Constructs for reprogramming of smooth muscle cells into endothelial cells
AssigneeThe Brigham and Women's Hospital, Inc.
InventorMark W. Feinberg
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Abstract
Described herein are compositions and methods using miR-143-3p and/or miR-145-5p inhibitors coupled with miR-146a-5p and miR-181b-5p mimics, to promote the transdifferentiation of vascular smooth muscle cells or fibroblasts into endothelial cells, and to treat certain cardiovascular conditions.
Claims21
A method for generating a population of inducible endothelial cells (iECs), the method comprising:
- (a) providing a population of cells comprising smooth muscle cells (SMCs) or fibroblasts;
- (b) contacting the population of cells comprising SMCs or fibroblasts with constructs for expression of transdifferentiation factors, wherein the constructs comprise one or both of (i) one, two, or more tough decoy RNA expression sequences for inhibiting miR-143 and miR-145 that is at least 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO:48, and/or (ii) a miR-146a/miR-181b-2 miRNA mimic expression sequence that is at least 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO:43, in an amount and for a time sufficient to induce transdifferentiation of the SMCs or fibroblasts to iECs, and
- (c) culturing the cells in supportive media, preferably for at least 10, 12, 14, 16, 18, or 20 days,
- thereby generating a population of iECs.
A composition comprising one or more expression constructs for expression of transdifferentiation factors, wherein the expression construct comprises one or both of (i) one, two, or more tough decoy RNA expression sequences for inhibiting miR-143 and miR-145 that is at least 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO:48, and/or (ii) a miR-146a/miR-181b-2 miRNA mimic expression sequence that is at least 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO:43, optionally in a carrier, optionally a pharmaceutically acceptable carrier.
Dependencies are inferred from the claim text.