TY - JOUR
AU - Atkinson, Stuart P.
AB - Non-coding RNAs (ncRNA) are an abundant family that includes transfer RNAs, ribosomal RNAs, a range of small ncRNAs (such as microRNAs), and long (l)ncRNAs. Members of the lncRNA family encompass transcribed RNAs of over 200 nucleotides in length that can function as guides for chromatin-modifying transcriptional complexes; therefore, the expression of lncRNAs represents another means to control gene expression. Multiple fundamental processes in normal cells require the proper expression and function of lncRNAs [1], and recent studies have described the dysregulated expression of lncRNAs during tumorigenesis [2], although only a few lncRNAs have been described in this context. Previously reported examples include MALAT1 in lung cancer metastasis [3] and HOTAIR in breast cancer [4]; however, the functions of most other cancer-associated lncRNAs remain mostly unknown. Meanwhile, a growing body of research into the therapeutic mechanisms behind stem cell-based therapies has highlighted the small ncRNAs present in secreted extracellular vesicles as crucial components of protective/regenerative effects. In our first Featured Article this month published in Stem Cells, Tu et al. report that mesenchymal stem cells (MSCs) present in the tumor microenvironment trigger an lncRNA pathway in neighboring triple-negative breast cancer (TNBC) cells that upregulates the pluripotency-determining gene Kruppel-Like Factor 4 (KLF4) and induces cancer stem cell-like traits [5]. In a Related Article published in Stem Cells Translational Medicine, Haga et al. report that the dramatic improvement in survival in response to the systemic administration of stem cell-derived extracellular vesicles in a mouse model of experimental lethal hepatic injury relies on the protective role of the Y-RNA-1 ncRNA in hepatocytes [6]. Endothelial progenitor cells (EPCs) are proliferative bone-marrow-derived stem cells that can differentiate into mature vascular endothelial cells and contribute to endothelial repair, angiogenesis (the sprouting of new blood vessels from pre-existing vessels), and vasculogenesis (de novo vascular network formation) [7]. EPCs can be isolated from adult peripheral blood and umbilical cord blood or efficiently differentiated from patient-specific induced pluripotent stem cells [8] for use in direct cell transplantation, tissue engineering approaches, and in vitro platforms for the evaluation of personalized therapeutic approaches [9]. With regards to their therapeutic utility, fully understanding the deregulation of EPC function that occurs in microvascular and macrovascular disorders may offer new means to treat the symptoms of a wide range of diseases, including diabetes and cancer. Additionally, many hope to harness the potent neovascularizing power of EPCs for the treatment of conditions such as stroke; however, the relative scarcity of human EPCs may represent a stumbling block. In our second Featured Article this month published in Stem Cells, Shao et al. report that the disrupted cellular metabolism associated with elevated Wnt signaling prompts EPCs to take on a more differentiated state that promotes the abnormal formation of blood vessels in the retina [10]. In a Related Article published in Stem Cells Translational Medicine, Fang et al. establish the long-term safety of transplanted ex vivo expanded autologous EPCs in patients with acute cerebral infarct, thereby providing evidence of the feasibility of this approach in the treatment of ischemic stroke [11]. Featured Articles MSC-Triggered lncRNA Expression in Triple-Negative Breast Cancer Cells Induces a Cancer Stem Cell-Like Fate Researchers led by Antoine E. Karnoub (Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA) previously described the enrichment of MSCs in the tumor microenvironment of TNBC [12] and the critical role MSCs in malignancy [13, 14]. TNBC is a highly aggressive breast cancer subtype that currently lacks effective treatment options, and targeting the communication between niche cells, such as MSCs, and TNBC cells may represent an efficient therapeutic approach. Therefore, the team evaluated the role of lncRNAs in the communication of tumor-associated MSCs with cancer cells in the context of TNBC. In their new Stem Cells study, Tu et al. discovered that the MSC-induced expression of the LINC01133 lncRNA prompted the appearance of cancer stem cell-like characteristics in TNBC cells, including the upregulation of cancer stem cell-associated cell surface marker expression and robust three-dimensional growth in serial tumorsphere assays [5]. The authors discovered that the LINC01133 lncRNA functioned as a direct mediator of an MSC-triggered miR-199a-FOXP2 pathway and promoted cancer stem cell-like traits in TNBC cells by inducing the expression of the KLF4 pluripotency-associated gene. Excitingly, analysis of human breast cancer samples also revealed that LINC01133 expression represents a clinically relevant prognostic indicator of TNBC patient outcomes. Overall, the authors believe that their new findings identify a potential biomarker for disease diagnosis, prognosis, and treatment outcomes, while also providing a new target for the generation of novel therapeutics for patients with TNBC.DOI: 10.1002/stem.3055 Open in new tabDownload slide Open in new tabDownload slide Wnt-Induced Alterations to EPC Metabolism and Cell Fate Prompt Abnormal Blood Vessel Formation While previous studies from the laboratories of Xiao-rong Li (Tianjin Medical University, Tianjin, China) and Jian-Xing Ma (University of Oklahoma, Oklahoma, USA) demonstrated that the knockout of the very low-density lipoprotein receptor (Vldlr) gene promoted dysregulated blood vessel formation in the retina thanks to the activation of Wnt signaling [15, 16], the specific impact of Vldlr loss on EPC number and metabolism remained unknown. Now, the team returns with a new Stem Cells article in which Shao et al. establish that Vldlr knockout mice displaying dysregulated retinal blood vessel formation induced by Wnt signaling over-activation present with increased numbers of EPCs in the bone marrow, blood, and retina [10]. Isolation of cells and analysis revealed that increased Wnt signaling in EPCs prompted the upregulation of mitochondrial biogenesis and function and the inhibition of glycolysis, which, in turn, prompted EPCs to shift from a self-renewing stem cell-like state to a more active differentiated state. The authors believe that this mechanism may represent the cause of pathologic vascular formation observed in Vldlr knockout mice. Interestingly, fenofibric acid, a drug applied as a treatment for diabetic retinopathy, inhibited Wnt signaling and mitochondrial function in EPCs and reduced EPC number in Vldlr knockout mice. Overall, the authors suggest that the metabolic profile of EPCs may represent both a prognostic factor and a therapeutic target for pathological vascular formation in ocular diseases.DOI: 10.1002/stem.3049 Open in new tabDownload slide Open in new tabDownload slide Related Articles Non-Coding RNAs as a Novel Therapeutic Target for Liver Failure Treatment Orthotopic liver transplantation is an effective intervention for patients with liver failure; however, donor organ scarcity and medical, financial, and socioeconomic considerations have limited this approach [17]. As previous findings from the group of Tushar Patel (Mayo Clinic, Jacksonville, Florida, USA) had demonstrated that hepatocytes released extracellular vesicles that modulated recipient cell behavior [18], the authors evaluated stem cell-derived extracellular vesicles as a means to promote tissue repair and functional restoration in the context of liver failure. In their recent Stem Cells Translational Medicine article, Haga et al. examined the effect of systemically administered bone marrow-derived MSC extracellular vesicles in a murine model of hepatic failure, discovering that extracellular vesicles accumulated within the injured liver, reduced hepatic injury, modulated cytokine expression, reduced inflammation, and dramatically increased survival [6]. Fascinatingly, the authors established that the elevated expression of the Y-RNA-1 ncRNA resident in extracellular vesicles mediated the protective effects observed in the murine hepatic failure model. The Y-RNA group of ncRNAs regulate cell proliferation and DNA replication through functional interactions with chromatin and initiation proteins and may also function as cellular stress sensors and promote cellular recovery by salvaging misfolded RNAs. Overall, this study highlights MSC-derived extracellular vesicles as a potentially effective means to treat liver injury and proposes the Y-RNA-1 ncRNA as a potential therapeutic target.DOI: 10.1002/sctm.16-0226 Open in new tabDownload slide Open in new tabDownload slide Trial Supports Endothelial Progenitor Cell Treatment of Ischemic Stroke While studies have demonstrated cerebral neovascularization by circulating EPCs following stroke [19], their relatively low number and the further decrease in this number in older patients and those with higher cardiovascular risk [20] promoted the investigation of ex vivo expanded EPC transplantation to promote recovery after stroke. To this end, researchers from the laboratories of Zhenzhou Chen and Xiaodan Jiang (Southern Medical University, Guangzhou, China) recently reported on their two-center, randomized, placebo-controlled phase I/IIa trial with blinded outcome assessment on eighteen patients with acute cerebral infarct within the middle cerebral artery territory with follow up for four years. In their Stem Cells Translational Medicine article [11], Fang et al. revealed that intravenous injections of autologous ex vivo expanded EPCs failed to elicit toxicity or infusional/allergic reactions. Additionally, EPC-treated patients suffered from fewer serious adverse events when compared with the placebo-controlled group. The trial also observed a degree of efficacy with this approach, as EPC-treated patients displayed improvements in one stroke scoring scale used at three months when compared with the placebo-controlled group. Overall, the authors believe that their findings provide evidence of the long-term safety and potential efficacy of the autologous transplantation of ex vivo expanded EPCs in patients with acute cerebral infarct, supporting the application of this approach in the treatment of ischemic stroke. However, the authors take care to note the requirement for larger phase II trials to overcome the inherent limitations of the trial design.DOI: 10.1002/sctm.18-0012 Open in new tabDownload slide Open in new tabDownload slide References 1 Ulitsky I , Bartel DP. lincRNAs: Genomics, evolution, and mechanisms . Cell 2013 ; 154 : 26 – 46 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Evans JR , Feng FY, Chinnaiyan AM. The bright side of dark matter: lncRNAs in cancer . J Clin Invest 2016 ; 126 : 2775 – 2782 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Gutschner T , Hämmerle M, Eißmann M et al. The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells . Cancer Res 2013 ; 73 : 1180 – 1189 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Gupta RA , Shah N, Wang KC et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis . Nature 2010 ; 464 : 1071 – 1076 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Tu Z , Schmollerl J, Cuiffo BG et al. Microenvironmental regulation of long non-coding RNA LINC01133 promotes cancer-stem-cell-like phenotypic traits in triple-negative breast cancers . Stem Cells 2019 ; 37 : 00 – 00 . Google Scholar Crossref Search ADS WorldCat 6 Haga H , Yan IK, Takahashi K et al. Extracellular vesicles from bone marrow-derived mesenchymal stem cells improve survival from lethal hepatic failure in mice . Stem Cells Translational Medicine 2017 ; 6 : 1262 – 1272 . Google Scholar Crossref Search ADS PubMed WorldCat 7 Sukmawati D , Tanaka R. Introduction to next generation of endothelial progenitor cell therapy: A promise in vascular medicine . Am J Transl Res 2015 ; 7 : 411 – 421 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 8 Samuel R , Daheron L, Liao S et al. Generation of functionally competent and durable engineered blood vessels from human induced pluripotent stem cells . Proc Natl Acad Sci U S A 2013 ; 110 : 12774 – 12779 . Google Scholar Crossref Search ADS PubMed WorldCat 9 Lam GC , Sefton MV. Harnessing gene and drug delivery for vascularizing engineered tissue platforms . Drug Discov Today 2016 ; 21 : 1532 – 1539 . Google Scholar Crossref Search ADS PubMed WorldCat 10 Shao Y , Chen J, Freeman W et al. Canonical Wnt signaling promotes neovascularization through determination of endothelial progenitor cell fate via metabolic profile regulation . Stem Cells 2019 ; 37 : 1331 – 1343 . Google Scholar Crossref Search ADS PubMed WorldCat 11 Fang J , Guo Y, Tan S et al. Autologous endothelial progenitor cells transplantation for acute ischemic stroke: A 4-year follow-up study . Stem Cells Translational Medicine 2019 ; 8 : 14 – 21 . Google Scholar Crossref Search ADS PubMed WorldCat 12 Karnoub AE , Dash AB, Vo AP et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis . Nature 2007 ; 449 : 557 – 563 . Google Scholar Crossref Search ADS PubMed WorldCat 13 Cuiffo Benjamin G , Campagne A, Bell George W et al. MSC-regulated microRNAs converge on the transcription factor FOXP2 and promote breast cancer metastasis . Cell Stem Cell 2014 ; 15 : 762 – 774 . Google Scholar Crossref Search ADS PubMed WorldCat 14 El-Haibi CP , Bell GW, Zhang J et al. Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy . Proc Natl Acad Sci 2012 ; 109 : 17460 – 17465 . Google Scholar Crossref Search ADS PubMed WorldCat 15 Chen Y , Hu Y, Lu K et al. Very low density lipoprotein receptor, a negative regulator of the wnt signaling pathway and choroidal neovascularization . J Biol Chem 2007 ; 282 : 34420 – 34428 . Google Scholar Crossref Search ADS PubMed WorldCat 16 Qiu F , Matlock G, Chen Q et al. Therapeutic effects of PPARα agonist on ocular neovascularization in models recapitulating neovascular age-related macular degeneration . Invest Ophthalmol Vis Sci 2017 ; 58 : 5065 – 5075 . Google Scholar Crossref Search ADS PubMed WorldCat 17 Sass DA , Shakil AO. Fulminant hepatic failure . Liver Transpl 2005 ; 11 : 594 – 605 . Google Scholar Crossref Search ADS PubMed WorldCat 18 Kogure T , Lin W-L, Yan IK et al. Intercellular nanovesicle-mediated microRNA transfer: A mechanism of environmental modulation of hepatocellular cancer cell growth . Hepatology 2011 ; 54 : 1237 – 1248 . Google Scholar Crossref Search ADS PubMed WorldCat 19 Zhang ZG , Zhang L, Jiang Q et al. Bone marrow-derived endothelial progenitor cells participate in cerebral neovascularization after focal cerebral ischemia in the adult mouse . Circ Res 2002 ; 90 : 284 – 288 . Google Scholar Crossref Search ADS PubMed WorldCat 20 Hill JM , Zalos G, Halcox JPJ et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk . N Engl J Med 2003 ; 348 : 593 – 600 . Google Scholar Crossref Search ADS PubMed WorldCat Author notes Received August 23, 2019; accepted for publication August 23, 2019 ©AlphaMed Press 2019 This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - A Preview of Selected Articles
JF - Stem Cells
DO - 10.1002/stem.3086
DA - 2019-10-01
UR - https://www.deepdyve.com/lp/oxford-university-press/a-preview-of-selected-articles-cy2NL13fnh
SP - 1249
EP - 1251
VL - 37
IS - 10
DP - DeepDyve
ER -