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Endothelial cell injury plays a critical part in ischemic acute kidney injury (AKI) and participates in the progression of AKI. Targeting renal endothelial cell therapy may ameliorate vascular injury and further improve the prognosis of ischemic AKI. Here, P‐selectin as a biomarker of ischemic AKI in endothelial cells is identified and P‐selectin binding peptide (PBP)‐engineered extracellular vesicles (PBP‐EVs) with imaging and therapeutic functions are developed. The results show that PBP‐EVs exhibit a selective targeting tendency to injured kidneys, while providing spatiotemporal information for the early diagnosis of AKI by quantifying the expression of P‐selectin in the kidneys by molecular imaging. Meanwhile, PBP‐EVs reveal superior nephroprotective functions in the promotion of renal repair and inhibition of fibrosis by alleviating inflammatory infiltration, improving reparative angiogenesis, and ameliorating maladaptive repair of the renal parenchyma. In conclusion, PBP‐EVs, as an ischemic AKI theranostic system that is designed in this study, provide a spatiotemporal diagnosis in the early stages of AKI to help guide personalized therapy and exhibit superior nephroprotective effects, offering proof‐of‐concept data to design EV‐based theranostic strategies to promote renal recovery and further improve long‐term outcomes following AKI. [ABSTRACT FROM AUTHOR]

Angiogenesis, the formation of new blood vessels from the pre-existing vasculature, is a complex multistage process regulated by a number of signal transduction pathways. Accumulating evidence suggests that signal transducer and activator of transcription (STATs), mainly STAT3, play an important role in angiogenesis under both physiological and pathological conditions in addition to cell survival, proliferation, differentiation, and oncogenesis. STAT3, as a critical multifunctional mediator, regulates many aspects of angiogenesis at the transcriptional level. This review will highlight the pivotal role of STAT3 in well-studied tumorous angiogenesis and cardiac angiogenesis, and summarize various potential mechanisms utilized by STAT3 to regulate the transcriptional activation of VEGF. © 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 2, 185-200, 2008 [ABSTRACT FROM AUTHOR]

ABSTRACT Several landmark clinical trials suggest that 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins) have additional cardiovascular protective activity that may function independently of their ability to lower serum cholesterol. The cardiovascular protective effects of statins are partly caused by the activation of postnatal neovascularization. At therapeutic doses, statins promote proliferation, migration and survival of endothelial cells, induce mobilization and differentiation of bone marrow-derived endothelial progenitor cells by stimulating the serine/threonine protein kinase Akt (also known as protein kinase B) and nitric oxide (NO) signal pathway. However, at excessive doses, statins may decrease protein isoprenylation as well as inhibit endothelial cell growth and migration. NO is an important signaling molecule that regulates a wide range of physiological and pathological processes in different tissues. There is substantial evidence that effective neovascularization requires endothelium-derived NO. Statins have pleiotropic effects on the expression and activity of endothelial nitric oxide synthase (eNOS) and lead to improved NO bioavailability. NO plays an important role in the effects of statins on neovascularization. In this review, we focus on the effects of statins on neovascularization and highlight specific novel targets, such as endothelial progenitor cells and NO. [ABSTRACT FROM AUTHOR]

Uncovering mechanisms of endogenous regeneration and repair through resident stem cell activation will allow us to develop specific therapies for injuries and diseases by targeting resident stem cell lineages. Sox9+ stem cells have been reported to play an essential role in acute kidney injury (AKI). However, a complete view of the Sox9+ lineage was not well investigated to accurately elucidate the functional end state and the choice of cell fate during tissue repair after AKI. To identify the mechanisms of fate determination of Sox9+ stem cells, we set up an AKI model with prostaglandin E2 (PGE2) treatment in a Sox9 lineage tracing mouse model. Single‐cell RNA sequencing (scRNA‐seq) was performed to analyse the transcriptomic profile of the Sox9+ lineage. Our results revealed that PGE2 could activate renal Sox9+ cells and promote the differentiation of Sox9+ cells into renal proximal tubular epithelial cells and inhibit the development of fibrosis. Furthermore, single‐cell transcriptome analysis demonstrated that PGE2 could regulate the restoration of lipid metabolism homeostasis in proximal tubular epithelial cells by participating in communication with different cell types. Our results highlight the prospects for the activation of endogenous renal Sox9+ stem cells with PGE2 for the regenerative therapy of AKI. [ABSTRACT FROM AUTHOR]

Background Information: Endothelial cells play a major role in angiogenesis, the process by which new blood vessels arise from a pre-existing vascular bed. VEGF-A (vascular endothelial growth factor-A) is a key regulator of angiogenesis during both development and in adults. HGF (hepatocyte growth factor) is a pleiotropic cytokine that may promote VEGF-A-driven angiogenesis, although the signalling mechanisms underlying this co-operation are not completely understood., Results: We analysed the effects of the combination of VEGF-A and HGF on the activation of VEGFR-2 (VEGF receptor-2) and c-met receptors, and on the stimulation of downstream signalling pathways in endothelial cells. We found that VEGFR-2 and c-met do not physically associate and do not transphosphorylate each other, suggesting that co-operation involves signalling events more distal from receptor activation. We demonstrate that the VEGF isoform VEGF-A(165) and HGF stimulate a similar set of MAPKs (mitogen-activated protein kinases), although the kinetics and strengths of the activation differ depending on the growth factor and pathway. An enhanced activation of the signalling was observed when endothelial cells were stimulated by the combination of VEGF-A(165) and HGF. Moreover, the combination of VEGF-A and HGF results in a statistically significant synergistic activation of ERK1/2 (extracellular-signal-regulated kinase 1/2) and p38 kinases. We demonstrated that VEGF-A(165) and HGF activate FAK (focal adhesion kinase) with different kinetics and stimulate the recruitment of phosphorylated FAK to different subsets of focal adhesions. VEGF-A(165) and HGF regulate distinct morphogenic aspects of the cytoskeletal remodelling that are associated with the preferential activation of Rho or Rac respectively, and induce structurally distinct vascular-like patterns in vitro in a Rho- or Rac-dependent manner., Conclusions: Under angiogenic conditions, combining VEGF-A with HGF can promote neovascularization by enhancing intracellular signalling and allowing more finely regulated control of the signalling molecules involved in the regulation of the cytoskeleton and cellular migration and morphogenesis.

BCR/ABL can cause chronic myelogenous leukaemia (CML) in part by altering the transcription of specific genes with growth- and/or survival-promoting functions. Recently, BCR/ABL has been shown to activate survivin, an important regulator of cell growth and survival, but the precise molecular mechanisms behind its expression and consequences thereof in CML cells remain unclear. Here, we reported that BCR/ABL promotes survivin expression and its cytoplasmic accumulation. The increase of survivin was largely controlled at the transcriptional level through a mechanism mediated by JAK2/PI3K signal pathways that activated c-Myc, leading to transactivation of survivin promoter. Dynamic down-regulation of survivin was a key event involved in imatinib-induced cell death while forced expression of survivin partially counteracted imatinib's effect on cell survival. Additionally, shRNA-mediated silencing of survivin or c-Myc eradicated colony formation of K562 cells in semi-solid culture system, implying an essential role for this transcriptional network in BCR/ABL-mediated cell transformation and survival. Finally, interruption of c-Myc activity by 10058-F4 exerted an anti-leukaemia effect with a synergistic interaction with imatinib and overcame the anti-apoptosis rescued by IL-3 supplement. In conclusion, we have identified JAK2/PI3K-mediated and c-Myc-dependent transactivation of survivin as a novel pathway in the transcriptional network orchestrated by BCR/ABL. These results suggest that the interference with this circuitry might be a potential utility for CML treatment.

Mesenchymal stem cells (MSCs) can be derived from adult bone marrow, fat and several foetal tissues. In vitro, MSCs have the capacity to differentiate into multiple mesodermal and non-mesodermal cell lineages. Besides, MSCs possess immunosuppressive effects by modulating the immune function of the major cell populations involved in alloantigen recognition and elimination. The intriguing biology of MSCs makes them strong candidates for cell-based therapy against various human diseases. Type 1 diabetes is caused by a cell-mediated autoimmune destruction of pancreatic beta-cells. While insulin replacement remains the cornerstone treatment for type 1 diabetes, the transplantation of pancreatic islets of Langerhans provides a cure for this disorder. And yet, islet transplantation is limited by the lack of donor pancreas. Generation of insulin-producing cells (IPCs) from MSCs represents an attractive alternative. On the one hand, MSCs from pancreas, bone marrow, adipose tissue, umbilical cord blood and cord tissue have the potential to differentiate into IPCs by genetic modification and/or defined culture conditions In vitro. On the other hand, MSCs are able to serve as a cellular vehicle for the expression of human insulin gene. Moreover, protein transduction technology could offer a novel approach for generating IPCs from stem cells including MSCs. In this review, we first summarize the current knowledge on the biological characterization of MSCs. Next, we consider MSCs as surrogate beta-cell source for islet transplantation, and present some basic requirements for these replacement cells. Finally, MSCs-mediated therapeutic neovascularization in type 1 diabetes is discussed.