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Inhibition of aberrant tissue remodelling by mesenchymal stromal cells singly coated with soft gels presenting defined chemomechanical cues

Abstract

The precise understanding and control of microenvironmental cues could be used to optimize the efficacy of cell therapeutics. Here, we show that mesenchymal stromal cells (MSCs) singly coated with a soft conformal gel presenting defined chemomechanical cues promote matrix remodelling by secreting soluble interstitial collagenases in response to the presence of tumour necrosis factor alpha (TNF-α). In mice with fibrotic lung injury, treatment with the coated MSCs maintained normal collagen levels, fibre density and microelasticity in lung tissue, and the continuous presentation of recombinant TNF-α in the gel facilitated the reversal of aberrant tissue remodelling by the cells when inflammation subsided in the host. Gel coatings with predefined chemomechanical cues could be used to tailor cells with specific mechanisms of action for desired therapeutic outcomes.

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Fig. 1: Defining chemomechanical cues that enhance the production of soluble interstitial collagenases in mouse MSCs.
Fig. 2: Packaging chemomechanical cues into engineered gel coating for single mouse MSCs to enable paracrine matrix remodelling.
Fig. 3: Mouse MSCs in gel coating promote normal tissue remodelling after fibrotic lung injury.
Fig. 4: Donor MMP13 and host TNF-α determine effects of gel-coated mouse MSCs on fibrotic lung injury.
Fig. 5: Deterministic model predicts the effect of gel-coated MSCs on lung tissue collagen levels in different stages of bleomycin-induced injury.
Fig. 6: Continuous presentation of recombinant TNF-α in gel coating enables mouse MSCs to accelerate the resolution of fibrotic phenotypes.

Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The data reported in the figures are available as Supplementary Information. The raw and analysed datasets generated during the study are available for research purposes from the corresponding authors on reasonable request.

Code availability

The codes used to solve ordinary differential equations for the mathematical modelling of MSC-mediated collagen degradation are available as Supplementary Information.

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Acknowledgements

We thank A. B. Malik and S. Lenzini (University of Illinois at Chicago) for critical reading of the manuscript and invaluable comments. This work made use of instruments in the Fluorescence Imaging Core (Research Resources Center, UIC). This work was supported by the National Institutes of Health grant nos. R01-HL141255 and R00-HL125884 (to J.-W.S.) and R01-GM124235 and R01-HL136946 (to S.P.R.).

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Authors

Contributions

Conceptualization, S.W.W. and J.-W.S.; data curation, S.W.W. and J.-W.S.; formal analysis, S.W.W. and J.-W.S.; funding acquisition, J.-W.S. and S.P.R.; investigation, S.W.W., I.S.C., C.R.T., P.T.T., R.B. and P.B.; methodology, S.W.W., I.S.C., C.R.T., P.T.T., P.B., S.P.R. and J.-W.S.; project administration, J.-W.S.; resources, J.C.L., J.R., S.P.R. and J.-W.S.; software, S.W.W.; supervision, J.-W.S.; validation, S.W.W., I.S.C., C.R.T., R.B. and J.-W.S.; visualization, S.W.W., P.T.T. and J.-W.S.; writing original draft, S.W.W. and J.-W.S.; editing original draft, S.W.W., J.R., S.P.R. and J.-W.S.

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Correspondence to Jae-Won Shin.

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Peer review information Nature Biomedical Engineering thanks James Ankrum, Matthew Dalby and Jeffrey Spees for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Text, references, Figs. 1–9 and Table 1.

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Supplementary Code

Source code for mathematical modelling.

Supplementary Dataset 1

Source data for the main figures.

Supplementary Dataset 2

Source data for the supplementary figures.

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Wong, S.W., Tamatam, C.R., Cho, I.S. et al. Inhibition of aberrant tissue remodelling by mesenchymal stromal cells singly coated with soft gels presenting defined chemomechanical cues. Nat Biomed Eng 6, 54–66 (2022). https://doi.org/10.1038/s41551-021-00740-x

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