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

  • Nature Biomedical Engineeringvolume 2pages104113 (2018)
  • doi:10.1038/s41551-018-0191-4
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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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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.

Author information

Author notes

  1. These authors contributed equally: Andrew S. Lee, Mohammed Inayathullah, Maarten A. Lijkwan and Xin Zhao.


  1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA

    • Andrew S. Lee
    • , Mohammed Inayathullah
    • , Maarten A. Lijkwan
    • , Xin Zhao
    • , Wenchao Sun
    • , Sujin Park
    • , Wan Xing Hong
    • , Edward Lau
    • , Xulei Qin
    • , Verónica Sanchez-Freire
    • , Wendy Y. Zhang
    • , Nigel G. Kooreman
    • , Antje D. Ebert
    • , Patricia K. Nguyen
    • , Jayakumar Rajadas
    •  & Joseph C. Wu
  2. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA

    • Andrew S. Lee
    • , Wenchao Sun
    • , Sujin Park
    • , Wan Xing Hong
    • , Verónica Sanchez-Freire
    • , Wendy Y. Zhang
    • , Nigel G. Kooreman
    • , Antje D. Ebert
    • , Charles K. F. Chan
    •  & Joseph C. Wu
  3. Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, CA, USA

    • Andrew S. Lee
    • , Wenchao Sun
    • , Sujin Park
    • , Wan Xing Hong
    • , Verónica Sanchez-Freire
    • , Wendy Y. Zhang
    • , Nigel G. Kooreman
    • , Antje D. Ebert
    • , Patricia K. Nguyen
    •  & Joseph C. Wu
  4. Biomaterials and Advanced Drug Delivery Laboratory, Stanford University School of Medicine, Stanford, CA, USA

    • Andrew S. Lee
    • , Mohammed Inayathullah
    • , Wenchao Sun
    • , Mansi B. Parekh
    • , Andrey V. Malkovskiy
    • , Venkata Raveendra Pothineni
    •  & Jayakumar Rajadas
  5. Pharmacology Division, Stanford University School of Medicine, Stanford, CA, USA

    • Andrew S. Lee
    • , Mohammed Inayathullah
    • , Wenchao Sun
    • , Jayakumar Rajadas
    •  & Joseph C. Wu
  6. Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA, USA

    • Charles K. F. Chan


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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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

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

Supplementary information

  1. Supplementary Information

    Supplementary methods, figures, tables and references.

  2. Life Sciences Reporting Summary