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Optimized Three-dimensional Microgels Boost the Therapeutic Potential of MSCs

Review of “Temporal changes guided by mesenchymal stem cells on a 3D microgel platform enhance angiogenesis in vivo at a low-cell dose” from PNAS by Stuart P. Atkinson

A previous study from the laboratories of Dilip Thomas and Abhay Pandit (National University of Ireland Galway, Galway, Ireland) demonstrated that a shape-controlled three-dimensional collagen-based microgel platform could be tuned to modulate the paracrine responses of human mesenchymal stem cells (MSCs) to boost angiogenesis [1]. Excitingly, the administration of optimized MSC-embedded microgels readily induced vascular repair and functional improvement in a mouse model of critical limb ischemia. 

In their more recent study that expands on their previous work, Thomas et al. now report on how the modulation of the stiffness of the extracellular environment during a microgel-mediated preconditioning period can alter the ability of MSCs and significantly improve therapeutic angiogenesis in a severe rodent model of critical limb ischemia [2].

The authors studied a 96-hour preconditioning stage of MSCs in three-dimensional collagen-based microgels of different stiffness, which they achieved by altering the macromolecular concentration surrounding the cells. Interestingly, altering microgel stiffness offered the ability to “tune” the proangiogenic phenotype of MSCs through induced alterations to cell morphology, extracellular matrix stiffness, and integrin signaling. Interestingly, soft microgels boosted the therapeutic abilities of numbers of cell doses significantly lower than the preclinical standard (50,000). Indeed, the in vivo administration of low numbers of soft microgel-cultured MSCs in a preclinical severe hindlimb ischemia model promoted accelerated de novo blood vessel formation with a reduced inflammatory response, which combined to impede ongoing tissue damage.

Overall, the authors provide evidence that microgel-mediated preconditioning can improve the therapeutic potential of MSCs to the degree that the localized administration of a low cell dose can prompt enhanced results in preclinical hindlimb ischemia studies. Importantly, low cell dose administration represents a promising treatment option that would aid faster tissue repair and reperfusion in “no-option” patients suffering from peripheral arterial diseases. 

The team notes that their subsequent studies will investigate how the MSC extracellular matrix composition alters during microgel-mediated preconditioning and how extracellular matrix mechanics impact the expression of cellular receptors. Additionally, the authors anticipate that their platform can be employed to replicate native cellular microenvironments that will enhance the regenerative capacity of a range of stem cell types.

For more on how enhanced culture substrates can boost stem cell-based regenerative therapies, stay tuned to the Stem Cells Portal!

References

  1. Thomas D, Fontana G, Chen X, et al., A shape-controlled tuneable microgel platform to modulate angiogenic paracrine responses in stem cells. Biomaterials 2014;35:8757-8766.
  2. Thomas D, Marsico G, Mohd Isa IL, et al., Temporal changes guided by mesenchymal stem cells on a 3D microgel platform enhance angiogenesis in vivo at a low-cell dose. Proceedings of the National Academy of Sciences 2020;117:19033.