Ligand presentation controls collective MSC response to matrix stress relaxation in hybrid PEG-HA hydrogels.
basic_science · Level V
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- Record sourced from PubMed, PMID 39474314.
- Also identified by DOI 10.1016/j.bioactmat.2024.10.007 and PMC identifier 11513683.
- Licence recorded as CC BY-NC-ND.
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Abstract
Cell interactions with the extracellular matrix (ECM) influence intracellular signaling pathways related to proliferation, differentiation, and secretion, amongst other functions. Herein, bone-marrow derived mesenchymal stromal cells (MSCs) are encapsulated in a hydrazone crosslinked hyaluronic acid (HA) hydrogel, and the extent of stress relaxation is controlled by systemic introduction of irreversible triazole crosslinks. MSCs form elongated multicellular structures within hydrogels containing RGD peptide and formulated with elastic composition slightly higher than the hydrogel percolation threshold (12 % triazole, 88 % hydrazone). A scaling analysis is presented ( <math xmlns="http://www.w3.org/1998/Math/MathML"> <mrow> <msup><mrow><mo><</mo> <msup><msub><mi>R</mi> <mrow><mi>g</mi> <mspace></mspace> <mtext>Structure</mtext></mrow> </msub> <mn>2</mn></msup> <mo>></mo></mrow> <mfrac><mn>1</mn> <mn>2</mn></mfrac> </msup> </mrow> </math> ∼N<sup>α</sup>) to quantify cell-material interactions within these structures with the scaling exponent (α) describing either elongated (0.66) or globular (0.33) structures. Cellular interactions with the material were controlled through peptides to present integrin binding ECM cues (RGD) or cadherin binding cell-cell cues (HAVDI) and MSCs were observed to form highly elongated structures in RGD containing hydrogels ( <math xmlns="http://www.w3.org/1998/Math/MathML"><mrow><mi>α</mi> <mo>=</mo> <mn>0.56</mn> <mo>±</mo> <mn>0.05</mn></mrow> </math> ), whereases collapsed structures were observed within HAVDI containing hydrogels ( <math xmlns="http://www.w3.org/1998/Math/MathML"><mrow><mi>α</mi> <mo>=</mo> <mn>0.39</mn> <mspace></mspace> <mo>±</mo> <mspace></mspace> <mn>0.04</mn></mrow> </math> ). Finally, cytokine secretion was investigated, and a global increase in secreted cytokines was observed for collapsed structures compared to elongated. Taken together, this study presents a novel method to characterize cellular interactions within a stress relaxing hydrogel where altered cluster morphology imparts changes to cluster secretory profiles.