Abstract
Experiments with 5′-azacytidine and hematopoietic growth factor approved for the transformation of human mesenchymal cells into hematopoietic cells have demonstrated that cell fate can be dramatically altered by changing the epigenetic state of cells. Here, we demonstrate that umbilical cord-derived human mesenchymal stem cells (uMSC) are easily accessible and could be induced into cells with hematopoietic function. Furthermore, we focused on the crucial miRNAs and relative transcription factors (TFs) in our study. We show that combined Aza/GF incubation can increase expression of miR-218, miR-150, and miR-451. Accordingly, miR-218 overexpression achieved an increase in expression of CD34 (3–13 %), CD45 (50–65 %), CD133 and c-Kit in uMSCs that cultured with Aza/GF. The expression of the relevant transcriptional factors, such as HoxB4 and NF-Ya, was higher than in the negative control group or miR-218 inhibitor transfected group, and microphthalmia-associated transcription factor (MITF) is regarded to be a direct target of miR-218, as demonstrated by luciferase assays. Overexpression of miR-218 might, in conjunction with the MITF, upregulate the expression of NF-Ya and HoxB4, which induce a hematopoietic state. We concluded that miR-218 might have a role in the transformation of hematopoietic cells through the MITF pathway.
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References
Jendiroba DB, Freireich EJ (2000) Granulocyte transfusions: from neutrophil replacement to immunereconstitution. Blood Rev 14:219–227
Rebulla P (2005) A mini-review on platelet refractoriness. Haematologica 90:247–253
Petvises S, O’Neill HC (2012) Hematopoiesis leading to a diversity of dendritic antigen-presenting cell types. Immunol Cell Biol 90(4):372–378
Moncharmont P, Rigal D (2012) Prevalence of platelet-specific antibodies in the recipients of platelet units with transfusion adverse event. Transfus Clin Biol 19(6):333–337
Sachs UJ (2007) The pathogenesis of transfusion-related acute lung injury and how to avoid this serious adverse reaction of transfusion. Transfus Apher Sci 37:273–282
Orkin SH, Zon LI (2008) Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132:631–644
Sandler VM, Lailler N, Bouhassira EE (2011) Reprogramming of embryonic human fibroblasts into fetal hematopoietic progenitors by fusion with human fetal liver CD34+ cells. PLoS One 6(4):e18265
Ramos-Mejía V, Montes R, Bueno C, Ayllón V, Real PJ, Rodríguez R, Menendez P (2012) Residual expression of the reprogramming factors prevents differentiation of iPSC generated from human fibroblasts and cord blood CD34+ progenitors. PLoS One 7(4):e35824
Szabo E, Rampalli S, Risueño RM, Schnerch A, Mitchell R, Fiebig-Comyn A, Levadoux-Martin M, Bhatia M (2010) Direct conversion of human fibroblasts to multilineage blood progenitors. Nature 468(7323):521–526
Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676
Weissman IL, Shizuru JA (2008) The origins of the identification and isolation of hematopoietic stem cells, and their capability to induce donor-specific transplantation tolerance and treat autoimmune diseases. Blood 112(9):3543–3553
Harris DM, Hazan-Haley I, Coombes K, Bueso-Ramos C, Singh S, Sun M, Kundra V, Kurzrock R, Estrov Z (2011) Transformation of human mesenchymal cells and skin fibroblasts into hematopoietic cells. PLoS One 6(6):e21250
Vanhees K, Coort S, Ruijters EJ, Godschalk RW, van Schooten FJ, Barjesteh van Waalwijk van Doorn-Khosrovani S (2011) Epigenetics: prenatal exposure to genistein leaves a permanent signature on the hematopoietic lineage. FASEB J 25(2):797–807
Jackson M, Axton RA, Taylor AH, Wilson JA, Gordon-Keylock SA, Kokkaliaris KD, Brickman JM, Schulz H, Hummel O, Hubner N, Forrester LM (2012) HOXB4 can enhance the differentiation of embryonic stem cells by modulating the hematopoietic niche. Stem Cells 30(2):150–160
Bissels U, Bosio A, Wagner W (2012) MicroRNAs are shaping the hematopoietic landscape. Haematologica 97(2):160–167
Kluiver J, Kroesen B-J, Poppema S, van den Berg A (2006) The role of microRNAs in normal hematopoiesis and hematopoietic malignancies. Leukemia 20:1931–1936
Ooi AG, Sahoo D, Adorno M, Wang Y, Weissman IL, Park CY (2010) MicroRNA-125b expands hematopoietic stem cells and enriches for the lymphoid-balanced and lymphoid-biased subsets. Proc Natl Acad Sci USA 107(50):21505–21510
Fazi F, Rosa A, Fatica A, Gelmetti V, De Marchis ML, Nervi C et al (2005) A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis. Cell 123(5):819–831
Felli N, Fontana L, Pelosi E, Botta R, Bonci D, Facchiano F, Liuzzi F, Peschle C (2005) MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation. Proc Natl Acad Sci USA 102(50):18081–18086
O’Connell RM, Baltimore D (2012) MicroRNAs and hematopoietic cell development. Curr Top Dev Biol 99:145–174
Forrester LM, Jackson M (2012) Mechanism of action of HOXB4 on the hematopoietic differentiation of embryonic stem cells. Stem Cells 30(3):379–385
Bungartz G, Land H, Scadden DT, Emerson SG (2012) NF-Y is necessary for hematopoietic stem cell proliferation and survival. Blood 119(6):1380–1389
Giannola DM, Shlomchik WD, Jegathesan M, Liebowitz D, Emerson SG (2000) Hematopoietic expression of HOXB4 is regulated in normal and leukemic stem cells through transcriptional activation of the HOXB4 promoter by upstream stimulating factor (USF)-1 and USF-2. J Exp Med 192(10):1479–1490
Domashenko AD, Danet-Desnoyers G, Aron A, Carroll MP, Emerson SG (2010) TAT-mediated transduction of NF-Ya peptide induces the ex vivo proliferation and engraftment potential of human hematopoietic progenitor cells. Blood 116(15):2676–2683
Gu J, Qian H, Shen L, Zhang X, Zhu W, Huang L, Yan Y, Mao F, Zhao C, Shi Y, Xu W (2012) Gastric cancer exosomes trigger differentiation of umbilical cord derived mesenchymal stem cells to carcinoma-associated fibroblasts through TGF-β/Smad pathway. PLoS One 7(12):e52465
Chao YH, Wu HP, Chan CK, Tsai C, Peng CT, Wu KH (2012) Umbilical cord-derived mesenchymal stem cells for hematopoietic stem cell transplantation. J Biomed Biotechnol 2012:759503
Arufe MC, De la Fuente A, Fuentes I, Toro FJ, Blanco FJ (2011) Umbilical cord as a mesenchymal stem cell source for treating joint pathologies. World J Orthop 2(6):43–50
Jones PA (1985) Altering gene expression with 5-azacytidine. Cell 40:485–486
Solary E, Fontenay M (2010) Myeloproliferative/myelodysplastic syndromes. Rev Prat 60(10):1413–1415
Issa JP (2007) DNA methylation as a therapeutic target in cancer. Clin Cancer Res 13:1634–1637
Alcazar O, Achberger S, Aldrich W, Hu Z, Negrotto S, Saunthararajah Y, Triozzi P (2012) Epigenetic regulation by decitabine of melanoma differentiation in vitro and in vivo. Int J Cancer 131(1):18–29
Baumert B, Kawa MP, Kotowski M, Grymuła K, Safranow K, Pabisiak K, Pius E, Peregud-Pogorzelski J, Walczak M, Ostrowski M, Machaliński B (2012) Bone marrow of multiorgan donors underutilized: implications for improvement of accessibility of hematopoietic cells for transplantations. Transplantation 93(2):165–171
Liu Y-P, Hemattia P (2009) Generation of mesenchymal stromal cells from a HOXB4-expressing human embryonic stem cells colony. Cytotherapy 11(6):716–725
Navarro F, Lieberman J (2010) Differentiation and function small RNAs guide hematopoietic cell. J Immunol 184:5939–5947
Edelstein LC, Bray PF (2012) Small RNAs as potential platelet therapeutics. Handb Exp Pharmacol 210:435–445
Alemdehy MF, Erkeland SJ (2012) MicroRNAs: key players of normal and malignant myelopoiesis. Curr Opin Hematol 19(4):261–267
Heuston EF, Lemon KT, Arceci RJ (2011) The beginning of the road for non-coding RNAs in normal hematopoiesis and hematologic malignancies. Front Genet 2:94
Huang X, Gschweng E, Van Handel B, Cheng D, Mikkola HK, Witte ON (2011) Regulated expression of microRNAs-126/126* inhibits erythropoiesis from human embryonic stem cells. Blood 117(7):2157–2165
Pritchard CC, Kroh E, Wood B, Arroyo JD, Dougherty KJ, Miyaji MM, Tait JF, Tewari M (2012) Blood cell origin of circulating microRNAs: a cautionary note for cancer biomarker studies. Cancer Prev Res (Phila) 5(3):492–497
Adams BD, Guo S, Bai H, Guo Y, Megyola CM, Cheng J, Heydari K, Xiao C, Reddy EP, Lu J (2012) An in vivo functional screen uncovers miR-150-mediated regulation of hematopoietic injury response. Cell Rep 2(4):1048–1060
Zanette DL, Rivadavia F, Molfetta GA, Barbuzano FG, Proto-Siqueira R, Silva WA Jr, Falcão RP, Zago MA (2007) miRNA expression profiles in chronic lymphocytic and acute lymphocytic leukemia. Braz J Med Biol Res 40(11):1435–1440
He X, Dong Y, Wu CW, Zhao Z, Ng SS, Chan FK, Sung JJ, Yu J (2012) MicroRNA-218 inhibits cell cycle progression and promotes apoptosis in colon cancer by downregulating oncogene BMI-1. Mol Med. doi:10.2119/molmed.2012.00304
Alajez NM, Lenarduzzi M, Ito E, Hui AB, Shi W, Bruce J, Yue S, Huang SH, Xu W, Waldron J, O’Sullivan B, Liu FF (2011) MiR-218 suppresses nasopharyngeal cancer progression through downregulation of survivin and the SLIT2-ROBO1 pathway. Cancer Res 71(6):2381–2391
Lee YN, Brandal S, Noel P, Wentzel E, Mendell JT, McDevitt MA, Kapur R, Carter M, Metcalfe DD, Takemoto CM (2011) KIT signaling regulates MITF expression through miRNAs in normal and malignant mast cell proliferation. Blood 117(13):3629–3640
Shen J, Wang S, Zhang YJ, Kappil MA, Chen Wu H, Kibriya MG, Wang Q, Jasmine F, Ahsan H, Lee PH, Yu MW, Chen CJ, Santella RM (2012) Genome-wide aberrant DNA methylation of microRNA host genes in hepatocellular carcinoma. Epigenetics 7(11):1230–1237
Wang P, Li Y, Hong W, Zhen J, Ren J, Li Z, Xu A (2012) The changes of microRNA expression profiles and tyrosinase related proteins in MITF knocked down melanocytes. Mol Biosyst 8(11):2924–2931
Gao C, Zhang Z, Liu W, Xiao S, Gu W, Lu H (2010) Reduced microRNA-218 expression is associated with high nuclear factor kappa B activation in gastric cancer. Cancer 116:41–49
Acknowledgments
We acknowledge Pengfei Luo, from Changhai Hospital, give us a kind aid of data analysis and interpretation. This study was supported by the National Key Basic Research and Development Project (Beijing, China) (No. 2011CB965101).
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The authors declare that they have no conflict of interest.
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Hu, K., Xu, C., Ni, H. et al. Mir-218 contributes to the transformation of 5-Aza/GF induced umbilical cord mesenchymal stem cells into hematopoietic cells through the MITF pathway. Mol Biol Rep 41, 4803–4816 (2014). https://doi.org/10.1007/s11033-014-3351-y
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DOI: https://doi.org/10.1007/s11033-014-3351-y