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In or Out? – Modifying MSCs to Enhance Bone Tropism



Review of “Glycoengineering of E-Selectin Ligands by Intracellular versus Extracellular Fucosylation Differentially Affects Osteotropism of Human Mesenchymal Stem Cells” from Stem Cells by Stuart P. Atkinson

Intravenous injection of mesenchymal stem cells (MSCs) holds great promise for the treatment of systemic bone diseases; however, the lack of MSC tropism to the bone represents a major stumbling block. This is partly due to the lack of E-selectin ligands on the surface of MSCs which mediate bone tropism.

Previous studies by the lab of Robert Sackstein (Harvard University, Massachusetts, USA) demonstrated how the extracellular modification of MSC surface glycans could create E-selectin ligands to enhance bone tropism [1] and this proved so successful as to warrant a clinical trial for the treatment of osteoporosis.

Conversely, there exists another strategy to create MSC E-selectin ligands: the intracellular introduction of synthetic modified mRNA (modRNA) coding for the same enzyme employed for extracellular modification. Questions still remain about this alternate approach, and so Dykstra et al set out to compare how the extracellular and intracellular strategies for MSC E-ligand formation differentially mediate bone tropism [2]. So is it in or out?

As expected, surface expression of the E-selectin ligands peaked immediately after extracellular modification and returned to baseline levels very quickly. However, intracellular modification mediated an E-selectin ligand peak at 2-3 days after modRNA transfection followed by a more gradual decrease. While both methods generated a similar expression level of maximal surface E-selectin ligands, intracellular modification also mediated additional intracellular E-selectin ligand expression. 

These differences did not lead to differences in MSC marker expression profiles or differentiation potential and shear-based functional assays demonstrated comparable increases in interactions with E-selectin-expressing human endothelial cells. However, despite these similarities, live imaging studies revealed an increase in tropism to mouse skull bone (calvarium) following intravenous administration of intracellularly modified MSCs compared to extracellularly modified MSCs. The authors also observed an increase in the ability of intracellularly modified MSCs (blue) traveling from blood vessels into bone marrow parenchyma (See Figure).

In or out? This excellent study, the first to compare intracellular and extracellular E-selectin ligand modification employing the same enzyme, suggests that the intracellular route wins this battle. This new strategy may permit intravenous injection of MSCs, instead of the potentially harmful direct injection of MSCs into injured/diseased organs, due to the increase systemic trafficking towards the bone. The authors do note that while their method is effective further combinations with other strategies to improve MSC-based bone tropism, such as the application of alendronate [3], the upregulation of CXCR4 [4], or the increase of integrin levels or activity [5, 6], may lead to potent synergistic effects and an increase in therapeutic responses.


  1. Sackstein R, Merzaban JS, Cain DW, et al. Ex vivo glycan engineering of CD44 programs human multipotent mesenchymal stromal cell trafficking to bone. Nat Med 2008;14:181-187.
  2. Dykstra B, Lee J, Mortensen LJ, et al. Glycoengineering of E-Selectin Ligands by Intracellular versus Extracellular Fucosylation Differentially Affects Osteotropism of Human Mesenchymal Stem Cells. Stem Cells 2016;34:2501-2511.
  3. Yao W, Guan M, Jia J, et al. Reversing bone loss by directing mesenchymal stem cells to bone. Stem Cells 2013;31:2003-2014.
  4. Jones GN, Moschidou D, Lay K, et al. Upregulating CXCR4 in human fetal mesenchymal stem cells enhances engraftment and bone mechanics in a mouse model of osteogenesis imperfecta. Stem Cells Transl Med 2012;1:70-78.
  5. Srouji S, Ben-David D, Fromigue O, et al. Lentiviral-mediated integrin alpha5 expression in human adult mesenchymal stromal cells promotes bone repair in mouse cranial and long-bone defects. Hum Gene Ther 2012;23:167-172.
  6. Hamidouche Z, Fromigue O, Ringe J, et al. Priming integrin alpha5 promotes human mesenchymal stromal cell osteoblast differentiation and osteogenesis. Proc Natl Acad Sci U S A 2009;106:18587-18591.