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Edited by Kristi S. Anseth, University of Colorado Boulder, Boulder, CO, and approved June 19, 2019 (received for review November 12, 2018)
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.
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
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- Engineering
- Biological Sciences
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