Calcium-microRNA Complexes Functionalized Nanotubular Implant Surface for Highly Efficient Transfection and Enhanced Osteogenesis of Mesenchymal Stem Cells

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DOI

  • Wen Song, State Key Laboratory of Military Stomatology, Department of Prothodontics, The School of Stomatology, Fourth Military Medical University, Xi-an, China
  • ,
  • Chuanxu Yang
  • Dang Quang Svend Le
  • Yumei Zhang, State Key Laboratory of Military Stomatology, Department of Periodontology, School of Stomatology, The Fourth Military Medical University, Xi-an, China.
  • ,
  • Jørgen Kjems

Controlling mesenchymal stem cells (MSCs) differentiation by RNA interference (RNAi) is a promising approach for next-generation regenerative medicine. However, efficient delivery of RNAi therapeutics is still a limiting factor. In this study, we have developed a simple, biocompatible and highly effective delivery method of small RNA therapeutics into hMSCs from an implant surface by calcium ions. First, we demonstrated that simple Ca/siGFP nanocomplexes were able to efficiently silence GFP in GFP-expressing hMSCs with adequate Ca2+ concentration (>5 mM). In addition, a single transfection could obtain a long-lasting silencing effect for more than two weeks. All three of the main endocytosis pathways (clathrin- and caveolin-mediated endocytosis and macropinocytosis) were involved in the internalization of the Ca/siRNA complexes by MSCs and macropinocytosis plays the most dominant role. Furthermore, the Ca/siRNA complexes could be efficiently loaded onto titanium implant surface when pre-treated with anodization to create a nanotubes (NTs) layer. Due to the hydrophilic property of the NTs surface, the Ca/siRNA was quickly loaded (less than 4 hours) with high efficiency (nearly 100%) forming an even amorphous coating. Ca/siRNA coated NTs surface showed an initial burst release of 80% of the siRNA complexes over 2 hours, which is adequate to achieve robust gene silencing of attached hMSCs. To demonstrate the therapeutic potential of our Ca/siRNA coating technology, Ca/antimiR-138 complexes were loaded on to NTs surface, which strongly enhanced osteogenic differentiation of hMSCs. In conclusion, our findings suggest that the Ca2+ is an effective and biocompatible carrier to deliver small RNA therapeutics into hMSCs, both in solution and from functionalized surfaces, which provide a novel approach to control the MSCs differentiation and tissue regeneration.

Original languageEnglish
JournalA C S Applied Materials and Interfaces
Volume10
Issue9
Pages (from-to)7756-7764
Number of pages9
ISSN1944-8244
DOIs
Publication statusPublished - 7 Mar 2018

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  • Journal Article

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