Modified mesenchymal stromal cells by in vitro transcribed mRNA: a therapeutic strategy for hepatocellular carcinoma.
Animals
Carcinoma, Hepatocellular
/ therapy
Mesenchymal Stem Cells
/ metabolism
Mice
Liver Neoplasms
/ therapy
RNA, Messenger
/ metabolism
Doxorubicin
/ pharmacology
Granulocyte-Macrophage Colony-Stimulating Factor
/ genetics
Cell Line, Tumor
Mesenchymal Stem Cell Transplantation
/ methods
Humans
Mice, Inbred C3H
Transfection
Granulocyte-macrophage colony-stimulating factor
Hepatocellular carcinoma
Immunogenic cell death
Immunotherapy
In vitro transcribed mRNA
Mesenchymal stromal cell
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:
11 Jul 2024
11 Jul 2024
Historique:
received:
29
12
2023
accepted:
18
06
2024
medline:
12
7
2024
pubmed:
12
7
2024
entrez:
11
7
2024
Statut:
epublish
Résumé
Mesenchymal stromal cells (MSCs) tropism for tumours allows their use as carriers of antitumoural factors and in vitro transcribed mRNA (IVT mRNA) is a promising tool for effective transient expression without insertional mutagenesis risk. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine with antitumor properties by stimulating the specific immune response. The aim of this work was to generate modified MSCs by IVT mRNA transfection to overexpress GM-CSF and determine their therapeutic effect alone or in combination with doxorubicin (Dox) in a murine model of hepatocellular carcinoma (HCC). DsRed or GM-CSF IVT mRNAs were generated from a cDNA template designed with specific primers followed by reverse transcription. Lipofectamine was used to transfect MSCs with DsRed (MSC/DsRed) or GM-CSF IVT mRNA (MSC/GM-CSF). Gene expression and cell surface markers were determined by flow cytometry. GM-CSF secretion was determined by ELISA. For in vitro experiments, the J774 macrophage line and bone marrow monocytes from mice were used to test GM-CSF function. An HCC model was developed by subcutaneous inoculation (s.c.) of Hepa129 cells into C3H/HeN mice. After s.c. injection of MSC/GM-CSF, Dox, or their combination, tumour size and mouse survival were evaluated. Tumour samples were collected for mRNA analysis and flow cytometry. DsRed expression by MSCs was observed from 2 h to 15 days after IVT mRNA transfection. Tumour growth remained unaltered after the administration of DsRed-expressing MSCs in a murine model of HCC and MSCs expressing GM-CSF maintained their phenotypic characteristic and migration capability. GM-CSF secreted by modified MSCs induced the differentiation of murine monocytes to dendritic cells and promoted a proinflammatory phenotype in the J774 macrophage cell line. In vivo, MSC/GM-CSF in combination with Dox strongly reduced HCC tumour growth in C3H/HeN mice and extended mouse survival in comparison with individual treatments. In addition, the tumours in the MSC/GM-CSF + Dox treated group exhibited elevated expression of proinflammatory genes and increased infiltration of CD8 + T cells and macrophages. Our results showed that IVT mRNA transfection is a suitable strategy for obtaining modified MSCs for therapeutic purposes. MSC/GM-CSF in combination with low doses of Dox led to a synergistic effect by increasing the proinflammatory tumour microenvironment, enhancing the antitumoural response in HCC.
Sections du résumé
BACKGROUND
BACKGROUND
Mesenchymal stromal cells (MSCs) tropism for tumours allows their use as carriers of antitumoural factors and in vitro transcribed mRNA (IVT mRNA) is a promising tool for effective transient expression without insertional mutagenesis risk. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine with antitumor properties by stimulating the specific immune response. The aim of this work was to generate modified MSCs by IVT mRNA transfection to overexpress GM-CSF and determine their therapeutic effect alone or in combination with doxorubicin (Dox) in a murine model of hepatocellular carcinoma (HCC).
METHODS
METHODS
DsRed or GM-CSF IVT mRNAs were generated from a cDNA template designed with specific primers followed by reverse transcription. Lipofectamine was used to transfect MSCs with DsRed (MSC/DsRed) or GM-CSF IVT mRNA (MSC/GM-CSF). Gene expression and cell surface markers were determined by flow cytometry. GM-CSF secretion was determined by ELISA. For in vitro experiments, the J774 macrophage line and bone marrow monocytes from mice were used to test GM-CSF function. An HCC model was developed by subcutaneous inoculation (s.c.) of Hepa129 cells into C3H/HeN mice. After s.c. injection of MSC/GM-CSF, Dox, or their combination, tumour size and mouse survival were evaluated. Tumour samples were collected for mRNA analysis and flow cytometry.
RESULTS
RESULTS
DsRed expression by MSCs was observed from 2 h to 15 days after IVT mRNA transfection. Tumour growth remained unaltered after the administration of DsRed-expressing MSCs in a murine model of HCC and MSCs expressing GM-CSF maintained their phenotypic characteristic and migration capability. GM-CSF secreted by modified MSCs induced the differentiation of murine monocytes to dendritic cells and promoted a proinflammatory phenotype in the J774 macrophage cell line. In vivo, MSC/GM-CSF in combination with Dox strongly reduced HCC tumour growth in C3H/HeN mice and extended mouse survival in comparison with individual treatments. In addition, the tumours in the MSC/GM-CSF + Dox treated group exhibited elevated expression of proinflammatory genes and increased infiltration of CD8 + T cells and macrophages.
CONCLUSIONS
CONCLUSIONS
Our results showed that IVT mRNA transfection is a suitable strategy for obtaining modified MSCs for therapeutic purposes. MSC/GM-CSF in combination with low doses of Dox led to a synergistic effect by increasing the proinflammatory tumour microenvironment, enhancing the antitumoural response in HCC.
Identifiants
pubmed: 38992782
doi: 10.1186/s13287-024-03806-0
pii: 10.1186/s13287-024-03806-0
doi:
Substances chimiques
RNA, Messenger
0
Doxorubicin
80168379AG
Granulocyte-Macrophage Colony-Stimulating Factor
83869-56-1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
208Subventions
Organisme : Agencia Nacional de Promoción Científica y Tecnológica
ID : PICT2018-4053
Organisme : Agencia Nacional de Promoción Científica y Tecnológica
ID : PICT2018-1036
Organisme : Agencia Nacional de Promoción Científica y Tecnológica
ID : PICT2019-01716
Organisme : Agencia Nacional de Promoción Científica y Tecnológica
ID : PICT2019-3282
Organisme : Agencia Nacional de Promoción Científica y Tecnológica
ID : PICT2021-GRF-TI-00397
Organisme : Agencia Nacional de Promoción Científica y Tecnológica
ID : PICT2021-I-A-00975
Organisme : Agencia Nacional de Promoción Científica y Tecnológica
ID : PICT2021-GRF-TII-00283
Organisme : Agencia Nacional de Promoción Científica y Tecnológica
ID : PICT2021-0164
Organisme : Consejo Nacional de Investigaciones Científicas y Técnicas
ID : PIBAA 2022-2023
Informations de copyright
© 2024. The Author(s).
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