Tunable hydrogels for mesenchymal stem cell delivery: Integrin-induced transcriptome alterations and hydrogel optimization for human wound healing

Alina I. Marusina, Alexander A. Merleev, Jesus I. Luna, Laura Olney, Nathan E. Haigh, Daniel Yoon, Chen Guo, Elisa M. Ovadia, Michiko Shimoda, Guillaume Luxardi, Sucharita Boddu, Nelvish N. Lal, Yoshikazu Takada, Kit S. Lam, Ruiwu Liu, R. Rivkah Isseroff, Stephanie Le, Jan A. Nolta, April M. Kloxin, Emanual Maverakis

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Therapeutic applications for mesenchymal stem/stromal cells (MSCs) are growing; however, the successful implementation of these therapies requires the development of appropriate MSC delivery systems. Hydrogels are ideally suited to cultivate MSCs but tuning hydrogel properties to match their specific in vivo applications remains a challenge. Thus, further characterization of how hydrogel-based delivery vehicles broadly influence MSC function and fate will help lead to the next generation of more intelligently designed delivery vehicles. To date, few attempts have been made to comprehensively characterize hydrogel impact on the MSC transcriptome. Herein, we have synthesized cell-degradable hydrogels based on bio-inert poly(ethylene glycol) tethered with specific integrin-binding small molecules and have characterized their resulting effect on the MSC transcriptome when compared with 2D cultured and untethered 3D hydrogel cultured MSCs. The 3D culture systems resulted in alterations in the MSC transcriptome, as is evident by the differential expression of genes related to extracellular matrix production, glycosylation, metabolism, signal transduction, gene epigenetic regulation, and development. For example, genes important for osteogenic differentiation were upregulated in 3D hydrogel cultures, and the expression of these genes could be partially suppressed by tethering an integrin-binding RGD peptide within the hydrogel. Highlighting the utility of tunable hydrogels, when applied to ex vivo human wounds the RGD-tethered hydrogel was able to support wound re-epithelialization, possibly due to its ability to increase PDGF expression and decrease IL-6 expression. These results will aid in future hydrogel design for a broad range of applications.

Original languageEnglish (US)
Pages (from-to)231-245
Number of pages15
JournalSTEM CELLS
Volume38
Issue number2
DOIs
StatePublished - Feb 1 2020

Bibliographical note

Funding Information:
This project was supported by funding from the California Institute for Regenerative Medicine (CIRM), RN3‐06460 (E.M.). Drs. Nolta and Isseroff were supported by TR2‐01787 and PC1‐0118 (R.R.I. and J.N.) and NIH Transformative Grant 1R01GM099688 (J.N.). L.O. and N.E.H. are scholars of the Bridges to Stem Cell Research Program (#TB1‐01190 and #TB1‐01184) from CIRM to promote undergraduate training in stem cell biology and regenerative medicine.

Funding Information:
This project was supported by funding from the California Institute for Regenerative Medicine (CIRM), RN3-06460 (E.M.). Drs. Nolta and Isseroff were supported by TR2-01787 and PC1-0118 (R.R.I. and J.N.) and NIH Transformative Grant 1R01GM099688 (J.N.). L.O. and N.E.H. are scholars of the Bridges to Stem Cell Research Program (#TB1-01190 and #TB1-01184) from CIRM to promote undergraduate training in stem cell biology and regenerative medicine.

Publisher Copyright:
©AlphaMed Press 2019

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

Keywords

  • Chemokine
  • Cytokines
  • Differentiation
  • Gene expression
  • Integrins
  • Mesenchymal stem cells (MSCs)
  • Stem cell culture
  • Tissue regeneration

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