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Carbon Dot-mediated Inhibition of Inflammation Boosts Cartilage Regeneration by MSCs

Review of “Bioconjugated Carbon Dots for Delivery of siTnfα to Enhance Chondrogenesis of Mesenchymal Stem Cells by Suppression of Inflammation” from STEM CELLS Translational Medicine by Stuart P. Atkinson 

The chronic inflammation associated with cartilage injury can dampen the effectiveness of mesenchymal stem cell (MSC) therapy by impairing their chondrogenic potential. As studies have implicated the proinflammatory cytokine tumor necrosis factor‐α (TNFα) in this process [1, 2], researchers from the laboratory of Maolin He, Jinmin Zhao, and Li Zheng (Guangxi Medical University, Nanning, China) sought to explore whether silencing TNFα may facilitate MSC-based therapy of cartilage injury.

A previous study from the authors reported that while small interfering (si)RNAs transfected using fluorescent quantum dots modified with a protein crosslinker as a vehicle effectively silenced gene expression in MSCs [3], the heavy metal toxicity associated with this approach hinders their in vivo application [4]. Now, the team returns with a new STEM CELLS Translational Medicine study that appraises the potential of biocompatible carbon dots [5] as a direct replacement for quantum dots as a means to transfect TNFα siRNA into MSCs and boost chondrogenic differentiation in vivo [6]. 

Liu et al. began by establishing that the highly homogenous modified carbon dots displayed intense fluorescence, allowing bioimaging, and had the characteristics that would favor TNFα siRNA binding, such as an overall positive charge. Encouragingly, the carbon dot-TNFα siRNA nanoformulation exhibited excellent transfection efficiency in MSCs, with carbon dots passing through the endocytotic pathway, and lacked cytotoxicity when compared to polyethyleneimine, a commercially available and widely used transfection agent. Furthermore, carbon dot mediated transfection prompted a greater decrease in TNFα levels, indicative of a reduction in inflammation, than polyethyleneimine, suggesting that carbon dots afforded greater siRNA protection from enzymatic degradation.

Encouragingly, transfection of MSCs with the carbon dot-TNFα siRNA led to an increase in the production of the GAG cartilage matrix marker and the expression of cartilage‐specific markers in MSCs (e.g., Sox9, Col2a1, and Acan), indicating a general increase in chondrogenic differentiation propensity in vitro. However, the authors also discovered that carbon dot-siRNA transfected MSCs prompted the accelerated regeneration of high-quality cartilage following transplantation into a rat cartilage defect model, suggesting their vast potential in cartilage injury treatment in vivo. 

The authors report their findings as the first application of carbon dots as a means to transfect MSCs with siRNA and improve chondrogenic differentiation and thereby promote cartilage repair. Can targeting additional inflammatory mediators further enhance this cartilage formation in vivo¬ and provide a real boost to human patients in the future? 

For the answers to this question, and more, stay tuned to the Stem Cells Portal!

References

  1. López-Armada MJ, Caramés B, Lires-Deán M, et al., Cytokines, tumor necrosis factor-α and interleukin-1β, differentially regulate apoptosis in osteoarthritis cultured human chondrocytes. Osteoarthritis and Cartilage 2006;14:660-669.
  2. Joos H, Wildner A, Hogrefe C, et al., Interleukin-1β and tumor necrosis factor-α inhibit migration activity of chondrogenic progenitor cells from non-fibrillated osteoarthritic cartilage. Arthritis Research & Therapy 2013;15:R119.
  3. Wu Y, Zhou B, Xu F, et al., Functional quantum dot-siRNA nanoplexes to regulate chondrogenic differentiation of mesenchymal stem cells. Acta Biomaterialia 2016;46:165-176.
  4. Tsoi KM, Dai Q, Alman BA, et al., Are Quantum Dots Toxic? Exploring the Discrepancy Between Cell Culture and Animal Studies. Accounts of Chemical Research 2013;46:662-671.
  5. Shao D, Lu M, Xu D, et al., Carbon dots for tracking and promoting the osteogenic differentiation of mesenchymal stem cells. Biomaterials Science 2017;5:1820-1827.
  6. Liu J, Jiang T, Li C, et al., Bioconjugated Carbon Dots for Delivery of siTnfα to Enhance Chondrogenesis of Mesenchymal Stem Cells by Suppression of Inflammation. STEM CELLS Translational Medicine 2019;8:724-736.