Performance-enhanced mesenchymal stem cells via intracellular delivery of steroids.
Inadequate immunomodulatory potency of mesenchymal stem cells (MSC) may limit their therapeutic efficacy. We report glucocorticoid steroids augment MSC expression and activity of indoleamine-2,3-dioxygenase (IDO), a primary mediator of MSC immunomodulatory function. This effect depends on signaling through the glucocorticoid receptor and is mediated through up-regulation of FOXO3. Treatment of MSCs with glucocorticoids, budesonide or dexamethasone, enhanced IDO expression following IFN-γ stimulation in multiple donors and was able to restore IDO expression in over-passaged MSCs. As IDO enhancement was most notable when cells were continuously exposed to budesonide, we engineered MSC with budesonide loaded PLGA microparticles. MSC efficiently internalized budesonide microparticles and exhibited 4-fold enhanced IDO activity compared to budesonide preconditioned and naïve MSC, resulting in a 2-fold improvement in suppression of stimulated peripheral blood mononuclear cells in an IDO-dependent manner. Thus, the augmentation of MSC immune modulation may abrogate challenges associated with inadequate potency and enhance their therapeutic efficacy.
1] Center for Regenerative Therapeutics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA [2] Harvard-MIT Division of Health Sciences & Technology, Cambridge, MA 02139, USA.
James A
JA
Ankrum
Center for Regenerative Therapeutics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Riddhi G
RG
Dastidar
Center for Regenerative Therapeutics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Joon Faii
JF
Ong
Center for Regenerative Therapeutics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Oren
O
Levy
1] Center for Regenerative Therapeutics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA [2] Harvard-MIT Division of Health Sciences & Technology, Cambridge, MA 02139, USA [3] Harvard Stem Cell Institute, 1350 Massachusetts Avenue, Cambridge, MA 02138, USA.
Jeffrey M
JM
Karp
D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology; D019819:Budesonide / Q000008:administration & dosage / Q000494:pharmacology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology*; D015234:HLA-A Antigens / Q000096:biosynthesis; D015235:HLA-B Antigens / Q000096:biosynthesis; D015236:HLA-C Antigens / Q000096:biosynthesis; D006684:HLA-DR Antigens / Q000096:biosynthesis; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis* / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D053758:Nanoparticles; D034622:RNA Interference; D034741:RNA, Small Interfering
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens; D006684:HLA-DR Antigens; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D034741:RNA, Small Interfering; D019819:Budesonide; D003907:Dexamethasone; D007371:Interferon-gamma