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Pluronic Micelle-Mediated Tissue Factor Silencing Enhances Hemocompatibility, Stemness, Differentiation Potential, and Paracrine Signaling of Mesenchymal Stem Cells
[Image: see text] 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 allotranspla...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American
Chemical Society
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154246/ https://www.ncbi.nlm.nih.gov/pubmed/33813822 http://dx.doi.org/10.1021/acs.biomac.1c00070 |
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author | 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. Oommen, Oommen P. |
author_facet | 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. Oommen, Oommen P. |
author_sort | Rangasami, Vignesh K. |
collection | PubMed |
description | [Image: see text] 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. |
format | Online Article Text |
id | pubmed-8154246 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American
Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-81542462021-05-27 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. Oommen, Oommen P. Biomacromolecules [Image: see text] 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. American Chemical Society 2021-04-05 2021-05-10 /pmc/articles/PMC8154246/ /pubmed/33813822 http://dx.doi.org/10.1021/acs.biomac.1c00070 Text en © 2021 The Authors. Published by American Chemical Society Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | 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. Oommen, Oommen P. Pluronic Micelle-Mediated Tissue Factor Silencing Enhances Hemocompatibility, Stemness, Differentiation Potential, and Paracrine Signaling of Mesenchymal Stem Cells |
title | Pluronic Micelle-Mediated Tissue Factor Silencing
Enhances Hemocompatibility, Stemness, Differentiation Potential, and
Paracrine Signaling of Mesenchymal Stem Cells |
title_full | Pluronic Micelle-Mediated Tissue Factor Silencing
Enhances Hemocompatibility, Stemness, Differentiation Potential, and
Paracrine Signaling of Mesenchymal Stem Cells |
title_fullStr | Pluronic Micelle-Mediated Tissue Factor Silencing
Enhances Hemocompatibility, Stemness, Differentiation Potential, and
Paracrine Signaling of Mesenchymal Stem Cells |
title_full_unstemmed | Pluronic Micelle-Mediated Tissue Factor Silencing
Enhances Hemocompatibility, Stemness, Differentiation Potential, and
Paracrine Signaling of Mesenchymal Stem Cells |
title_short | Pluronic Micelle-Mediated Tissue Factor Silencing
Enhances Hemocompatibility, Stemness, Differentiation Potential, and
Paracrine Signaling of Mesenchymal Stem Cells |
title_sort | pluronic micelle-mediated tissue factor silencing
enhances hemocompatibility, stemness, differentiation potential, and
paracrine signaling of mesenchymal stem cells |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154246/ https://www.ncbi.nlm.nih.gov/pubmed/33813822 http://dx.doi.org/10.1021/acs.biomac.1c00070 |
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