Various detailed characteristics of a new enhanced neurotrophic factor secreting rat derived bone marrow mesenchymal stem cells and its preliminary application in rat models of ischemic stroke.

Because MSC-NTF has a higher ability to secrete neurotrophic factors, it may have a greater potential than ordinary MSC in clinical applications. At present, research on MSC-NTF mainly focuses on clinical aspects, but its basic research is relatively few. In particular, the research on the comprehensive and detailed characteristics of MSC-NTF is missing. And its in vivo research in animals is also rare. Since the transplantation of human-derived MSC-NTF into rats is cross-species, its survival in the rat and the therapeutic effect may be seriously affected due to severe immune rejection. This will inevitably affect the research on the basic characteristics and the therapeutic mechanisms of MSC-NTF in vivo. Therefore, we chose the rat-derived MSCs to be induced as the MSC-NTF which had a stronger neurotrophic factor secretion function. This will also be helpful to perform the research of the basic therapeutic mechanisms of MSC-NTF in vivo. In addition, we have established some important characteristics that can be used to distinguish between MSC-NTF and MSCs: different multi-factor secretion ability and secretion characteristics, immunogenicity, three-line differentiation ability, stemness, etc. In addition to paying attention to their safety differences, this study also explored the differences in their in vivo survivability. Finally, we applied this newly induced rat-derived MSC-NTF in a rat model of ischemic stroke, and obtained beneficial therapeutic effects.

The clinical relevance of epithelial-mesenchymal transition and its correlations with tumorigenic immune infiltrates in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a cancer with extremely high mortality. Epithelial-mesenchymal transition (EMT) may play an important role in the occurrence, invasion and prognosis of HCC; however, its relationship with immunity in HCC has not yet been studied. Therefore, we investigated the diagnostic and prognostic values of EMT and explored its potential connections with tumorigenic immune infiltrates in HCC. We first proposed a quantitative metric of EMT activity, the EMT score. After applying this metric to 20 datasets from the Integrative Molecular Database of Hepatocellular Carcinoma, the Cancer Genome Atlas, and the Gene Expression Omnibus, we explored the ability of the EMT score to stratify across sample types. We then applied the EMT score for survival analysis and to differentiate patients with/without vascular invasion to test its prognostic value. We also collected and calculated data on the abundance of immune cells and immune cell markers in HCC and investigated their correlations with EMT scores. Finally, we synthesized and analyzed 20 datasets and constructed an EMT-gene-immune linkage network. The results showed higher EMT scores in HCC samples than in cirrhotic and normal livers. The cases with higher EMT scores also showed poorer performance in terms of prognostic factors such as vascular invasion and overall survival time. Our research demonstrated a broad correlation between EMT and the tumor immune microenvironment, and we uncovered multiple potential linkers associated with both EMT and immunity. Studying EMT has clinical relevance and high diagnostic and prognostic value for HCC.

Predicting the prognosis of glioma by pyroptosis-related signature.

Glioma is the most common malignant primary brain tumour. It is of great significance for the prognosis and personalized treatment of glioma patients to accurate identification of glioma based on biomarkers. Pyroptosis, a kind of programmed cell death, is closely related to tumour progression and tumour immune microenvironment. However, the role of pyroptosis in glioma remained unclear. Herein, we used glioma clinical and expression data from TCGA and CGGA to explore the relationship between pyroptosis and glioma. We first summarized the incidence of copy number variations and somatic mutations of 33 pyroptosis-related genes and explored prognostic correlation of these genes. Based on pyroptosis-related genes, three molecular subgroups of glioma related to prognosis were identified. We also found that each subgroup has unique immune and biological behaviours characteristics. Finally, based on 7 pyroptosis-related genes (CASP3, CASP4, CASP6, CASP8, CASP9, PRKACA and ELANE), we constructed a prognosis model by Lasso and Cox regression, which had a strong predictive power for the overall survival in CGGA test cohort (p < 0.05). In summary, we explored the role of pyroptosis-related genes in gliomas and the association of these genes with tumour immunity. We found the biomarkers valuable to diagnosis and prognosis, hence, provide reference to the development and treatment of tumorigenesis in glioma.

Restoring electrical connection using a conductive biomaterial provides a new therapeutic strategy for rats with spinal cord injury.

Spinal cord injury (SCI) involves damage to the central nervous system, and there is no effective treatment available currently. The injured spinal cord is unable to transmit physiological electrical signals caudal to the location of the injury after a complete transection. In this study, we attempted to use a conductive biomaterial as a novel scaffold to aid SCI repair. A composite biomaterial was fabricated by embedding conductive polypyrrole (PPy) in an electrospun polylactic acid (PLA) nanofibrous scaffold (PLA/PPy scaffold), and an electrospun PLA nanofibrous scaffold without the PPy component was used as a control. The scaffolds were implanted into rats having complete T9 spinal cord resection. Immunofluorescent staining, western blot analysis, and TUNEL assay were used to study histological changes in injured spinal cord tissues. Our data demonstrated that PLA/PPy scaffolds had beneficial effects, as evident from the motor evoked-potentials (MEPs) test and Basso, Beattie, and Bresnahan (BBB) locomotion rating scale. Implantation of the PLA/PPy scaffold significantly alleviated secondary tissue damage by reducing apoptosis and autophagy in neural cells in comparison with the implantation of the control PLA scaffold. Notably, six weeks after injury, the use of PLA/PPy scaffolds significantly reduced the activation of astrocytes and increased axonal regeneration, as indicated by immunofluorescent markers (GFAP and NF200) in the region of injury. Our present study suggests that restoring electrical conductivity using a biological scaffold is beneficial to the microenvironment and favorable for the regeneration and functional recovery of spinal cord tissue in an SCI rat model.

The hetero-transplantation of human bone marrow stromal cells carried by hydrogel unexpectedly demonstrates a significant role in the functional recovery in the injured spinal cord of rats.

Spinal cord injury (SCI) often causes a disturbance in the microenvironment in the lesion site resulting in sudden loss of sensory and motor function. Transplantation of stem cells provides a promising strategy in the treatment of SCI. But limited growth and immunological incompatibility of the stem cells with the host limits the application of this strategy. In order to get better survival and integration with the host, we employed a hyaluronic acid (HA) based scaffold covalently modified by poly-l-Lysine (PLL) as a vehicle to deliver the human bone marrow stromal cells (BMSCs) to the injured spinal cord of rats. The BMSCs were chosen as an ideal candidate for its advantage of low expression of major histocompatibility complex II. The data unexpectedly showed that the hetero-transplanted cells survived well in the lesion site even at 8 weeks post injury. Both the immunofluorescent and the electrophysiological assay indicated better survival of the transplanted cells and improved axonal growth in SCI rats transplanted with BMSCs in HA-PLL in contrast to the groups without either BMSCs or the HA scaffold transplantation. These promotions may account for the functional recovery assessed by Basso-Beattie-Bresnahan (BBB) locomotor rating scale in the HA-PLL seeded with BMSCs group. These data suggests that hetero-transplantation of human BMSCs delivered by HA scaffold demonstrates a significant role in the functional recovery in the injured spinal cord of rats.

Dual roles of Atg8-PE deconjugation by Atg4 in autophagy.

Modification of target molecules by ubiquitin or ubiquitin-like (Ubl) proteins is generally reversible. Little is known, however, about the physiological function of the reverse reaction, deconjugation. Atg8 is a unique Ubl protein whose conjugation target is the lipid phosphatidylethanolamine (PE). Atg8 functions in the formation of double-membrane autophagosomes, a central step in the well-conserved intracellular degradation pathway of macroautophagy (hereafter autophagy). Here we show that the deconjugation of Atg8-PE by the cysteine protease Atg4 plays dual roles in the formation of autophagosomes. During the early stage of autophagosome formation, deconjugation releases Atg8 from non-autophagosomal membranes to maintain a proper supply of Atg8. At a later stage, the release of Atg8 from intermediate autophagosomal membranes facilitates the maturation of these structures into fusion-capable autophagosomes. These results provide new insights into the functions of Atg8-PE and its deconjugation.