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Boosting Repair by Getting Stem Cells out of their Trap?

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Review of “Excess integrins cause lung entrapment of mesenchymal stem cells” from Stem Cells by Stuart P. Atkinson

Getting trapped in an unwanted situation is never a good thing and it’s no different for the mesenchymal stem cells (MSCs) used in the treatment of multiple diseases/disorders. Following intravenous delivery, their preferred route of ingress into the human body [1], they tend to get trapped in the lungs and many do not reach their intended therapeutic target elsewhere in the body [2, 3]. Unfortunately, the causes for this well-known problem are little understood, and we currently lack the means to avoid lung accumulation of MSCs.

In a new study, the laboratory of Yaojiong Wu (Tsinghua University, People's Republic of China) has now found that the overexpression of activated forms of proteins belonging to the Integrin family cause lung entrapment of MSCs. Excitingly, by interfering with Integrin-ligand binding, the group has also described a strategy to boost MSC homing and engraftment to sites of tissue injury [4].

The Integrin proteins are transmembrane receptors which mediate cell-cell and cell-extracellular matrix (ECM) interactions, and the authors found that cultivation and expansion in conventional 2D adherent culture boosted the levels of some of this protein family. Specifically, they found that the expression of integrins β1, α5, and αVβ3 expression increased in 2D culture, but not in 3D non-adherent culture (See figure), and that lung vascular endothelial cells expressed the ligands for these receptors (fibronectin and vitronectin). Put two and two together, and you have a culture-induced recipe for MSC entrapment in the lungs.

In an attempt to avoid this entrapment, the authors incubated MSCs with blocking antibodies against these Integrins. Encouragingly, this pre-treatment effectively reduced the level of MSCs entrapped in the lungs, increased MSC levels in the peripheral blood, and in turn improved the homing and engraftment of MSCs to sites of damage (ischemic myocardium) or inflammation (inflamed ear). The study did not, however, quantify any changes in regenerative/reparative function, although the increase in homing and engraftment suggests that these functions are likely to be enhanced.

Many studies have aimed to improve MSC homing and engraftment via overexpression of chemotactic factors or pre-conditioning with inflammatory compounds, but interfering with integrins to inhibit lung entrapment may provide the biggest therapeutic boost of all. However, current strategies to interfere with or inhibit Integrin-ligand interactions are expensive (blocking antibodies) or time-consuming (3D culture), and any proof of an elevated regenerative/reparative effect remains undemonstrated. Furthermore, the authors implicate further additional adhesive molecules in MSC entrapment, and so there may be more complexity to this trap still to uncover.

Discussion Points

 

  • Will the reduction in entrapment lead to an increase in the therapeutic effect of MSCs?
  • What other adhesive molecules could be involved?
  • Does Integrin-mediated entrapment represent a common mechanism between stem cells or are there cell-specific differences?
  • What other methods can we apply to reduce integrin expression?

 

References

  1. Wu Y and Zhao RC The role of chemokines in mesenchymal stem cell homing to myocardium. Stem Cell Rev 2012;8:243-250.
  2. Lee RH, Pulin AA, Seo MJ, et al. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 2009;5:54-63.
  3. Toma C, Wagner WR, Bowry S, et al. Fate of culture-expanded mesenchymal stem cells in the microvasculature: in vivo observations of cell kinetics. Circ Res 2009;104:398-402.
  4. Wang S, Guo L, Ge J, et al. Excess Integrins Cause Lung Entrapment of Mesenchymal Stem Cells. Stem Cells 2015;33:3315-3326.