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Proc Natl Acad Sci U S A. 2019 Jul 30;116(31):15392-15397. doi: 10.1073/pnas.1819415116. Epub 2019 Jul 16.

Programmable microencapsulation for enhanced mesenchymal stem cell persistence and immunomodulation.

Author information

1
John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138.
2
Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02138.
3
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.
4
Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
5
Department of Physics, Harvard University, Cambridge, MA 02138.
6
Harvard Program in Biophysics, Harvard University, Cambridge, MA 02138.
7
Harvard-MIT Division in Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139.
8
Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612.
9
Department of Bioengineering, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612.
10
John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138; mooneyd@seas.harvard.edu.

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.

KEYWORDS:

MSC; biomaterials; immune modulation; microfluidics; regenerative medicine

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