Comparing the renoprotective effects of BM-MSCs versus BM-MSC-exosomes, when combined with an anti-fibrotic drug, in hypertensive mice

Fibrosis, a hallmark of chronic kidney disease (CKD), impairs the viability of human bone marrow derived-mesenchymal stromal cells (BM-MSCs) post-transplantation. To address this, we demonstrated that combining BM-MSCs with the anti-fibrotic drug, serelaxin (RLX), enhanced BM-MSC-induced renoprotect...

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Autores principales:	Yifang Li, Amlan Chakraborty, Brad R.S. Broughton, Dorota Ferens, Robert E. Widdop, Sharon D. Ricardo, Chrishan S. Samuel
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Hypertensive CKD Fibrosis Mesenchymal stem cells Exosomes Relaxin Combination therapy Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/b54d14cd5a744650955a465e368c1bac
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spelling	oai:doaj.org-article:b54d14cd5a744650955a465e368c1bac2021-11-14T04:28:54ZComparing the renoprotective effects of BM-MSCs versus BM-MSC-exosomes, when combined with an anti-fibrotic drug, in hypertensive mice0753-332210.1016/j.biopha.2021.112256https://doaj.org/article/b54d14cd5a744650955a465e368c1bac2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0753332221010404https://doaj.org/toc/0753-3322Fibrosis, a hallmark of chronic kidney disease (CKD), impairs the viability of human bone marrow derived-mesenchymal stromal cells (BM-MSCs) post-transplantation. To address this, we demonstrated that combining BM-MSCs with the anti-fibrotic drug, serelaxin (RLX), enhanced BM-MSC-induced renoprotection in preclinical CKD models. Given the increased interest and manufacturing advantages to using stem cell-derived exosomes (EXO) as therapeutics, this study determined whether RLX could enhance the therapeutic efficacy of BM-MSC-EXO, and compared the renoprotective effects of RLX and BM-MSC-EXO versus RLX and BM-MSCs in mice with hypertensive CKD. Adult male C57BL/6 mice were uninephrectomised, received deoxycorticosterone acetate and given saline to drink (1K/DOCA/salt) for 21 days. Control mice were uninephrectomised and given normal drinking water for the same time-period. Subgroups of 1K/DOCA/salt-hypertensive mice were then treated with either RLX (0.5 mg/kg/day) or BM-MSC-EXO (25 μg/mouse; equivalent to 1–2 × 106 BM-MSCs/mouse) alone; combinations of RLX and BM-MSC-EXO or BM-MSCs (1 × 106/mouse); or the mineralocorticoid receptor antagonist, spironolactone (20 mg/kg/day), from days 14–21. 1K/DOCA/salt-hypertensive mice developed kidney tubular damage, inflammation and fibrosis, and impaired kidney function 21 days post-injury. Whilst RLX alone attenuated the 1K/DOCA/salt-induced fibrosis, BM-MSC-EXO alone only diminished measures of tissue inflammation post-treatment. Comparatively, the combined effects of RLX and BM-MSC-EXO or BM-MSCs demonstrated similar anti-fibrotic efficacy, but RLX and BM-MSCs offered broader renoprotection over RLX and/or BM-MSC-EXO, and comparable effects to spironolactone. Only RLX and BM-MSCs, but not RLX and/or BM-MSC-EXO, also attenuated the 1K/DOCA/salt-induced hypertension. Hence, although RLX improved the renoprotective effects of BM-MSC-EXO, combining RLX with BM-MSCs provided a better therapeutic option for hypertensive CKD.Yifang LiAmlan ChakrabortyBrad R.S. BroughtonDorota FerensRobert E. WiddopSharon D. RicardoChrishan S. SamuelElsevierarticleHypertensive CKDFibrosisMesenchymal stem cellsExosomesRelaxinCombination therapyTherapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 144, Iss , Pp 112256- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Hypertensive CKD Fibrosis Mesenchymal stem cells Exosomes Relaxin Combination therapy Therapeutics. Pharmacology RM1-950
spellingShingle	Hypertensive CKD Fibrosis Mesenchymal stem cells Exosomes Relaxin Combination therapy Therapeutics. Pharmacology RM1-950 Yifang Li Amlan Chakraborty Brad R.S. Broughton Dorota Ferens Robert E. Widdop Sharon D. Ricardo Chrishan S. Samuel Comparing the renoprotective effects of BM-MSCs versus BM-MSC-exosomes, when combined with an anti-fibrotic drug, in hypertensive mice
description	Fibrosis, a hallmark of chronic kidney disease (CKD), impairs the viability of human bone marrow derived-mesenchymal stromal cells (BM-MSCs) post-transplantation. To address this, we demonstrated that combining BM-MSCs with the anti-fibrotic drug, serelaxin (RLX), enhanced BM-MSC-induced renoprotection in preclinical CKD models. Given the increased interest and manufacturing advantages to using stem cell-derived exosomes (EXO) as therapeutics, this study determined whether RLX could enhance the therapeutic efficacy of BM-MSC-EXO, and compared the renoprotective effects of RLX and BM-MSC-EXO versus RLX and BM-MSCs in mice with hypertensive CKD. Adult male C57BL/6 mice were uninephrectomised, received deoxycorticosterone acetate and given saline to drink (1K/DOCA/salt) for 21 days. Control mice were uninephrectomised and given normal drinking water for the same time-period. Subgroups of 1K/DOCA/salt-hypertensive mice were then treated with either RLX (0.5 mg/kg/day) or BM-MSC-EXO (25 μg/mouse; equivalent to 1–2 × 106 BM-MSCs/mouse) alone; combinations of RLX and BM-MSC-EXO or BM-MSCs (1 × 106/mouse); or the mineralocorticoid receptor antagonist, spironolactone (20 mg/kg/day), from days 14–21. 1K/DOCA/salt-hypertensive mice developed kidney tubular damage, inflammation and fibrosis, and impaired kidney function 21 days post-injury. Whilst RLX alone attenuated the 1K/DOCA/salt-induced fibrosis, BM-MSC-EXO alone only diminished measures of tissue inflammation post-treatment. Comparatively, the combined effects of RLX and BM-MSC-EXO or BM-MSCs demonstrated similar anti-fibrotic efficacy, but RLX and BM-MSCs offered broader renoprotection over RLX and/or BM-MSC-EXO, and comparable effects to spironolactone. Only RLX and BM-MSCs, but not RLX and/or BM-MSC-EXO, also attenuated the 1K/DOCA/salt-induced hypertension. Hence, although RLX improved the renoprotective effects of BM-MSC-EXO, combining RLX with BM-MSCs provided a better therapeutic option for hypertensive CKD.
format	article
author	Yifang Li Amlan Chakraborty Brad R.S. Broughton Dorota Ferens Robert E. Widdop Sharon D. Ricardo Chrishan S. Samuel
author_facet	Yifang Li Amlan Chakraborty Brad R.S. Broughton Dorota Ferens Robert E. Widdop Sharon D. Ricardo Chrishan S. Samuel
author_sort	Yifang Li
title	Comparing the renoprotective effects of BM-MSCs versus BM-MSC-exosomes, when combined with an anti-fibrotic drug, in hypertensive mice
title_short	Comparing the renoprotective effects of BM-MSCs versus BM-MSC-exosomes, when combined with an anti-fibrotic drug, in hypertensive mice
title_full	Comparing the renoprotective effects of BM-MSCs versus BM-MSC-exosomes, when combined with an anti-fibrotic drug, in hypertensive mice
title_fullStr	Comparing the renoprotective effects of BM-MSCs versus BM-MSC-exosomes, when combined with an anti-fibrotic drug, in hypertensive mice
title_full_unstemmed	Comparing the renoprotective effects of BM-MSCs versus BM-MSC-exosomes, when combined with an anti-fibrotic drug, in hypertensive mice
title_sort	comparing the renoprotective effects of bm-mscs versus bm-msc-exosomes, when combined with an anti-fibrotic drug, in hypertensive mice
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/b54d14cd5a744650955a465e368c1bac
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Comparing the renoprotective effects of BM-MSCs versus BM-MSC-exosomes, when combined with an anti-fibrotic drug, in hypertensive mice

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