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Research Article

Programmable microencapsulation for enhanced mesenchymal stem cell persistence and immunomodulation

Angelo S. Mao, Berna Özkale, Nisarg J. Shah, View ORCID ProfileKyle H. Vining, Tiphaine Descombes, Liyuan Zhang, Christina M. Tringides, Sing-Wan Wong, Jae-Won Shin, David T. Scadden, David A. Weitz, and David J. Mooney
  1. aJohn A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138;
  2. bWyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02138;
  3. cDepartment of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138;
  4. dInstitute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland;
  5. eDepartment of Physics, Harvard University, Cambridge, MA 02138;
  6. fHarvard Program in Biophysics, Harvard University, Cambridge, MA 02138;
  7. gHarvard–MIT Division in Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139;
  8. hDepartment of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612;
  9. iDepartment of Bioengineering, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612

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PNAS July 30, 2019 116 (31) 15392-15397; first published July 16, 2019; https://doi.org/10.1073/pnas.1819415116
Angelo S. Mao
aJohn A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138;
bWyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02138;
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Berna Özkale
aJohn A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138;
bWyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02138;
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Nisarg J. Shah
aJohn A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138;
bWyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02138;
cDepartment of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138;
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Kyle H. Vining
aJohn A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138;
bWyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02138;
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  • ORCID record for Kyle H. Vining
Tiphaine Descombes
aJohn A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138;
dInstitute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland;
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Liyuan Zhang
bWyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02138;
eDepartment of Physics, Harvard University, Cambridge, MA 02138;
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Christina M. Tringides
aJohn A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138;
fHarvard Program in Biophysics, Harvard University, Cambridge, MA 02138;
gHarvard–MIT Division in Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139;
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Sing-Wan Wong
hDepartment of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612;
iDepartment of Bioengineering, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612
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Jae-Won Shin
hDepartment of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612;
iDepartment of Bioengineering, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612
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David T. Scadden
cDepartment of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138;
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David A. Weitz
aJohn A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138;
bWyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02138;
eDepartment of Physics, Harvard University, Cambridge, MA 02138;
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David J. Mooney
aJohn A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138;
bWyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02138;
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  • For correspondence: mooneyd@seas.harvard.edu
  1. Edited by Kristi S. Anseth, University of Colorado Boulder, Boulder, CO, and approved June 19, 2019 (received for review November 12, 2018)

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Significance

Mesenchymal stem cell (MSC) therapies have shown strong preclinical promise, particularly in ameliorating diseases of immune dysregulation. However, these results have largely failed to demonstrate efficacy in clinical settings, likely due to large dosages necessitated by the short residence time of infused cells, suboptimal cell phenotype, and immune rejection. We demonstrate that a microfluidic-based biomaterial encapsulation approach can increase in vivo residence time after intravenous (i.v.) delivery by more than an order of magnitude. Encapsulated cells up-regulated immunomodulatory genes upon exposure to inflammatory cytokines and promoted engraftment of major histocompatibility complex (MHC)-mismatched donor cells in a bone marrow transplant model. The ability to retain i.v. infused MSCs for longer durations may be broadly applicable toward improving MSC therapies.

Abstract

Mesenchymal stem cell (MSC) therapies demonstrate particular promise in ameliorating diseases of immune dysregulation but are hampered by short in vivo cell persistence and inconsistencies in phenotype. Here, we demonstrate that biomaterial encapsulation into alginate using a microfluidic device could substantially increase in vivo MSC persistence after intravenous (i.v.) injection. A combination of cell cluster formation and subsequent cross-linking with polylysine led to an increase in injected MSC half-life by more than an order of magnitude. These modifications extended persistence even in the presence of innate and adaptive immunity-mediated clearance. Licensing of encapsulated MSCs with inflammatory cytokine pretransplantation increased expression of immunomodulatory-associated genes, and licensed encapsulates promoted repopulation of recipient blood and bone marrow with allogeneic donor cells after sublethal irradiation by a ∼2-fold increase. The ability of microgel encapsulation to sustain MSC survival and increase overall immunomodulatory capacity may be applicable for improving MSC therapies in general.

  • biomaterials
  • regenerative medicine
  • MSC
  • microfluidics
  • immune modulation

Footnotes

  • ↵1To whom correspondence may be addressed. Email: mooneyd{at}seas.harvard.edu.
  • Author contributions: A.S.M., N.J.S., J.-W.S., D.T.S., D.A.W., and D.J.M. designed research; A.S.M., B.Ö., N.J.S., K.H.V., T.D., C.M.T., and S.-W.W. performed research; A.S.M. and L.Z. contributed new reagents/analytic tools; A.S.M., B.Ö., K.H.V., T.D., C.M.T., and S.-W.W. analyzed data; and A.S.M. and D.J.M. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1819415116/-/DCSupplemental.

Published under the PNAS license.

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Programmable microencapsulation for enhanced mesenchymal stem cell persistence and immunomodulation
Angelo S. Mao, Berna Özkale, Nisarg J. Shah, Kyle H. Vining, Tiphaine Descombes, Liyuan Zhang, Christina M. Tringides, Sing-Wan Wong, Jae-Won Shin, David T. Scadden, David A. Weitz, David J. Mooney
Proceedings of the National Academy of Sciences Jul 2019, 116 (31) 15392-15397; DOI: 10.1073/pnas.1819415116

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Programmable microencapsulation for enhanced mesenchymal stem cell persistence and immunomodulation
Angelo S. Mao, Berna Özkale, Nisarg J. Shah, Kyle H. Vining, Tiphaine Descombes, Liyuan Zhang, Christina M. Tringides, Sing-Wan Wong, Jae-Won Shin, David T. Scadden, David A. Weitz, David J. Mooney
Proceedings of the National Academy of Sciences Jul 2019, 116 (31) 15392-15397; DOI: 10.1073/pnas.1819415116
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