The renoprotective efficacy and safety of genetically-engineered human bone marrow-derived mesenchymal stromal cells expressing anti-fibrotic cargo.

Mesenchymal Stem Cells / metabolism Humans Mesenchymal Stem Cell Transplantation / methods Animals Relaxin / genetics Fibrosis Male Renal Insufficiency, Chronic / therapy Cell Differentiation Bone Marrow Cells / metabolism Green Fluorescent Proteins / metabolism Genetic Engineering Kidney / pathology Reperfusion Injury / metabolism Mice
BM-MSCs Chronic kidney disease Fibrosis Genetic engineering Relaxin

Journal

Stem cell research & therapy
ISSN: 1757-6512
Titre abrégé: Stem Cell Res Ther
Pays: England
ID NLM: 101527581

Informations de publication

Date de publication:
23 Oct 2024
Historique:
received: 06 08 2024
accepted: 09 10 2024
medline: 24 10 2024
pubmed: 24 10 2024
entrez: 24 10 2024
Statut: epublish

Résumé

Kidney fibrosis is a hallmark of chronic kidney disease (CKD) and compromises the viability of transplanted human bone marrow-derived mesenchymal stromal cells (BM-MSCs). Hence, BM-MSCs were genetically-engineered to express the anti-fibrotic and renoprotective hormone, human relaxin-2 (RLX) and green fluorescent protein (BM-MSCs-eRLX + GFP), which enabled BM-MSCs-eRLX + GFP delivery via a single intravenous injection. BM-MSCs were lentiviral-transduced with human relaxin-2 cDNA and GFP, under a eukaryotic translation elongation factor-1α promoter (BM-MSCs-eRLX + GFP) or GFP alone (BM-MSCs-eGFP). The ability of BM-MSCs-eRLX + GFP to differentiate, proliferate, migrate, produce RLX and cytokines was evaluated in vitro, whilst BM-MSC-eRLX + GFP vs BM-MSCs-eGFP homing to the injured kidney and renoprotective effects were evaluated in preclinical models of ischemia reperfusion injury (IRI) and high salt (HS)-induced hypertensive CKD in vivo. The long-term safety of BM-MSCs-RLX + GFP was also determined 9-months after treatment cessation in vivo. When cultured for 3- or 7-days in vitro, 1 × 10 BM-MSCs-eRLX + GFP produced greater renoprotective and therapeutic efficacy over that of BM-MSCs-eGFP or ACE inhibition, and may represent a novel and safe treatment option for acute kidney injury and hypertensive CKD.

Sections du résumé

BACKGROUND BACKGROUND
Kidney fibrosis is a hallmark of chronic kidney disease (CKD) and compromises the viability of transplanted human bone marrow-derived mesenchymal stromal cells (BM-MSCs). Hence, BM-MSCs were genetically-engineered to express the anti-fibrotic and renoprotective hormone, human relaxin-2 (RLX) and green fluorescent protein (BM-MSCs-eRLX + GFP), which enabled BM-MSCs-eRLX + GFP delivery via a single intravenous injection.
METHODS METHODS
BM-MSCs were lentiviral-transduced with human relaxin-2 cDNA and GFP, under a eukaryotic translation elongation factor-1α promoter (BM-MSCs-eRLX + GFP) or GFP alone (BM-MSCs-eGFP). The ability of BM-MSCs-eRLX + GFP to differentiate, proliferate, migrate, produce RLX and cytokines was evaluated in vitro, whilst BM-MSC-eRLX + GFP vs BM-MSCs-eGFP homing to the injured kidney and renoprotective effects were evaluated in preclinical models of ischemia reperfusion injury (IRI) and high salt (HS)-induced hypertensive CKD in vivo. The long-term safety of BM-MSCs-RLX + GFP was also determined 9-months after treatment cessation in vivo.
RESULTS RESULTS
When cultured for 3- or 7-days in vitro, 1 × 10
CONCLUSIONS CONCLUSIONS
BM-MSCs-eRLX + GFP produced greater renoprotective and therapeutic efficacy over that of BM-MSCs-eGFP or ACE inhibition, and may represent a novel and safe treatment option for acute kidney injury and hypertensive CKD.

Identifiants

DOI: 10.1186/s13287-024-03992-x PMID: 39443975
pubmed: 39443975
doi: 10.1186/s13287-024-03992-x
pii: 10.1186/s13287-024-03992-x
doi:

Substances chimiques

Relaxin 9002-69-1
Green Fluorescent Proteins 147336-22-9

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

375

Subventions

Organisme : National Health and Medical Research Council
ID : GNT1156446
Organisme : National Health and Medical Research Council
ID : GNT2019014

Informations de copyright

© 2024. The Author(s).

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Auteurs

Yifang Li (Y)

Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia.

Alex Hunter (A)

Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia.

Miqdad M Wakeel (MM)

Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia.

Guizhi Sun (G)

Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia.

Ricky W K Lau (RWK)

Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia.

Brad R S Broughton (BRS)

Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia.

Ivan E Oyarce Pino (IEO)

Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia.

Zihao Deng (Z)

Department of Medicine (Alfred Hospital), Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia.

Tingfang Zhang (T)

Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia.

Padma Murthi (P)

Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia.

Mark P Del Borgo (MP)

Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia.

Robert E Widdop (RE)

Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia.

Jose M Polo (JM)

Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia.
Adelaide Centre for Epigenetics, School of Biomedicine, The University of Adelaide, Adelaide, SA, 5005, Australia.
The South Australian Immunogenomics Cancer Institute, The University of Adelaide, Adelaide, SA, 5005, Australia.

Sharon D Ricardo (SD)

Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia. sharon.ricardo@monash.edu.
Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia. sharon.ricardo@monash.edu.

Chrishan S Samuel (CS)

Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia. chrishan.samuel@monash.edu.
Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia. chrishan.samuel@monash.edu.
Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia. chrishan.samuel@monash.edu.
Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, VIC, 3010, Australia. chrishan.samuel@monash.edu.
ORCID: 0000-0003-0295-4214

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Classifications MeSH

questionsmedicales.fr › Cellules › Cellules souches › Cellules souches multipotentes › Cellules souches mésenchymateuses › The renoprotective efficacy and safety of...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The renoprotective efficacy and safety of...
questionsmedicales.fr › Procédures de chirurgie opératoire › Transplantation › Transplantation cellulaire › Transplantation de cellules souches › Transplantation de cellules souches mésenchymateuses › The renoprotective efficacy and safety of...
questionsmedicales.fr › Eucaryotes › Animaux › The renoprotective efficacy and safety of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Peptides › Hormones peptidiques › Relaxine › The renoprotective efficacy and safety of...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Fibrose › The renoprotective efficacy and safety of...
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