Controlled Inhibition of the Mesenchymal Stromal Cell Pro-inflammatory Secretome via Microparticle Engineering.
Mesenchymal stromal cells (MSCs) are promising therapeutic candidates given their potent immunomodulatory and anti-inflammatory secretome. However, controlling the MSC secretome post-transplantation is considered a major challenge that hinders their clinical efficacy. To address this, we used a microparticle-based engineering approach to non-genetically modulate pro-inflammatory pathways in human MSCs (hMSCs) under simulated inflammatory conditions. Here we show that microparticles loaded with TPCA-1, a small-molecule NF-κB inhibitor, when delivered to hMSCs can attenuate secretion of pro-inflammatory factors for at least 6 days in vitro. Conditioned medium (CM) derived from TPCA-1-loaded hMSCs also showed reduced ability to attract human monocytes and prevented differentiation of human cardiac fibroblasts to myofibroblasts, compared with CM from untreated or TPCA-1-preconditioned hMSCs. Thus, we provide a broadly applicable bioengineering solution to facilitate intracellular sustained release of agents that modulate signaling. We propose that this approach could be harnessed to improve control over MSC secretome post-transplantation, especially to prevent adverse remodeling post-myocardial infarction.
Molecular Biology and Genetics Unit, Jawaharlal Nehru Center for Advanced Scientific Research, Jakkur, Bangalore 560064, India; Division of Biomedical Engineering, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA; Institute for Stem Cell Biology and Regenerative Medicine, GKVK - Post, Bellary Road, Bangalore 560065, India; Harvard-MIT Division of Health Sciences and Technology, 65 Landsdowne Street, Cambridge, MA 02139, USA; Department of Chemical Engineering, Siddaganga Institute of Technology, B.H. Road, Tumkur 572103, India.
Sudhir H
SH
Ranganath
Division of Biomedical Engineering, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, 65 Landsdowne Street, Cambridge, MA 02139, USA; Harvard Stem Cell Institute, 1350 Massachusetts Avenue, Cambridge, MA 02138, USA.
Zhixiang
Z
Tong
Division of Biomedical Engineering, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, 65 Landsdowne Street, Cambridge, MA 02139, USA; Harvard Stem Cell Institute, 1350 Massachusetts Avenue, Cambridge, MA 02138, USA.
Oren
O
Levy
Division of Biomedical Engineering, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, 65 Landsdowne Street, Cambridge, MA 02139, USA; Harvard Stem Cell Institute, 1350 Massachusetts Avenue, Cambridge, MA 02138, USA.
Keir
K
Martyn
Division of Biomedical Engineering, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, 65 Landsdowne Street, Cambridge, MA 02139, USA; Harvard Stem Cell Institute, 1350 Massachusetts Avenue, Cambridge, MA 02138, USA. Electronic address: jeffkarp.bwh@gmail.com.
Jeffrey M
JM
Karp
Molecular Biology and Genetics Unit, Jawaharlal Nehru Center for Advanced Scientific Research, Jakkur, Bangalore 560064, India; Institute for Stem Cell Biology and Regenerative Medicine, GKVK - Post, Bellary Road, Bangalore 560065, India. Electronic address: inamdar@jncasr.ac.in.
Maneesha S
MS
Inamdar
D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002454:Cell Differentiation; D002616:Chemical Engineering / Q000379:methods; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004339:Drug Compounding; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D015870:Gene Expression; D006801:Humans; D007249:Inflammation; D019344:Lactic Acid / Q000737:chemistry; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D061251:Primary Cell Culture; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000577:Amides; D017077:Culture Media, Conditioned; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D016328:NF-kappa B; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C499326:2-((aminocarbonyl)amino)-5-(4-fluorophenyl)-3-thiophenecarboxamide