You are here

| Haematopoetic Stem Cells

Regulating the Haematopoietic Niche with Nanoparticle-targeted Small Interfering RNAs

Review of "Nanoparticle-encapsulated siRNAs for gene silencing in the haematopoietic stem-cell niche" from Nature Biomedical Engineering by Stuart P. Atkinson

Technologies that modulate cell behavior within the hematopoietic niche could improve our fundamental understanding and treatment of a range of disease processes governed by bone-marrow-derived leukocytes. In this respect, small interfering (si)RNA [1, 2] combined with an appropriate delivery system [3, 4] have the potential to influence protein expression within the hematopoietic niche.

In a previous study, researchers from the laboratory of Daniel G. Anderson (MIT, Cambridge, MA, USA) and Matthias Nahrendorf (Harvard Medical School, Boston, MA, USA) reported that a low-molecular-weight polyamine and lipid nanoparticle allowed for efficient siRNA-mediated gene silencing in mouse lung endothelial cells in vivo [5]. In their new study, the team now describes a novel nanoparticle carrying an siRNA cargo that targets the endothelial cells of the hematopoietic niche to silence two niche factors that alter hematopoietic stem/progenitor cell behavior and systemic leukocyte supply [6].

Krohn-Grimberghe, Mitchell, Schloss, Anderson, and Nahrendorf et al. began by screening nanoparticle materials synthesized by reacting low-molecular-weight polyamines with epoxide-terminated lipids using an epoxide ring-opening reaction [5, 7] and developed a polyethylene glycol (PEG)-lipid hybrid nanoparticle (which they termed NicheEC-15) for the systemic delivery of siRNA to bone marrow endothelial cells. To avoid entrapment in the lungs, increase blood circulation time, and enhance specific delivery to endothelial cells, the authors fine-tuned the nanoparticle's PEG architecture through strategies that included modulating PEG molecular weight and surface density.

The study employed siRNAs to silence niche factors to either enhance (by silencing stromal-derived factor 1 [Sdf1]) or inhibit (by silencing monocyte chemotactic protein 1 [Mcp1]) the release of hematopoietic stem/progenitor cells from the bone marrow and the number of systemic leukocytes. Sdf1 normally promotes stem cell quiescence and bone marrow retention of leukocytes via interaction with its cognate receptor Cxcr4, while Mcp1 is a chemokine that triggers bone marrow monocyte release. Excitingly, the in vivo nanoparticle-mediated silencing of Mcpl1 in a mouse model of myocardial infarction effectively reduced the number of leukocytes in the diseased heart, improved healing, and attenuated heart failure.

The authors note that their approach can be modified to silence a range of endothelial-cell-derived bone marrow niche factors, target other niche cells, including bone marrow macrophages, mesenchymal stem cells, or osteoblasts, or provide therapeutic approaches to the treatment of diseases such as leukemia, infections, or cardiovascular disease.

For more on the silencing of hematopoietic niche factors using nanoparticle-targeted siRNA, stay tuned to the Stem Cells Portal!

References

  1. Whitehead KA, Langer R, and Anderson DG, Knocking down barriers: advances in siRNA delivery. Nature Reviews Drug Discovery 2009;8:129-138.
  2. Titze-de-Almeida R, David C, and Titze-de-Almeida SS, The Race of 10 Synthetic RNAi-Based Drugs to the Pharmaceutical Market. Pharmaceutical Research 2017;34:1339-1363.
  3. Anselmo AC and Mitragotri S, Nanoparticles in the clinic: An update. Bioengineering & Translational Medicine 2019;4:e10143.
  4. Anselmo AC and Mitragotri S, Nanoparticles in the clinic. Bioengineering & Translational Medicine 2016;1:10-29.
  5. Dahlman JE, Barnes C, Khan OF, et al., In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight. Nature Nanotechnology 2014;9:648-655.
  6. Krohn-Grimberghe M, Mitchell MJ, Schloss MJ, et al., Nanoparticle-encapsulated siRNAs for gene silencing in the haematopoietic stem-cell niche. Nature Biomedical Engineering 2020;4:1076-1089.
  7. Whitehead KA, Dorkin JR, Vegas AJ, et al., Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity. Nature Communications 2014;5:4277.