Administration of mesenchymal stem cells (MSCs) improves the recovery from acute kidney injury (AKI).The mechanism may involve paracrine factors promoting proliferation of surviving intrinsic epithelial cells, but these factors remain unknown. In the current study, we found that microvesicles derived from human bone marrow MSCs stimulated proliferation in vitro and conferred resistance of tubular epithelial cells to apoptosis. The biologic action of microvesicles required their CD44-and ␤1-integrin-dependent incorporation into tubular cells. In vivo, microvesicles accelerated the morphologic and functional recovery of glycerol-induced AKI in SCID mice by inducing proliferation of tubular cells. The effect of microvesicles on the recovery of AKI was similar to the effect of human MSCs. RNase abolished the aforementioned effects of microvesicles in vitro and in vivo, suggesting RNA-dependent biologic effects. Microarray analysis and quantitative real time PCR of microvesicle-RNA extracts indicate that microvesicles shuttle a specific subset of cellular mRNA, such as mRNAs associated with the mesenchymal phenotype and with control of transcription, proliferation, and immunoregulation. These results suggest that microvesicles derived from MSCs may activate a proliferative program in surviving tubular cells after injury via a horizontal transfer of mRNA.

Membrane-derived microvesicles (MVs) are released from the cell surface and are implicated in cell-to-cell communication. We evaluated whether MVs derived from endothelial progenitor cells (EPCs) are able to trigger angiogenesis. We found that EPC-derived MVs were incor- IntroductionStem cells have been proposed as a new opportunity for tissue repair in several diseases. Experimental studies have suggested that transplantation of stem and progenitor cells may have a beneficial effect on functional and structural recovery in several organs, including heart, liver, and kidney. [1][2][3] The mechanisms underlining stem-cell therapy are still intensely debated. Some studies have suggested an engraftment of stem cells by transdifferentiation or fusion in targeted organs. [1][2][3] However, a growing number of evidences indicate that transient cell localization in the injured tissue may be sufficient to favor functional and regenerative events, suggesting the release of paracrine mediators. [1][2][3] Several mechanisms involved in cell-tocell communication have been identified, including secretion of growth factors, cytokines, surface receptors, and nucleotides. [4][5][6][7] It has been suggested that microvesicles (MVs) actively released from cells may play an important role in cell-to-cell communication. [8][9][10][11] MVs are derived from the endosomal membrane compartment after fusion with the plasma membrane and are shed from the cell surface of activated cells. 12,13 Several studies suggest that MVs may stimulate target cells directly or by transferring surface receptors. [8][9][10]13,14 It has been shown that MVs derived from activated platelets induce metastasis and angiogenesis in lung cancer. 14 Moreover, tumorderived MVs were shown to transfer surface determinants and mRNA of tumor cells to monocytes. 15 It has been also postulated that MVs may contribute in spreading certain infective agents such as HIV or prions. 16,17 Embryonic stem cells were recently shown to represent an abundant source of MVs, and it was suggested that MVs derived from these cells may represent one of the critical components supporting self-renewal and expansion of stem cells. 18,19 In addition, Ratajczak et al 18 demonstrated that embryonic stem cell-derived MVs are able to reprogram hematopoietic progenitors by a horizontal transfer of mRNA and protein delivery.These experimental evidences rise the question whether a stemcell regenerative therapy is feasible without transplantation of stem cells by using MVs as a carrier of genetic information or proteins able to reprogram tissue resident cells to repair injury.In the present study, we aimed to investigate whether MVs, derived from human circulating endothelial progenitor cells (EPCs), were able to trigger neoangiogenesis. Materials and methodsApproval of the study was obtained from the Center for Molecular Biotechnology Institutional Review Board. Adult peripheral blood was collected from healthy volunteers with informed consent obtained in accordance with the Declaration of Hels...

SUMMARY Hematopoiesis, the process of mature blood and immune cell production, is functionally organized as a hierarchy, with self-renewing hematopoietic stem cells (HSCs) and multipotent progenitor (MPP) cells sitting at the very top1,2. Multiple models have been proposed as to what the earliest lineage choices are in these primitive hematopoietic compartments, the cellular intermediates, and the resulting lineage trees that emerge from them3–10. Given that the bulk of studies addressing lineage outcomes have been performed in the context of hematopoietic transplantation, current lineage branching models are more likely to represent roadmaps of lineage potential rather than native fate. Here, we utilize transposon (Tn) tagging to clonally trace the fates of progenitors and stem cells in unperturbed hematopoiesis. Our results describe a distinct clonal roadmap in which the megakaryocyte (Mk) lineage arises largely independently of other hematopoietic fates. Our data, combined with single cell RNAseq, identify a functional hierarchy of uni- and oligolineage producing clones within the MPP population. Finally, our results demonstrate that traditionally defined long-term HSCs (LT-HSCs) are a significant source of Mk-restricted progenitors, suggesting that the Mk-lineage is the predominant native fate of LT-HSCs. Our study provides evidence for a substantially revised roadmap for unperturbed hematopoiesis, and highlights unique properties of MPPs and HSCs in situ.

SUMMARY The Hippo/YAP signaling pathway is a crucial regulator of tissue growth, stem cell activity and tumorigenesis. However, the mechanism by which YAP controls transcription remains to be fully elucidated. Here, we utilize global chromatin occupancy analyses to demonstrate that robust YAP binding is restricted to a relatively small number of distal regulatory elements in the genome. YAP-occupancy defines a subset of enhancers and super-enhancers with the highest transcriptional outputs. YAP modulates transcription from these elements predominantly by regulating promoter-proximal Polymerase II (PolII) pause release. Mechanistically, YAP interacts and recruits the Mediator complex to enhancers, allowing the recruitment of the CDK9 elongating kinase. Genetic and chemical perturbation experiments demonstrate the requirement for Mediator and CDK9 in YAP-driven phenotypes of overgrowth and tumorigenesis. Our results here uncover the molecular mechanisms employed by YAP to exert its growth and oncogenic functions, and suggest strategies for intervention.

This retrospective study further validates ERCC1 and RRM1 genes as reliable candidates for customized chemotherapy and shows a higher impact on the survival of NSCLC patients treated with cisplatin/gemcitabine for ERCC1. Prospective pharmacogenomic studies represent a research priority in early and advanced NSCLC.