Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro

Hydroxyurea (HU) is an antineoplastic agent that functions as an antimetabolite compound by inhibiting the ribonucleotide reductase. HU acts mainly as a cytostatic drug that through DNA replication stress may trigger a premature senescence-like cell phenotype, though its influence on bone marrow-der...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Sunčica Kapor, Milica Vukotić, Tijana Subotički, Dragoslava Đikić, Olivera Mitrović Ajtić, Milica Radojković, Vladan P. Čokić, Juan F. Santibanez
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	hydroxyurea bone marrow mesenchymal stem cells senescence differentiation immunosuppression Medicine R
Acceso en línea:	https://doaj.org/article/12042089d7074df19c9805d4a519fb13
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:12042089d7074df19c9805d4a519fb13
record_format	dspace
spelling	oai:doaj.org-article:12042089d7074df19c9805d4a519fb132021-11-25T18:06:42ZHydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro10.3390/jpm111110482075-4426https://doaj.org/article/12042089d7074df19c9805d4a519fb132021-10-01T00:00:00Zhttps://www.mdpi.com/2075-4426/11/11/1048https://doaj.org/toc/2075-4426Hydroxyurea (HU) is an antineoplastic agent that functions as an antimetabolite compound by inhibiting the ribonucleotide reductase. HU acts mainly as a cytostatic drug that through DNA replication stress may trigger a premature senescence-like cell phenotype, though its influence on bone marrow-derived mesenchymal stem/stromal cell (BMMSC) functions has not elucidated yet. Our results indicate that HU inhibits the growth of human BMMSC alongside senescence-like changes in both morphology and replicative potential, provokes cell cycle arrest at the S phase without affecting cellular viability and induces the expression of senescence-associated β-galactosidase and p16INK4. Moreover, HU-induced senescent BMMSC, although they did not change MSC markers expression, exhibited reduced capacity osteogenic and adipogenic differentiation. Conversely, HU treatment increased immunoregulatory functions of BMMSC compared with untreated cells and determined by T-cell proliferation. Interestingly, HU did not influence the capacity of BMMSC to induce monocytic myeloid-derived suppressor cells. Thus, these results suggest that HU improves the BMMSC functions on the T-cell inhibition and preserves their interaction with myeloid cell compartment. Mechanistically, BMMSC under HU treatment displayed a downregulation of mTOR and p38 MAPK signaling that may explain the reduced cell differentiation and increased immunomodulation activities. Together, the results obtained in this investigation suggest that HU by inducing senescence-like phenotype of BMMSC influences their cellular differentiation and immunoregulatory functions.Sunčica KaporMilica VukotićTijana SubotičkiDragoslava ĐikićOlivera Mitrović AjtićMilica RadojkovićVladan P. ČokićJuan F. SantibanezMDPI AGarticlehydroxyureabone marrow mesenchymal stem cellssenescencedifferentiationimmunosuppressionMedicineRENJournal of Personalized Medicine, Vol 11, Iss 1048, p 1048 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	hydroxyurea bone marrow mesenchymal stem cells senescence differentiation immunosuppression Medicine R
spellingShingle	hydroxyurea bone marrow mesenchymal stem cells senescence differentiation immunosuppression Medicine R Sunčica Kapor Milica Vukotić Tijana Subotički Dragoslava Đikić Olivera Mitrović Ajtić Milica Radojković Vladan P. Čokić Juan F. Santibanez Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro
description	Hydroxyurea (HU) is an antineoplastic agent that functions as an antimetabolite compound by inhibiting the ribonucleotide reductase. HU acts mainly as a cytostatic drug that through DNA replication stress may trigger a premature senescence-like cell phenotype, though its influence on bone marrow-derived mesenchymal stem/stromal cell (BMMSC) functions has not elucidated yet. Our results indicate that HU inhibits the growth of human BMMSC alongside senescence-like changes in both morphology and replicative potential, provokes cell cycle arrest at the S phase without affecting cellular viability and induces the expression of senescence-associated β-galactosidase and p16INK4. Moreover, HU-induced senescent BMMSC, although they did not change MSC markers expression, exhibited reduced capacity osteogenic and adipogenic differentiation. Conversely, HU treatment increased immunoregulatory functions of BMMSC compared with untreated cells and determined by T-cell proliferation. Interestingly, HU did not influence the capacity of BMMSC to induce monocytic myeloid-derived suppressor cells. Thus, these results suggest that HU improves the BMMSC functions on the T-cell inhibition and preserves their interaction with myeloid cell compartment. Mechanistically, BMMSC under HU treatment displayed a downregulation of mTOR and p38 MAPK signaling that may explain the reduced cell differentiation and increased immunomodulation activities. Together, the results obtained in this investigation suggest that HU by inducing senescence-like phenotype of BMMSC influences their cellular differentiation and immunoregulatory functions.
format	article
author	Sunčica Kapor Milica Vukotić Tijana Subotički Dragoslava Đikić Olivera Mitrović Ajtić Milica Radojković Vladan P. Čokić Juan F. Santibanez
author_facet	Sunčica Kapor Milica Vukotić Tijana Subotički Dragoslava Đikić Olivera Mitrović Ajtić Milica Radojković Vladan P. Čokić Juan F. Santibanez
author_sort	Sunčica Kapor
title	Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro
title_short	Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro
title_full	Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro
title_fullStr	Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro
title_full_unstemmed	Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro
title_sort	hydroxyurea induces bone marrow mesenchymal stromal cells senescence and modifies cell functionality in vitro
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/12042089d7074df19c9805d4a519fb13
work_keys_str_mv	AT suncicakapor hydroxyureainducesbonemarrowmesenchymalstromalcellssenescenceandmodifiescellfunctionalityinvitro AT milicavukotic hydroxyureainducesbonemarrowmesenchymalstromalcellssenescenceandmodifiescellfunctionalityinvitro AT tijanasuboticki hydroxyureainducesbonemarrowmesenchymalstromalcellssenescenceandmodifiescellfunctionalityinvitro AT dragoslavađikic hydroxyureainducesbonemarrowmesenchymalstromalcellssenescenceandmodifiescellfunctionalityinvitro AT oliveramitrovicajtic hydroxyureainducesbonemarrowmesenchymalstromalcellssenescenceandmodifiescellfunctionalityinvitro AT milicaradojkovic hydroxyureainducesbonemarrowmesenchymalstromalcellssenescenceandmodifiescellfunctionalityinvitro AT vladanpcokic hydroxyureainducesbonemarrowmesenchymalstromalcellssenescenceandmodifiescellfunctionalityinvitro AT juanfsantibanez hydroxyureainducesbonemarrowmesenchymalstromalcellssenescenceandmodifiescellfunctionalityinvitro
_version_	1718411602520178688

Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro

Ejemplares similares