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Novel Approach Enhances Mesenchymal Stem Cell-mediated Bone Repair

Review of “Smurf1 silencing using an LNA-ASOS/lipid nanoparticle system to promote bone regeneration” from STEM CELLS Translational Medicine by Stuart P. Atkinson

A previous study from the laboratory of Flor Maria Pérez-Campo (University of Cantabria, IDIVAL, Santander, Spain) discovered that the small interfering (si)RNA-mediated knockdown of the HECT-type ubiquitin ligase Smurf1 (Smad ubiquitination regulatory factor 1) [1] in rat mesenchymal stem cells (MSCs) induced bone formation through an increase in BMP-Smad signaling and the enhanced expression of osteogenic genes [2]. However, as the instability of siRNA molecules and the viral delivery vehicles required present significant problems to clinical translational, the team sought to develop a new, more widely applicable approach.

In their new STEM CELLS Translational Medicine study, researchers from the Pérez-Campo laboratory explored the transient silencing of Smurf1 in MSCs using GapmeRs, a variety of clinically safe and highly effective locked nucleic acid antisense oligonucleotides (LNA-ASOs) that display increased stability, RNA binding, and RNA cleavage [3]. To deliver a relatively small amount of anti-Smurf1 GapmeRs but still induce significant gene silencing and prime osteogenic differentiation of MSCs, the authors turned to a non-toxic lipidic transfection agent that promotes cell uptake through endocytosis [4]. Garcia-Garcia et al. combine this strategy with biocompatible scaffolds that sustainably release low BMP-2 doses [2] to demonstrate the potential of this approach as a safe, effective and clinically translatable means to treat critical size fractures or improve bone regeneration [5].

Overall, the authors found that silencing of Smurf1 via a single transient transfection of anti-Smurf1 LNA-ASOs increased the responsiveness of rat MSCs to BMP-2, allowing a reduction in the levels of BMP-2 required to promote osteogenic differentiation and, as a consequence, a reduction in the potential adverse side-effects caused by overexposure to BMP-2. Said side-effects include increased in inflammatory cell infiltration, increased serum levels of anti-BMP antibodies, generalized edema, and heterotrophic ossification [6].

While the authors established that Smurf1-silenced MSCs induced the enhanced formation of mature bone matrix in osteoporotic rat calvaria (skullcap) defects and a mouse ectopic model when combined with alginate scaffolds designed to release low doses of BMP-2, they also provided evidence that their approach could enhance the in vitro osteogenic differentiation of human MSCs derived from osteoporotic patients that suffer from reduced bone-forming potential. 

The authors of this interesting new study propose the synergistic implementation of BMP-2 releasing scaffolds and LNA-ASO-mediated Smurf1 silencing in MSCs as a promising strategy to heal large bone defects, thereby contributing to the overall improvement of bone quality and the prevention of fractures. Additionally, their analysis using osteoporotic MSCs suggests paves the way for the rapid translation of this promising strategy into those patients who would benefit most.

For more novel mesenchymal stem cell-based approaches to bone repair, stay tuned to the Stem Cells Portal

 

References

  1. Zhu H, Kavsak P, Abdollah S, et al., A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature 1999;400:687-693.
  2. Rodríguez-Évora M, García-Pizarro E, del Rosario C, et al., Smurf1 Knocked-Down, Mesenchymal Stem Cells and BMP-2 in an Electrospun System for Bone Regeneration. Biomacromolecules 2014;15:1311-1322.
  3. Fluiter K, Mook ORF, Vreijling J, et al., Filling the gap in LNA antisense oligo gapmers: the effects of unlocked nucleic acid (UNA) and 4′-C-hydroxymethyl-DNA modifications on RNase H recruitment and efficacy of an LNA gapmer. Molecular BioSystems 2009;5:838-843.
  4. Schroeder A, Levins CG, Cortez C, et al., Lipid-based nanotherapeutics for siRNA delivery. Journal of Internal Medicine 2010;267:9-21.
  5. García-García P, Ruiz M, Reyes R, et al., Smurf1 Silencing Using a LNA-ASOs/Lipid Nanoparticle System to Promote Bone Regeneration. STEM CELLS Translational Medicine 2019;8:1306-1317.
  6. James AW, LaChaud G, Shen J, et al., A Review of the Clinical Side Effects of Bone Morphogenetic Protein-2. Tissue Engineering Part B: Reviews 2016;22:284-297.