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A Little “Treat” Makes MSCs Go a Long Way

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Review of “Pre-exposure of Human Adipose Mesenchymal Stem Cells to Soluble Factors Enhances their Homing to Brain Cancer” from Stem Cells TM by Stuart P. Atkinson

Multiple studies have firmly placed mesenchymal stem cells (MSCs) at the top of the list when it comes to the cell of choice for stem cell therapy. They are easy to isolate, non-immunogenic, and have great potential in the treatment of many different diseases/disorders. They are also known for their ability to hone to sites of stress or inflammation, but this is not so true when using MSCs to treat neurological conditions [1-3], where engraftment can be less than 1%. Alfredo Quiñones-Hinojosa (Johns Hopkins Hospital) and Andre Levchenko (Yale University)  have hypothesized that pre-incubating cells under conditions that mimic the local microenvironment (in this case a glioma brain cancer model) of the tissue of interest could improve the homing of MSCs. Now, in a study published in Stem Cells TM, they apply micro-and nanotechnological tools (See figure) to systematically model the homing process, finding that specific pre-treatments have great potential in increasing MSCs therapeutic potential [4].

The homing process begins with MSCs interacting with the vascular endothelium, and adhering to the vessel wall, and the authors modelled this using a glass microfluidic flow chamber coated with human brain microvascular endothelial cells (hBMECs). Use of GCM (glioma-conditioned medium) simulated the inflamed microenvironment associated with disease (e.g. glioma), and mediated increased MSC adhesion compared to a non-inflamed control (astrocyte CM). Pre-treatment of MSCs further increased this adhesion, mediated through the VLA-4 integrin cell-cell interaction protein, and pre-treatment of MSCs with a VLA-4 ligand (fibronectin [FN]) also induced greater adherence to the hBMEC laden flow chamber.

Analysis of the next stage, transmigration through the blood-brain barrier (BBB), used hBMECs grown in Transwell inserts and assessing the ability of MSCs grown atop this layer to pass through towards GCM conditioned medium. GCM addition promoted MSCs through the endothelial monolayers, and again, pre-treatment of MSCs with GCM or FN further promoted this.

Modeling of the subsequent passage of MSCs through the brain parenchyma toward the tumor used nanometer scale-patterned surfaces consisting of parallel ridges coated with laminin (LM) to facilitate cell attachment and mimic brain tissue microenvironment. Speed, alignment, and persistence analysis of single MSCs using time-lapse microscopy found that overall, GCM addition enhanced migration, while pre-treatment of MSCs with GCM and LM both boosted migration speed and alignment. Protein assessment demonstrated higher expression of proinflammatory markers (interferon-, IL-6, IL-8, and TNF-) in GCM as compared to the control astrocyte CM, and as such, these may be mediating increased homing.

Finally, the authors validated the in vitro findings in an orthotopic animal model of human GBM. Injected MSCs pre-treated with GCM, FN and LM homed and grafted in greater numbers than control MSCs in tumors formed by injection of human glioma cells into the right striatum of athymic nude mice.

Overall, these experiments show that pre-treatment of easy to obtain MSCs significantly boosts their homing abilities and therefore, their therapeutic potential. Importantly, the study noted no changes to MSC marker expression, differentiation capabilities, or growth rate, and so cells should still be therapeutically active. The partial in vivo ratification of the in vitro findings should promote the advancement of this research using modified MSCs which can be furthered therapeutically “armed” to carry anti-tumor cargos, and we expect that this strategy will be applicable to other neurological pathologies.

References

  1. Karp JM and Leng Teo GS Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell 2009;4:206-216.
  2. Bexell D, Gunnarsson S, Tormin A, et al. Bone marrow multipotent mesenchymal stroma cells act as pericyte-like migratory vehicles in experimental gliomas. Molecular therapy : the journal of the American Society of Gene Therapy 2009;17:183-190.
  3. Kim SM, Lim JY, Park SI, et al. Gene therapy using TRAIL-secreting human umbilical cord blood-derived mesenchymal stem cells against intracranial glioma. Cancer research 2008;68:9614-9623.
  4. Smith CL, Chaichana KL, Lee YM, et al. Pre-exposure of human adipose mesenchymal stem cells to soluble factors enhances their homing to brain cancer. Stem Cells Translational Medicine 2015;4:239-251.