Abstract
Over the past decade, adult stem cells have attracted great attention because of their ability to potentially regenerate desired tissues or entire organs. With the emergence of nanomaterial-based gene therapy, adult stem cells have been considered as a proper tool for the biomedical field. In this study, we utilized organically modified silica (ORMOSIL) nanoparticles to deliver small interfering RNA (siRNA) against pigment epithelium-derived factor (PEDF) and induce the differentiation of human cardiac stem cells (CSCs). We found that the down-regulation of PEDF can inhibit the proliferation of human CSCs and induce cell differentiation. To further study the mechanism, we have tested the Notch signalling pathway genes, Hes1 and Hes5, and found that their expressions were inhibited by the PEDF down-regulation. Furthermore, with the restoration of PEDF, both the proliferation of human CSCs and expressions of Hes1 and Hes5 were recovered. Our results suggest for the first time the use of ORMOSIL as nanocarriers for the delivery of PEDF siRNA in human CSCs, and demonstrated the cooperation between PEDF and the Notch signalling pathway in maintaining the self-renewal and pluripotency of stem cells. PEDF as the essential controller in differentiation may be a promising target for the regulation of cardiac homeostasis and damage repair, which opens new treatment strategies using nanomaterials for heart disease therapy.
Similar content being viewed by others
References
Aguirre A, Rubio ME, Gallo V (2010) Notch and EGFR pathway interaction regulates neural stem cell number and self-renewal. Nature 467:323-U101
Ahuja P, Sdek P, MaClellan WR (2007) Cardiac myocyte cell cycle control in development, disease, and regeneration. Physiol Rev 87:521–544
Alkilany AM, Nagaria PK, Hexel CR, Shaw TJ, Murphy CJ, Wyatt MD (2009) Cellular uptake and cytotoxicity of gold nanorods: molecular origin of cytotoxicity and surface effects. Small 5:701–708
Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R, Poser SW, Rueger MA, Bae SK, Kittappa R, McKay RDG (2006) Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442:823–826
Bao ZZ, Cepko CL (1997) The expression and function of Notch pathway genes in the developing rat eye. J Neurosci 17:1425–1434
Baron M (2003) An overview of the Notch signalling pathway. Semin Cell Dev Biol 14:113–119
Bharali DJ, Klejbor I, Stachowiak EK, Dutta P, Roy I, Kaur N, Bergey EJ, Prasad PN, Stachowiak MK (2005) Organically modified silica nanoparticles: a nonviral vector for in vivo gene delivery and expression in the brain. Proc Natl Acad Sci U S A 102:11539–11544
Bhutto IA, McLeod DS, Hasegawa T, Kim SY, Merges C, Tong P, Lutty GA (2006) Pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) in aged human choroid and eyes with age-related macular degeneration. Exp Eye Res 82:99–110
Bilak MM, Corse AM, Bilak SR, Lehar M, Tombran-Tink J, Kuncl RW (1999) Pigment epithelium-derived factor (PEDF) protects motor neurons from chronic glutamate-mediated neurodegeneration. J Neuropathol Exp Neurol 58:719–728
Borchardt T, Braun T (2007) Cardiovascular regeneration in non-mammalian model systems: what are the differences between newts and man? Thromb Haemost 98:311–318
Bray SJ (2006) Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7:678–689
Brohl D, Vasyutina E, Czajkowski MT, Griger J, Rassek C, Rahn HP, Purfurst B, Wende H, Birchmeier C (2012) Colonization of the satellite cell niche by skeletal muscle progenitor cells depends on notch signals. Dev Cell 23:469–481
Campochiaro PA, Sugg R, Grotendorst G, Hjelmeland LM (1989) Retinal-pigment epithelial-cells produce Pdgf-like proteins and secrete them into their media. Exp Eye Res 49:217–227
Colter DC, Sekiya I, Prockop DJ (2001) Identification of a subpopulation of rapidly self-renewing and multipotential adult stem cells in colonies of human marrow stromal cells. Proc Natl Acad Sci U S A 98:7841–7845
Dawson DW, Volpert OV, Gillis P, Crawford SE, Xu H, Benedict W, Bouck NP (1999) Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 285:245–248
Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM, Wicha MS (2004) Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res 6:R605–R615
Ek ETH, Dass CR, Choong PFM (2006) PEDF: a potential molecular therapeutic target with multiple anti-cancer activities. Trends Mol Med 12:497–502
Garbern JC, Lee RT (2013) Cardiac stem cell therapy and the promise of heart regeneration. Cell Stem Cell 12:689–698
Jackson KA, Majka SM, Wang HY, Pocius J, Hartley CJ, Majesky MW, Entman ML, Michael LH, Hirschi KK, Goodell MA (2001) Regeneration of ischemic cardiac muscle and vascular endothelium by adult hematopoietic stem cells. Circulation 104:289–289
Karakousis PC, John SK, Behling KC, Surace EM, Smith JE, Hendrickson A, Tang WX, Bennett J, Milam AH (2001) Localization of pigment epithelium derived factor (PEDF) in developing and adult human ocular tissues. Mol Vis 7:154–163
Korbling M, Estrov Z (2003) Adult stem cells for tissue repair—a new therapeutic concept? N Engl J Med 349:570–582
Kumar R, Roy I, Hulchanskyy TY, Goswami LN, Bonoiu AC, Bergey EJ, Tramposch KM, Maitra A, Prasad PN (2008) Covalently dye-linked, surface-controlled, and bioconjugated organically modified silica nanoparticles as targeted probes for optical imaging. ACS Nano 2:449–456
Lepilina A, Coon AN, Kikuchi K, Holdway JE, Roberts RW, Burns CG, Poss KD (2006) A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration. Cell 127:607–619
Liang HL, Hou HY, Yi W, Yang GD, Gu CH, Lau WB, Gao EH, Ma XL, Lu ZF, Wei XF, Pei JM, Yi DH (2013) Increased expression of pigment epithelium-derived factor in aged mesenchymal stem cells impairs their therapeutic efficacy for attenuating myocardial infarction injury. Eur Heart J 34:1681–1690
Lu J, Liong M, Li ZX, Zink JI, Tamanoi F (2010) Biocompatibility, biodistribution, and drug-delivery efficiency of mesoporous silica nanoparticles for cancer therapy in animals. Small 6:1794–1805
Menasche P, Hagege AA, Scorsin M, Pouzet B, Desnos M, Duboc D, Schwartz K, Vilquin JT, Marolleau JP (2001) Myoblast transplantation for heart failure. Lancet 357:279–280
Mori K, Duh E, Gehlbach P, Ando A, Takahashi K, Pearlman J, Yang HS, Zack DJ, Ettyreddy D, Brough DE, Wei LL, Campochiaro PA (2001) Pigment epithelium-derived factor inhibits retinal and choroidal neovascularization. J Cell Physiol 188:253–263
Ow H, Larson DR, Srivastava M, Baird BA, Webb WW, Wiesner U (2005) Bright and stable core-shell fluorescent silica nanoparticles. Nano Lett 5:113–117
Park EJ, Park K (2009) Oxidative stress and pro-inflammatory responses induced by silica nanoparticles in vivo and in vitro. Toxicol Lett 184:18–25
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147
Poss KD (2007) Getting to the heart of regeneration in zebrafish. Semin Cell Dev Biol 18:36–45
Ramirez-Castillejo C, Sanchez-Sanchez F, Andreu-Agullo C, Ferron SR, Aroca-Aguilar JD, Sanchez P, Mira H, Escribano J, Farinas I (2006) Pigment epithelium-derived factor is a niche signal for neural stem cell renewal. Nat Neurosci 9:331–339
Rayavarapu RG, Petersen W, Hartsuiker L, Chin P, Janssen H, van Leeuwen FW, Otto C, Manohar S, van Leeuwen TG (2010) In vitro toxicity studies of polymer-coated gold nanorods. Nanotechnology 21:145101
Rychli K, Huber K, Wojta J (2009) Pigment epithelium-derived factor (PEDF) as a therapeutic target in cardiovascular disease. Expert Opin Ther Targets 13:1295–1302
Sarker B, Lyer S, Arkudas A, Boccaccini AR (2013) Collagen/silica nanocomposites and hybrids for bone tissue engineering. Nanotechnol Rev 2:427–447
Slowing II, Trewyn BG, Giri S, Lin VSY (2007) Mesoporous silica nanoparticles for drug delivery and biosensing applications. Adv Funct Mater 17:1225–1236
Stingl J, Eirew P, Ricketson I, Shackleton M, Vaillant F, Choi D, Li HI, Eaves CJ (2006) Purification and unique properties of mammary epithelial stem cells. Nature 439:993–997
Tombran-Tink J, Barnstable CJ (2003) PEDF: a multifaceted neurotrophic factor. Nat Rev Neurosci 4:628–636
Vallet-Regi M, Ramila A, del Real RP, Perez-Pariente J (2001) A new property of MCM-41: drug delivery system. Chem Mater 13:308–311
Yin F, Lan R, Zhang X, Zhu L, Chen F, Xu Z, Liu Y, Ye T, Sun H, Lu F, Zhang H (2014) LSD1 regulates pluripotency of embryonic stem/carcinoma cells through histone deacetylase 1-mediated deacetylation of histone H4 at lysine 16. Mol Cell Biol 34:158–179
Yin F, Yang CB, Wang QQ, Zeng SW, Hui R, Lin GM, Tian JL, Hu SY, Lan RF, Yoon SH, Lu F, Wang K, Yong KT (2015) A light-driven therapy of pancreatic adenocarcinoma using gold nanorods-based nanocarriers for Co-delivery of doxorubicin and siRNA. Theranostics 5:818–833
Zhao YN, Trewyn BG, Slowing II, Lin VSY (2009) Mesoporous silica nanoparticle-based double drug delivery system for glucose-responsive controlled release of insulin and cyclic AMP. J Am Chem Soc 131:8398
Acknowledgments
This work was supported by National Natural Science Foundation of China (81200151), National Science and Technology Support Program (2011BAI11B20), and Shanxi Province Technology Project (2013KTCL03-01).
Conflict of interest
The authors declare that they have no competing interest.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Hongliang Liang, Weixun Duan and Huiyuan Hou contributed equally to this work.
Rights and permissions
About this article
Cite this article
Liang, H., Duan, W., Hou, H. et al. The roles of nanocarriers on pigment epithelium-derived factor in the differentiation of human cardiac stem cells. Cell Tissue Res 362, 611–621 (2015). https://doi.org/10.1007/s00441-015-2235-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00441-015-2235-3