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Magnetic MSCs Mediate Maximal Mineralization!



Review of Remotely Activated Mechanotransduction via Magnetic Nanoparticles Promotes Mineralization Synergistically With Bone Morphogenetic Protein 2”  from Stem Cells TM by Stuart P. Atkinson

Mechanotransduction is an essential mediator of bone turnover and, as studies have suggested, the osteoblastic differentiation of mesenchymal stem cells (MSCs) [1, 2]. The mechanotransduction of stem cells applied in a therapeutic context is often overlooked due to inherent difficulties of application in patients. Indirect methods have been investigated, such as ultrasound, piezoelectric biomaterials or oscillating electrical fields, although the most advanced option is currently the specific targeting of cell-surface mechanoreceptors with functionalized magnetic nanoparticles which are then excited using external magnetic fields [3]. In a recent report in Stem Cells TM, the group of Alicia J. El Haj (Keele University, Stoke-on-Trent, United Kingdomhave tested this method in two animal models of bone formation using human stem cells (See Figure for Experimental Overview), finding a positive effect on bone formation [4].

The group used an organotypic culture model (ex vivo developing chick fetal femur) which allows the monitoring of mineralization and osteogenic effects using x-ray microtomography, and a tissue-engineered collagen hydrogel, allowing more finely controlled conditions with direct relevance to biomaterial strategies for regenerative medicine. The group mixed human MSCs collected from bone marrow aspirates with nanoparticles conjugated with antibodies against TREK1 (mechanically gated ion channel) or Arg-Gly-Asp (RGD)-binding sites of integrins. The authors then assessed each model after the addition of the functionalized MSCs and culture in incubators above a custom-built vertical oscillating magnetic force bioreactor. Assessment of the chick culture 14 days after injection of MSCs into the femur found more widespread mineralization as compared to the various control groups (sham-injected, MSCs only or oscillating magnet alone). Overall, RGD-coated magnetic nanoparticles led to a 34% increase in bone formation, while TREK1 mediated a 31% increase. The more detailed approach (collagen hydrogel), analyzed at 28 days, found a similar effect for the functionalized MSCs - significant increases in both volume and density of mineralized matrix which stained intensely for both collagen and calcium. The authors then assessed both systems after the co-addition of bone morphogenetic protein 2 (BMP2)-releasing polymer microspheres, which mediate a controlled daily release. BMP2 addition by this means significantly increased the density of the chick bone collar above BMP2 treatment alone (which elicited a non-significant increase) or either of the functionalized MSC groups, with similar trends found in the collagen hydrogel system.

These fascinating findings highlight a important therapeutic modality towards improving the treatment of bone defects. Controlled mechanotransduction represents an exciting step forward, and the use of adaptable nanoparticles already have existing regulatory approval as magnetic resonance imaging contrast agents [5] making such studies immediately applicable. Further work to refine the process and further improve bone formation through adding or defining better cell surface targets lies ahead, but their potential as injectable therapies for regenerative medicine is plain to see.


  1. Kim IS, Song YM, Cho TH, et al. Synergistic action of static stretching and BMP-2 stimulation in the osteoblast differentiation of C2C12 myoblasts. Journal of biomechanics 2009;42:2721-2727.
  2. Kopf J, Petersen A, Duda GN, et al. BMP2 and mechanical loading cooperatively regulate immediate early signalling events in the BMP pathway. BMC Biol 2012;10:37.
  3. Wimpenny I, Markides H, and El Haj AJ Orthopaedic applications of nanoparticle-based stem cell therapies. Stem cell research & therapy 2012;3:13.
  4. Henstock JR, Rotherham M, Rashidi H, et al. Remotely Activated Mechanotransduction via Magnetic Nanoparticles Promotes Mineralization Synergistically With Bone Morphogenetic Protein 2: Applications for Injectable Cell Therapy. Stem Cells Translational Medicine 2014;
  5. Markides H, Kehoe O, Morris RH, et al. Whole body tracking of superparamagnetic iron oxide nanoparticle-labelled cells--a rheumatoid arthritis mouse model. Stem cell research & therapy 2013;4:126.