Longitudinal studies have indicated the involvement and performance of multitudinous biomaterials for stem cell-based cytotherapy and regenerative medicine largely attribute to their specific biocompatibility. Currently, stem cells and biomaterial scaffolds have been considered as the two essential elements of the cornerstone of tissue engineering. On the one hand, biomaterials are beneficial to provide suitable microenvironments for enhancing the cellular vitality and therapeutic effect of stem cells. On the other hand, biomaterial-induced fibrosis and inflammation remain a prominent challenge in designing and synthesizing appropriate materials to facilitate tissue repair and organ regeneration. In this book chapter, we summarize the classification and physicochemical properties of the indicated biomaterials, and appraise the latest literatures of biomaterial and stem cell composite for broad biomedical applications in tissue engineering and regenerative medicine. Collectively, we retrospect the current advancement of biomaterial engineering and science, and highlight the multifaceted biomaterial-assisted stem cell-based tissue engineering and regenerative medicine, and in particular, the biomaterial-based composites with mesenchymal stem/stromal cells (MSCs) and the derivatives (e.g., exosomes, small microvesicles) for intractable disease administration.<br>
Human hepassocin (HPS) was originally detected by subtractive and differential cDNA cloning as a liver-specific gene that was markedly upregulated during liver regeneration. Previous studies suggested that HPS showed mitogenic activity on isolated hepatocytes in vitro. However, its in vivo functions remained largely unknown. Therefore, the function of recombinant human HPS during liver regeneration and chemically induced liver injury was investigated.
Methods
The proliferation of primary hepatocytes was examined by [3H]thymidine incorporation and immunohistological staining of proliferating cell nuclear antigen (PCNA). RNA interference was performed to knock down the endogenous expression of HPS. The proliferation of L02 cells was examined by MTS assay. The phosphorylation of ERK1/2 (extracellular signal-regulated kinase 1/2) was investigated by western blotting analysis. Assessment of liver injury (histology, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels) and of apoptosis, by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) assay, was performed.
Results
Purified recombinant human HPS showed specific mitogenic activity on primary hepatocytes and normal liver cell lines in a mitogen-activated protein kinase (MAPK)-dependent manner and stimulated the proliferation of hepatocytes in rats with 70% partial hepatectomy. Administration of HPS to rats after d-galactose and carbon tetrachloride (CCl4) treatment protected against liver injury (minimal liver necrosis, depressed ALT and AST levels, and decreased lethality), reduced apoptosis and enhanced proliferation. Knock-down of endogenous HPS in vivo enhanced the liver injury induced by d-galactose by increasing the apoptosis and elevating ALT and AST levels.
Conclusions
HPS is a hepatic growth factor which can accelerate hepatocyte proliferation in vivo and protect against liver injury. These data point to the potential interest of HPS in the treatment of fulminant hepatic failure.
Hepatocyte nuclear factor 1α (HNF1α) plays essential roles in controlling development and metabolism; its mutations are clearly linked to the occurrence of maturity-onset diabetes of the young (MODY3) in humans. Lysine 117 (K117) to glutamic acid (E117) mutation in the HNF1α gene has been clinically associated with MODY3, but no functional data on this variant are available. Here, we addressed the role of lysine 117 in HNF1α function using a knock-in animal model and site-directed mutagenesis. HNF1α K117E homozygous mice exhibited dwarfism, hepatic dysfunction, renal Fanconi syndrome, and progressive wasting syndrome. These phenotypes were very similar to those of mice with complete HNF1α deficiency, suggesting that K117 is critical to HNF1α functions. K117E homozygotes developed diabetes in the early postnatal period. The relative deficiency of serum insulin levels and the normal response to insulin treatment in homozygous mice were markedly similar to those in the MODY3 disorder in humans. Moreover, K117E heterozygous mutant causes age-dependent glucose intolerance, which is similar to the pathogenesis of MODY3 as well. K117 mutants significantly reduced the overall transactivation and DNA binding capacity of HNF1α by disrupting dimerization. Collectively, our findings reveal a previously unappreciated role of POU domain of HNF1α in homodimerization and provide important clues for identifying the molecular basis of HNF1α-related diseases such as MODY3.HNF1α K117E homozygous mice exhibited dwarfism, hepatic dysfunction, renal Fanconi syndrome, and progressive wasting syndrome. K117E homozygotes developed diabetes in the early postnatal period. K117E heterozygous mutant causes age-dependent glucose intolerance, which is similar to the pathogenesis of maturity-onset diabetes of the young. K117 mutants significantly reduced the overall transactivation and DNA binding capacity of HNF1α by disrupting dimerization.
Abstract Aim Deficit schizophrenia (DS), defined by primary and enduring negative symptoms, has been proposed as a promising homogeneous subtype of schizophrenia. It has been demonstrated that unimodal neuroimaging characteristics of DS were different from non‐deficit schizophrenia (NDS), however, whether multimodal‐based neuroimaging features could identify deficit syndrome remains to be determined. Methods Functional and structural multimodal magnetic resonance imaging of DS, NDS and healthy controls were scanned. Voxel‐based features of gray matter volume, fractional amplitude of low‐frequency fluctuations, and regional homogeneity were extracted. The support vector machine classification models were constructed using these features separately and jointly. The most discriminative features were defined as the first 10% of features with the greatest weights. Moreover, relevance vector regression was applied to explore the predictive values of these top‐weighted features in predicting negative symptoms. Results The multimodal classifier achieved a higher accuracy (75.48%) compared with the single modal model in distinguishing DS from NDS. The most predictive brain regions were mainly located in the default mode and visual networks, exhibiting differences between functional and structural features. Further, the identified discriminative features significantly predicted scores of diminished expressivity factor in DS but not NDS. Conclusions The present study demonstrated that local properties of brain regions extracted from multimodal imaging data could distinguish DS from NDS with a machine learning‐based approach and confirmed the relationship between distinctive features and the negative symptoms subdomain. These findings may improve the identification of potential neuroimaging signatures and improve the clinical assessment of the deficit syndrome.
The relationship between the tumor microenvironment and the network of key signaling pathways in cancer plays a key role in the occurrence and development of tumors. Tumor-associated macrophages (TAMs) are important inflammatory cells in the tumor microenvironment and play an important role in tumorigenesis and progression. Macrophages in malignant tumors, mainly the M2 subtype, promote tumor progression by producing cytokines and down-regulating anti-inflammatory immune responses. Several articles have investigated the effect of macrophages on the sensitivity of cancer chemotherapeutic agents, but few such articles have been reported in cholangiocarcinoma, so we investigated the effect of M2 macrophage on the sensitivity of cholangiocarcinoma cells to Lenvatinib compared to M1.THP-1 monocytes were polarized to M0 macrophage by phorbol 12-myristate 13-acetate (PMA) and then induced to differentiate into M1 and M2 macrophages by LPS, IFN-γ and IL-4 and IL-13, respectively. Macrophages and cholangiocarcinoma cells were co-cultured prior to 24 hours of Lenvatinib administration, cancer cell apoptosis was detected by western-blot, FACS analysis of Annexin V and PI staining. Furthermore, we use xCELLigence RTCA SP Instrument (ACEA Bio-sciences) to monitor cell viability of Lenvatinib administration in co-culture of cholangiocarcinoma cells and macrophages. After tumorigenesis in immunodeficient mice, Lenvatinib was administered, and the effects of M2 on biological characteristics of cholangiocarcinoma cells were investigated by immuno-histochemistry.mRNA and protein expression of M1 and M2 markers confirmed the polarization of THP-1 derived macrophages, which provided a successful and efficient model of monocyte polarization to TAMs. Lenvatinib-induced apoptosis of cholangiocarcinoma cells was significantly reduced when co-cultured with M2 macrophage, whereas apoptosis of cholangiocarcinoma cells co-cultured with M1 macrophage was increased. In the CDX model, Lenvatinib-induced cancer cell apoptosis was markedly reduced, and proliferative cells increased in the presence of M2 macrophages. Angiogenesis related factors was significantly increased in cholangiocarcinoma cells co-cultured with M2.Compared with M1, M2 macrophages can inhibit the anti-tumor effect of Lenvatinib on cholangiocarcinoma through immune regulation, which may be related to the tumor angiogenesis factor effect of M2 macrophage.
Abstract Transcriptional Mediator controls diverse gene programs for various developmental and pathological processes. The human Mediator MED23/R617Q mutation was reported in a familial intellectual disability (ID) disorder, although the underlying mechanisms remain poorly understood. Constructed by gene editing, the Med23/R617Q knock-in mutant mice exhibited embryonic lethality due to the largely reduced Med23/R617Q protein level, but the R617Q mutation in HEK293T cells didn’t change its expression and incorporation into Mediator Complex. RNA-seq revealed that MED23/R617Q mutation disturbed gene expression, related to neural development, learning and memory. Specifically, R617Q mutation reduced the MED23-dependent activities of ELK1 and E1A, but in contrast, upregulated the MAPK/ELK1-driven early immediate genes (IEGs) JUN and FOS. ChIP-seq and Hi-C revealed that the MED23 R617Q mutation reprogramed a subset of enhancers and local chromatin interactions, which correlated well with the corresponding gene expression. Importantly, the enhancers and chromatin interactions surrounding IEGs were unchanged by the R617Q mutation, but DACH1, an upstream repressor of IEGs, showed reduced enhancer-promoter interactions and decreased expression in mutant cells, thus relieving its inhibition to the intellectual-related IEGs. Overall, unraveling the MED23-DACH1-IEG axis provides a mechanistic explanation for the effects of the MED23/R617Q mutation on gene dysregulation and inherited ID.
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