Activity

Ex vivo expansion strategies of human hematopoietic stem cell (HSC) grafts with suboptimal stem cell dose have emerged as promising strategies for improving outcomes of HSC transplantation in patients with hematological malignancies. While exposure of HSCs to ex vivo cultures expands the number of phenotypically identifiable HSCs, it frequently alters the transcriptomic and metabolic profiles, therefore, compromising their long-term (LT) hematopoietic reconstitution capacity. Within the heterogeneous pool of expanded HSCs, the precise phenotypic, transcriptomic and metabolic profile and thus, the identity of HSCs that confer LT repopulation potential remains poorly described. Utilizing valproic acid (VPA) in ex vivo cultures of umbilical cord blood (UCB)-CD34+ cells, we demonstrate that expanded HSCs phenotypically marked by expression of the stem cell markers CD34, CD90 and EPCR (CD201) are highly enriched for LT-HSCs. Furthermore, we report that low mitochondrial membrane potential, and, hence, mitochondrial activity distinguishes LT-HSCs within the expanded pool of phenotypically defined HSCs. Remarkably, such reduced mitochondrial activity is restricted to cells with the highest expression levels of CD34, CD90 and EPCR phenotypic markers. Together, our findings reveal that high expression of CD34, CD90 and EPCR in conjunction with low mitochondrial activity is critical for identification of functional LT-HSCs generated within ex vivo expansion cultures.

Organotropism is primarily determined by tumor-derived exosomes. To date, the role of lung cancer cells-derived exosomes underlying the pre-metastatic niche formation is unclear.

The animal models of retro-orbital and intra-ventricular injection were constructed to administrate lung cancer cells-derived exosomes. Cytokine array was used to screen the cytokines released from brain endothelium after internalization of lung cancer cells-derived exosomes. The cellular co-culture system was established to mimic microglia-vascular niche contained lung cancer cells-derived exosomes. The levels of Dkk-1 and the activities of microglia were analyzed by qRT-PCR, western blot and immunofluorescence.

selections of highly brain metastatic cells were performed to analyze the direct interaction of lung cancer cells with microglia.

Animal studies demonstrated that there was a suppressive signal transferred from brain endothelium to microglia after internalization of lung cancer cells-derived exosomes into brain endothelium, which caused an absolutely less M1 phenotypic microglia and a relatively more M2 phenotypic microglia. Further results indicated that lung cancer cells-derived exosomes induced a release of endogenous Dkk-1 from brain endothelium, which rendered microglia to acquire a pro-tumorigenic feature in pre-metastatic niche. Subsequently, the declines of Dkk-1 in metastatic lung cancer cells removed the suppression on microglia and enhanced microglial activation in metastatic niche.

Our findings shed a new light on the synergistic reaction of the different cells in “neurovascular units” toward the metastatic messages from lung cancer cells and provided a potential therapeutic pathway for lung cancer metastasis to brain.

Our findings shed a new light on the synergistic reaction of the different cells in “neurovascular units” toward the metastatic messages from lung cancer cells and provided a potential therapeutic pathway for lung cancer metastasis to brain.Avian leukosis virus subgroup J disease (ALV-J) is a contagious and immunosuppressive avian disease caused by ALV-J virus. Although miRNA participate in various biological processes of tumors, little is known about the potential role of miRNA in ALV-J. Our previous miRNA and RNA sequencing data showed that the expression of gga-miR-148a-5p was significantly different in ALV-J-infected chicken spleens compared with non-infected chickens. The aim of this study was to investigate the functional roles of gga-miR-148a-5p and identify downstream targets regulated by gga-miR-148a-5p in ALV-J-infected chickens. We found that the expression of gga-miR-148a-5p was significantly downregulated during ALV-J infection of chicken embryo fibroblasts (CEF). Dual luciferase reporter assays demonstrated that PDPK1 is a direct target gene of gga-miR-148a-5p. In vitro, overexpression of gga-miR-148a-5p significantly promoted ALV-J-infected CEF cell proliferation, included cell cycle, whereas inhibition of gga-miR-148a-5p had an opposite effect. Inhibition of PDPK1 promoted the proliferation of ALV-J-infected cells but had no effect on the activity of NF-κB. Together, these results suggested that gga-miR-148a-5p targets PDPK1 to inhibit the proliferation and cell cycle of ALV-J-infected CEF cells. Our study provides a new understanding for the tumor mechanism of ALV-J infection.The proteotranscriptomic landscape depends on the transcription, mRNA-turnover, translation, and regulated-destruction of proteins. Gene-specific mRNA-to-protein correlation is the consequence of the dynamic interplays of the different regulatory processes of proteotranscriptomic landscape. So far, the critical impact of mRNA and protein stability on their subsequent correlation on a global scale remained unresolved. Whether the mRNA-to-protein correlations are constrained by their stability and conserved across mammalian species including human is unknown. Moreover, whether the stability-dependent correlation pattern is altered in the tumor has not been explored. check details To establish the quantitative relationship between stability and correlation between mRNA and protein levels, we performed a multi-omics data integration study across mammalian systems including diverse types of human tissues and cell lines in a genome-wide manner. The current study illuminated an important aspect of the mammalian proteotranscriptomays prioritized by the tumor cells at different clinical stages. The component of transcriptional regulatory circuits identified by the current study can serve as potential candidates for stage-dependent anticancer therapy.Mesenchymal stromal cell (MSC)-based cell therapy has received great interest in regenerative medicine. Priming the cells during the culture phase can improve their efficacy and/or survival after injection. The literature suggests that MSC extracellular vesicles (EV) can recapitulate a substantial part of the beneficial effects of the cells they originate from, and that micro-RNAs (miRNAs) are important players in EV biological action. Here, our aim was to determine if two classical priming methods of MSC, interferon-gamma (IFNγ) and hypoxia (HYP), could modify their EV miRNA content. Human bone marrow MSCs (BM-MSCs) from five healthy donors were cultured with IFNγ or in HYP or in control (CONT) conditions. The conditioned media were collected after 48 h in serum-free condition and EV were isolated by ultracentrifugation. Total RNA was isolated, pools of CONT, IFN, and HYP cDNA were prepared, and a miRNA profiling was performed using RT-qPCR. Then, miRNAs were selected based on their detectability and measured on each individual EV sample.