Global knockdown of microRNAs affects the expression of growth factors and cytokines in human adipose-derived mesenchymal stem cells
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Cell therapies utilizing mesenchymal stem cells (MSCs) have agreat potential in many research and clinical settings. Themechanisms underlying the therapeutic effects of MSCs havebeen studied previously and the paracrine effects elicited bytheir production of various growth factors and cytokines wererecognized as being crucial. However, the molecular controlsthat govern these paracrine effects remain poorly understood. To elucidate the molecular regulators of this process, weperformed a global knockdown of microRNAs (miRNAs) inhuman adipose-derived mesenchymal stem cells (hADSCs) byinhibiting DGCR8, a key protein in miRNA biogenesis. Globaldisruption of miRNA biogenesis in hADSCs caused dramaticchanges in the expression of subsets of growth factors andcytokines. By performing an extensive bioinformatic analysis,we were able to associate numerous putative miRNAs withthese genes. Taken together, our results strongly suggest thatmiRNAs are essential for the production of growth factors and cytokines in hADSCs.
Abstract
Cell therapies utilizing mesenchymal stem cells (MSCs) have agreat potential in many research and clinical settings. Themechanisms underlying the therapeutic effects of MSCs havebeen studied previously and the paracrine effects elicited bytheir production of various growth factors and cytokines wererecognized as being crucial. However, the molecular controlsthat govern these paracrine effects remain poorly understood. To elucidate the molecular regulators of this process, weperformed a global knockdown of microRNAs (miRNAs) inhuman adipose-derived mesenchymal stem cells (hADSCs) byinhibiting DGCR8, a key protein in miRNA biogenesis. Globaldisruption of miRNA biogenesis in hADSCs caused dramaticchanges in the expression of subsets of growth factors andcytokines. By performing an extensive bioinformatic analysis,we were able to associate numerous putative miRNAs withthese genes. Taken together, our results strongly suggest thatmiRNAs are essential for the production of growth factors and cytokines in hADSCs.
참고문헌 (29)
- Bianco, P., "The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine", Nat. Med, 19, pp.35~42 (2013)
- da Silva Meirelles, L., "Mesenchymal stem cells reside in virtually all post-natal organs and tissues", J. Cell Sci, 119, pp.2204~2213 (2006)
- Brighton, C. T., "Early histological and ultrastructural changes in medullary fracture callus", J. Bone Joint Surg. Am, 73, pp.832~847 (1991)
- Brighton, C. T., "Early histologic and ultrastructural changes in microvessels of periosteal callus", J. Orthop. Trauma, 11, pp.244~253 (1997)
- Kopen, G. C., "Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains", Proc. Natl. Acad. Sci. U. S. A, 96, pp.10711~10716 (1999)
- Mackenzie, T. C., "Human mesenchymal stem cells persist, demonstrate site-specific multipotential differentiation, and are present in sites of wound healing and tissue regeneration after transplantation into fetal sheep", Blood Cells Mol. Dis, 27, pp.601~604 (2001)
- Prockop, D. J., "Repair of tissues by adult stem", progenitor cells (MSCs): controversies, myths, and changing paradigms, 2009, pp.17, 939~946
- Caplan, A. I., "Why are MSCs therapeutic? New data: new insight", J. Pathol, 217, pp.318~324 (2009)
- Salgado, A. J., "Adipose tissue derived stem cells secretome: soluble factors and their roles in regenerative medicine", Curr. Stem Cell Res. Ther, 5, pp.103~110 (2010)
- Chen, L., "Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing", PLoS One, 3, pp.e1886~ (2008)
- Kinnaird, T., "Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms", Circ. Res, 94, pp.678~685 (2004)
- Fabian, M. R., "The mechanics of miRNA-mediated gene silencing: a look under the hood of miRISC", Nat. Struct. Mol. Biol, 19, pp.586~593 (2012)
- Gregory, R. I., "The Microprocessor complex mediates the genesis of micro RNAs", Nature, 432, pp.235~240 (2004)
- Denli, A. M., "Processing of primary microRNAs by the Microprocessor complex", Nature, 432, pp.231~235 (2004)
- Han, J., "The Drosha-DGCR8 complex in primary microRNA processing", Genes Dev, 18, pp.3016~3027 (2004)
- Bernstein, E., "Role for a bidentate ribonuclease in the initiation step of RNA interference", Nature, 409, pp.363~366 (2001)
- Hutvagner, G., "A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA", Science, 293, pp.834~838 (2001)
- Guo, L., "The role of microRNAs in self-renewal and differentiation of mesenchymal stem cells", Exp. Hematol, 39, pp.608~616 (2011)
- Dominici, M., "Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement", Cytotherapy, 8, pp.315~317 (2006)
- Han, J., "Posttranscriptional crossregulation between Drosha and DGCR8", Cell, 136, pp.75~84 (2009)
- Wang, Y., "DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal", Nat. Genet, 39, pp.380~385 (2007)
- Lewis, B. P., "Prediction of mammalian microRNA targets", Cell, 115, pp.787~798 (2003)
- Suh, N., "Small RNAs in early mammalian development: from gametes to gastrulation", Development, 138, pp.1653~1661 (2011)
- Baek, D., "The impact of microRNAs on protein output", Nature, 455, pp.64~71 (2008)
- Selbach, M., "Widespread changes in protein synthesis induced by microRNAs", Nature, 455, pp.58~63 (2008)
- Guo, H., "Mammalian microRNAs predominantly act to decrease target mRNA levels", Nature, 466, pp.835~840 (2010)
- Haider, H., "IGF-1-overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1alpha", CXCR4 signaling to promote myocardial repair, 2008, pp.103, 1300~1308
- Zuk, P. A., "Multilineage cells from human adipose tissue: implications for cell-based therapies", Tissue Eng, 7, pp.211~228 (2001)
- Zuk, P. A., "Human adipose tissue is a source of multipotent stem cells", Mol. Biol. Cell, 13, pp.4279~4295 (2002)