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Injectable biomimetic liquid crystalline scaffolds enhance muscle stem cell transplantation

  1. Samuel I. Stuppa,d,e,i,j,4,5
  1. aSimpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL 60611-2875;
  2. bBaxter Laboratory for Stem Cell Biology, Stanford University School of Medicine, Stanford, CA 94305-5175;
  3. cMeinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853;
  4. dDepartment of Chemistry, Northwestern University, Evanston, IL 60208;
  5. eDepartment of Biomedical Engineering, Northwestern University, Evanston, IL 60208;
  6. fDepartment of Molecular Biosciences, Northwestern University, Evanston, IL 60208;
  7. gDepartment of Neurobiology, Northwestern University, Evanston, IL 60208;
  8. hDepartment of Radiology, Northwestern University, Evanston, IL 60208;
  9. iDepartment of Materials Science and Engineering, Northwestern University, Evanston, IL 60208;
  10. jDepartment of Medicine, Northwestern University, Chicago, IL 60611
  1. Contributed by Helen M. Blau, August 4, 2017 (sent for review November 6, 2016; reviewed by Kristi S. Anseth and Jason A. Burdick)

Significance

Most research aiming to achieve muscle regeneration focuses on the biology of “muscle stem cells,” but delivery methods that enhance transplantation efficiency of these cells are at early stages. We report on a liquid crystalline scaffold that encapsulates the cells and gels upon injection in vivo without requiring an external stimulus. As a unique structural feature, the scaffold contains nanofibers that align preferentially with surrounding natural muscle fibers. The biomimetic scaffold can have a stiffness that matches that of muscle, has great ability to retain growth factors, and has a biodegradation rate that is compatible with regeneration time scales. Most importantly, the scaffold enhances engraftment efficiency of the cells in injured muscle, and without injury when combined with growth factors.

Abstract

Muscle stem cells are a potent cell population dedicated to efficacious skeletal muscle regeneration, but their therapeutic utility is currently limited by mode of delivery. We developed a cell delivery strategy based on a supramolecular liquid crystal formed by peptide amphiphiles (PAs) that encapsulates cells and growth factors within a muscle-like unidirectionally ordered environment of nanofibers. The stiffness of the PA scaffolds, dependent on amino acid sequence, was found to determine the macroscopic degree of cell alignment templated by the nanofibers in vitro. Furthermore, these PA scaffolds support myogenic progenitor cell survival and proliferation and they can be optimized to induce cell differentiation and maturation. We engineered an in vivo delivery system to assemble scaffolds by injection of a PA solution that enabled coalignment of scaffold nanofibers with endogenous myofibers. These scaffolds locally retained growth factors, displayed degradation rates matching the time course of muscle tissue regeneration, and markedly enhanced the engraftment of muscle stem cells in injured and noninjured muscles in mice.

Footnotes

  • ?1E.S. and B.D.C. contributed equally to this work.

  • ?2Present address: Department of Chemistry, DePaul University, Chicago, IL 60614.

  • ?3Present address: Teikoku Pharma USA, San Jose, CA 95131.

  • ?4H.M.B. and S.I.S. contributed equally to this work.

  • ?5To whom correspondence may be addressed. Email: hblau{at}stanford.edu or s-stupp{at}northwestern.edu.
  • Author contributions: E.S., B.D.C., M.T.M., A.T.P., C.H.C., M.H.S., C.M.R.P., R.D.H., T.J.M., H.M.B., and S.I.S. designed research; E.S., B.D.C., M.T.M., A.T.P., C.H.C., M.H.S., C.M.R.P., and R.D.H. performed research; E.S., B.D.C., M.T.M., A.T.P., C.H.C., M.H.S., C.M.R.P., T.J.M., H.M.B., and S.I.S. analyzed data; and E.S., B.D.C., M.T.M., A.T.P., M.H.S., H.M.B., and S.I.S. wrote the paper.

  • Reviewers: K.S.A., Howard Hughes Medical Institute and University of Colorado Boulder; and J.A.B., University of Pennsylvania.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1708142114/-/DCSupplemental.

Freely available online through the PNAS open access option.

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