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Advanced Tunable MSC Delivery Strategy Promises to Boost Regenerative Approaches

Review of “Tunable hydrogels for mesenchymal stem cell delivery: Integrin‐induced transcriptome alterations and hydrogel optimization for human wound healing” from STEM CELLS by Stuart P. Atkinson

The implementation of three-dimensional (3D) functionalized hydrogels as a delivery platform for mesenchymal stem cells (MSCs) may permit improved therapeutic outcomes in areas that include cutaneous wound healing, as hydrogels can be precisely manipulated to guide stem cell growth, maintenance, and differentiation. Said manipulations include the modulation of degradation rates, changes to biophysical and biochemical properties, loading with bioactive molecules, and the incorporation of peptides present within the extracellular matrix of the MSC niche [1, 2].

Reporting in their recent STEM CELLS article, researchers from the laboratory of Emanual Maverakis (University of California Davis, Sacramento, CA, USA) recently focused on understanding how biodegradable polyethylene glycol-norbornene (PEG‐8‐Nb) hydrogels influence the regenerative responses of MSCs, which included an evaluation of the expression of genes associated with lineage differentiation, wound healing, and inflammatory responses, and if MSC-laden hydrogels can be employed to enhance human cutaneous wound treatment [3].

Marusina and Merleev et al. found that unmodified 3D hydrogels tuned to mimic the rigidity of soft tissue prompted significant alterations to the MSC transcriptome when compared to standard 2D tissue culture, highlighting the differential expression of genes associated with extracellular matrix production, glycosylation, metabolism, signal transduction, gene epigenetic regulation, and development. As an example of the consequences of such changes, the authors highlighted the increased osteogenic differentiation potential of MSCs grown within unmodified 3D hydrogels; however, they also established that the incorporation of a monocysteine‐tethered integrin‐binding amino acid sequence (arginine‐glycine‐aspartic acid or RGD) [4, 5] promoted MSC adhesion and binding within the hydrogel, and this compensated for this skewed differentiation potential, via the suppression of the expression of gene such as BMP8A. 

Encouragingly, the authors finally demonstrated that the delivery of MSCs within an RGD-containing 3D hydrogel to an ex vivo organotypic wound model led to robust wound healing via re‐epithelialization, with evidence for the increased expression of platelet-derived growth factor and the decreased expression of the pro-inflammatory cytokine interleukin 6 as a potential therapeutic mechanism.

Overall, the authors establish the regenerative potential of a highly-modifiable 3D hydrogel delivery system for MSCs that can be “tuned” to suit a wide range of clinical situations. 

For more on how this tunable MSC delivery strategy may provide a much-needed boost to a range of regenerative approaches, stay tuned to the Stem Cells Portal!


  1. Liu SQ, Tay R, Khan M, et al., Synthetic hydrogels for controlled stem cell differentiation. Soft Matter 2010;6:67-81.
  2. LeValley PJ, Ovadia EM, Bresette CA, et al., Design of functionalized cyclic peptides through orthogonal click reactions for cell culture and targeting applications. Chemical Communications 2018;54:6923-6926.
  3. Marusina AI, Merleev AA, Luna JI, et al., Tunable hydrogels for mesenchymal stem cell delivery: Integrin-induced transcriptome alterations and hydrogel optimization for human wound healing. STEM CELLS 2020;38:231-245.
  4. Smithmyer ME, Sawicki LA, and Kloxin AM, Hydrogel scaffolds as in vitro models to study fibroblast activation in wound healing and disease. Biomaterials Science 2014;2:634-650.
  5. Kapp TG, Rechenmacher F, Neubauer S, et al., A Comprehensive Evaluation of the Activity and Selectivity Profile of Ligands for RGD-binding Integrins. Scientific Reports 2017;7:39805.