Prolonged survival of transplanted stem cells after ischaemic injury via the slow release of pro-survival peptides from a collagen matrix

Abstract

Stem-cell-based therapies hold considerable promise for regenerative medicine. However, acute donor-cell death within several weeks after cell delivery remains a critical hurdle for clinical translation. Co-transplantation of stem cells with pro-survival factors can improve cell engraftment, but this strategy has been hampered by the typically short half-lives of the factors and by the use of Matrigel and other scaffolds that are not chemically defined. Here, we report a collagen–dendrimer biomaterial crosslinked with pro-survival peptide analogues that adheres to the extracellular matrix and slowly releases the peptides, significantly prolonging stem cell survival in mouse models of ischaemic injury. The biomaterial can serve as a generic delivery system to improve functional outcomes in cell-replacement therapy.

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Fig. 1: Preparation of peptide-linked collagen.
Fig. 2: Slow release of peptides from the col×D×pep pro-survival matrix in vitro and in vivo.
Fig. 3: Evaluation of cell survival and limb perfusion after implanting BMMNCs with col×D×pep in SCID and immunocompetent mice after femoral artery ligation.
Fig. 4: Evaluation of limb perfusion after implanting BMMNCs with col×D×pep in immunocompetent mice after femoral artery ligation.
Fig. 5: The col×D×pep pro-survival matrix promotes long-term cell survival in vivo.
Fig. 6: Evaluation of graft function after implanting cardiac progenitor cells with col×D×pep in a SCID model of myocardial infarction.
Fig. 7: Evaluation of the effects of CPC delivery with col×D×pep pro-survival matrix on post-infarct ventricular function by echocardiography and MRI.
Fig. 8: Evaluation of left ventricular remodelling in immunodeficient mice by MRI after delivery of col×D×pep.

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Acknowledgements

We would like to thank J. Tao for her assistance with the performance of the bindingassay detailed in Supplementary Fig. 16. We would also like to thank Stanford Bio-X (A.S.L.), the National Institutes of Health (grants HL133272 (J.C.W.), HL132875 (J.C.W.),113006 (J.C.W.), EB009035 (J.C.W.) and HL134830-01 (P.K.N.)) and California Institute of Regenerative Medicine (CIRM; grants DR2-05394 and RT3-07798 (J.C.W.)) for funding support forthis study.

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A.S.L., M.I., M.A.L., J.R. and P.K.N. conceived, performed and interpreted the experiments and wrote the manuscript. W.S., M.I. and J.R. formulated and produced the col×D×pep cocktail and characterized it by biophysical and biochemical methods. X.Z., S.P., W.Y.Z. and M.B.P. injected col×D×pep with cells into the animals and performed BLI. A.V.M. performed atomic force microscopy, dynamic light scattering and Raman experiments. X.Z., X.Q., S.P., W.X.H., N.G.K. and W.Y.Z. performed BLI, MRI, echo, Doppler assays and data analysis. S.P., V.S.F., W.Y.Z. and A.D.E. performed the western blot and immunostaining experiments. E.L. performed RNA sequencing. C.K.F.C. performed dissection and fluorescence microscopy experiments and provided experimental advice. P.K.N. performed the imaging experiments and data analysis, provided experimental advice and contributed to manuscript writing. J.R. conceived col×D×pep cocktail formulation, provided experimental advice and contributed to manuscript writing. V.R.P. performed BMMNCs culture. J.C.W. conceived the idea, provided experimental advice and funding support, and contributed to manuscript writing.

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Correspondence to Patricia K. Nguyen or Jayakumar Rajadas or Joseph C. Wu.

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Lee, A.S., Inayathullah, M., Lijkwan, M.A. et al. Prolonged survival of transplanted stem cells after ischaemic injury via the slow release of pro-survival peptides from a collagen matrix. Nat Biomed Eng 2, 104–113 (2018). https://doi.org/10.1038/s41551-018-0191-4

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