Genetically Engineered Macrophages Derived from iPSCs for Self-Regulating Delivery of Anti-Inflammatory Biologic Drugs

In rheumatoid arthritis, dysregulated cytokine signaling has been implicated as a primary factor in chronic inflammation. Many antirheumatic and biological therapies are used to suppress joint inflammation, but despite these advances, effectiveness is not universal, and delivery is often at high dos...

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Bibliographic Details
Published in:	Journal of tissue engineering and regenerative medicine 2024, Vol.2024, p.1-11
Main Authors:	Klimak, Molly, Guilak, Farshid
Format:	Article
Language:	eng
Subjects:	Animals Anti-Inflammatory Agents - pharmacology Biological Products - therapeutic use Bone marrow Circuits Cytokines Cytokines - pharmacology Drug delivery Drugs Fibroblasts Flow cytometry Gene expression Genetic engineering Genomes Humans Immunomodulation Induced Pluripotent Stem Cells - pathology Inflammation Inflammation - pathology Inflammatory diseases Inhibitory postsynaptic potentials Macrophages Medical research Mice Penicillin Phenotypes Pluripotency Proteins Regenerative medicine Rheumatoid arthritis Stem cells Tissue engineering Tumor necrosis factor receptors Tumor Necrosis Factor-alpha - pharmacology Tumor necrosis factor-TNF Tumor necrosis factor-α
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Summary:	In rheumatoid arthritis, dysregulated cytokine signaling has been implicated as a primary factor in chronic inflammation. Many antirheumatic and biological therapies are used to suppress joint inflammation, but despite these advances, effectiveness is not universal, and delivery is often at high doses, which can predispose patients to significant off-target effects. During chronic inflammation, the inappropriate regulation of signaling factors by macrophages accelerates the progression of disease by driving an imbalance of inflammatory cytokines, making macrophages an ideal cellular target. To develop a macrophage-based therapy to treat chronic inflammation, we engineered a novel induced pluripotent stem cell (iPSC)-derived macrophage capable of delivering soluble TNF receptor 1 (sTNFR1), an anti-inflammatory biologic inhibitor of tumor necrosis factor alpha (TNF-α), in an autoregulated manner in response to TNF-α. Murine iPSCs were differentiated into macrophages (iMACs) over a 17-day optimized protocol with continued successful differentiation confirmed at key timepoints. Varying inflammatory and immunomodulatory stimuli demonstrated traditional macrophage function and phenotypes. In response to TNF-α, therapeutic iMACs produced high levels of sTNFR1 in an autoregulated manner, which inhibited inflammatory signaling. This self-regulating iMAC system demonstrated the potential for macrophage-based drug delivery as a novel therapeutic approach for a variety of chronic inflammatory diseases.
ISSN:	1932-6254 1932-7005