization and blunts DNA damage response. Moreover, MSCs derived from Kdm3a−/− mice exhibit defective chromosome organization and exacerbated DNA damage response, which are associated with accelerated bone aging. Consistently, analysis of human bone marrow MSCs and transcriptome database reveals inverse correlation of KDM3A/KDM4C and/or NCAPD2/NCAPG2 with aging. Taken together, the present finding unveils that H3K9 demethylases function as a surveillance mechanism to restrain DNA damage accumulation in stem cells during aging.

BackgroundNecrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) are acute intestinal conditions which could result in mortality and severe morbidity in preterm infants. Our objective was to identify dysregulated micro-RNAs (miRNAs) in small bowel tissues of NEC and SIP, and their possible roles in disease pathophysiology.MethodsWe performed differential miRNA arrays on tissues of NEC (n = 4), SIP (n = 4) and surgical-control (Surg-CTL; n = 4), and validated target miRNAs by qPCR (n = 10 each group). The association of target miRNAs with 52 dysregulated mRNAs was investigated by bioinformatics on functional and base-pair sequence algorithms, and correlation in same tissue samples.ResultsWe presented the first miRNA profiles of NEC, SIP and Surg-CTL intestinal tissues in preterm infants. Of 28 validated miRNAs, 21 were significantly different between NEC or SIP and Surg-CTL. Limited overlapping in the aberrant expression of miRNAs between NEC and SIP indicated their distinct molecular mechanisms. A proposed network of dysregulated miRNA/mRNA pairs in NEC suggested interaction at bacterial receptor TLR4 (miR-31, miR-451, miR-203, miR-4793-3p), mediated via key transcription factors NFKB2 (miR-203), AP-1/FOSL1 (miR-194-3p), FOXA1 (miR-21-3p, miR-431 and miR-1290) and HIF1A (miR-31), and extended downstream to pathways of angiogenesis, arginine metabolism, cell adhesion and chemotaxis, extracellular matrix remodeling, hypoxia/oxidative stress, inflammation and muscle contraction. In contrast, upregulation of miR-451 and miR-223 in SIP suggested modulation of G-protein-mediated muscle contraction.ConclusionsThe robust response of miRNA dysregulation in NEC and SIP, and concerted involvement of specific miRNAs in the molecular networks indicated their crucial roles in mucosa integrity and disease pathophysiology.