Pluronic micelle-mediated tissue factor silencing enhances hemocompatibility, stemness, differentiation potential, and paracrine signaling of mesenchymal stem cells.

Rangasami, Vignesh K., Nawale, Ganesh, Asawa, Kenta, Kadekar, Sandeep, Samanta, Sumanta, Nilsson, Bo, Ekdahl, Kristina N., Miettinen, Susanna, Hilborn, Jöns, Teramura, Yuji, Varghese, Oommen P. and Oommen, Oommen P. ORCID: https://orcid.org/0000-0003-2768-0133 2021. Pluronic micelle-mediated tissue factor silencing enhances hemocompatibility, stemness, differentiation potential, and paracrine signaling of mesenchymal stem cells. Biomacromolecules 22 (8) , pp. 1980-1989. 10.1021/acs.biomac.1c00070

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Abstract

Mesenchymal stem/stromal cells (MSCs) evoke great excitement for treating different human diseases due to their ability to home inflamed tissues, suppress inflammation, and promote tissue regeneration. Despite great promises, clinical trial results are disappointing as allotransplantation of MSCs trigger thrombotic activity and are damaged by the complement system, compromising their survival and function. To overcome this, a new strategy is presented by the silencing of tissue factor (TF), a transmembrane protein that mediates procoagulant activity. Novel Pluronic-based micelles are designed with the pendant pyridyl disulfide group, which are used to conjugate TF-targeting siRNA by the thiol-exchange reaction. This nanocarrier design effectively delivered the payload to MSCs resulting in ∼72% TF knockdown (KD) without significant cytotoxicity. Hematological evaluation of MSCs and TF-KD MSCs in an ex vivo human whole blood model revealed a significant reduction in an instant-blood-mediated-inflammatory reaction as evidenced by reduced platelet aggregation (93% of free platelets in the TF-KD group, compared to 22% in untreated bone marrow-derived MSCs) and thrombin–antithrombin complex formation. Effective TF silencing induced higher MSC differentiation in osteogenic and adipogenic media and showed stronger paracrine suppression of proinflammatory cytokines in macrophages and higher stimulation in the presence of endotoxins. Thus, TF silencing can produce functional cells with higher fidelity, efficacy, and functions.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Publisher:	American Chemical Society
ISSN:	1525-7797
Last Modified:	29 Oct 2024 18:45
URI:	https://orca.cardiff.ac.uk/id/eprint/173019

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