TY  - JOUR
AU  - Kapor, Sunčica
AU  - Vukotić, Milica
AU  - Subotički, Tijana
AU  - Đikić, Dragoslava
AU  - Mitrović-Ajtić, Olivera
AU  - Radojković, Milica
AU  - Čokić, Vladan
AU  - Santibanez, Juan F.
PY  - 2021
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1172
AB  - 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.
PB  - MDPI
T2  - Journal of Personalized Medicine
T1  - Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro
IS  - 11
SP  - 1048
VL  - 11
DO  - 10.3390/jpm11111048
ER  - 

@article{
author = "Kapor, Sunčica and Vukotić, Milica and Subotički, Tijana and Đikić, Dragoslava and Mitrović-Ajtić, Olivera and Radojković, Milica and Čokić, Vladan and Santibanez, Juan F.",
year = "2021",
abstract = "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.",
publisher = "MDPI",
journal = "Journal of Personalized Medicine",
title = "Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro",
number = "11",
pages = "1048",
volume = "11",
doi = "10.3390/jpm11111048"
}

Kapor, S., Vukotić, M., Subotički, T., Đikić, D., Mitrović-Ajtić, O., Radojković, M., Čokić, V.,& Santibanez, J. F.. (2021). Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro. in Journal of Personalized Medicine
MDPI., 11(11), 1048.
https://doi.org/10.3390/jpm11111048

Kapor S, Vukotić M, Subotički T, Đikić D, Mitrović-Ajtić O, Radojković M, Čokić V, Santibanez JF. Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro. in Journal of Personalized Medicine. 2021;11(11):1048.
doi:10.3390/jpm11111048 .

Kapor, Sunčica, Vukotić, Milica, Subotički, Tijana, Đikić, Dragoslava, Mitrović-Ajtić, Olivera, Radojković, Milica, Čokić, Vladan, Santibanez, Juan F., "Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro" in Journal of Personalized Medicine, 11, no. 11 (2021):1048,
https://doi.org/10.3390/jpm11111048 . .

TY  - JOUR
AU  - Bjelica, Sunčica
AU  - Diklić, Miloš
AU  - Đikić, Dragoslava
AU  - Kovačić, Marijana
AU  - Subotički, Tijana
AU  - Mitrović-Ajtić, Olivera
AU  - Radojković, Milica
AU  - Čokić, Vladan
AU  - Santibanez, Juan F.
PY  - 2019
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/907
AB  - Hydroxyurea (HU) is a nonalkylating antineoplastic agent used in the treatment of hematological malignancies. HU is a DNA replication stress inducer, and as such, it may induce a premature senescence-like cell phenotype; however, its repercussion on bystander cell proliferation has not been revealed so far. Our results indicate that HU strongly inhibited peripheral blood mesenchymal stromal cells (PBMSC) proliferation by cell cycle arrest in S phase, and that, consequently, PBMSC acquire senescence-related phenotypical changes. HU-treated PBMSC display increased senescence-associated beta-galactosidase levels and p16(INK4) expression, as well as DNA damage response and genotoxic effects, evidenced by expression of gamma H2A.X and micronuclei. Moreover, HU-induced PBMSC senescence is mediated by increased reactive oxygen species (ROS) levels, as demonstrated by the inhibition of senescence markers in the presence of ROS scavenger N-acetylcysteine and NADPH oxidase inhibitor Apocynin. To determine the HU-induced bystander effect, we used the JAK2V617F-positive human erythroleukemia 92.1.7 (HEL) cells. Co-culture with HU-induced senescent PBMSC (HU-S-PBMSC) strongly inhibited bystander HEL cell proliferation, and this effect is mediated by both ROS and transforming growth factor (TGF)-beta expression. Besides induction of premature senescence, HU educates PBMSC toward an inhibitory phenotype of HEL cell proliferation. Finally, our study contributes to the understanding of the role of HU-induced PBMSC senescence as a potential adjuvant in hematological malignancy therapies.
PB  - Wiley, Hoboken
T2  - FEBS Journal
T1  - Hydroxyurea-induced senescent peripheral blood mesenchymal stromal cells inhibit bystander cell proliferation of JAK2V617F-positive human erythroleukemia cells
EP  - 3663
IS  - 18
SP  - 3647
VL  - 286
DO  - 10.1111/febs.14927
ER  - 

@article{
author = "Bjelica, Sunčica and Diklić, Miloš and Đikić, Dragoslava and Kovačić, Marijana and Subotički, Tijana and Mitrović-Ajtić, Olivera and Radojković, Milica and Čokić, Vladan and Santibanez, Juan F.",
year = "2019",
abstract = "Hydroxyurea (HU) is a nonalkylating antineoplastic agent used in the treatment of hematological malignancies. HU is a DNA replication stress inducer, and as such, it may induce a premature senescence-like cell phenotype; however, its repercussion on bystander cell proliferation has not been revealed so far. Our results indicate that HU strongly inhibited peripheral blood mesenchymal stromal cells (PBMSC) proliferation by cell cycle arrest in S phase, and that, consequently, PBMSC acquire senescence-related phenotypical changes. HU-treated PBMSC display increased senescence-associated beta-galactosidase levels and p16(INK4) expression, as well as DNA damage response and genotoxic effects, evidenced by expression of gamma H2A.X and micronuclei. Moreover, HU-induced PBMSC senescence is mediated by increased reactive oxygen species (ROS) levels, as demonstrated by the inhibition of senescence markers in the presence of ROS scavenger N-acetylcysteine and NADPH oxidase inhibitor Apocynin. To determine the HU-induced bystander effect, we used the JAK2V617F-positive human erythroleukemia 92.1.7 (HEL) cells. Co-culture with HU-induced senescent PBMSC (HU-S-PBMSC) strongly inhibited bystander HEL cell proliferation, and this effect is mediated by both ROS and transforming growth factor (TGF)-beta expression. Besides induction of premature senescence, HU educates PBMSC toward an inhibitory phenotype of HEL cell proliferation. Finally, our study contributes to the understanding of the role of HU-induced PBMSC senescence as a potential adjuvant in hematological malignancy therapies.",
publisher = "Wiley, Hoboken",
journal = "FEBS Journal",
title = "Hydroxyurea-induced senescent peripheral blood mesenchymal stromal cells inhibit bystander cell proliferation of JAK2V617F-positive human erythroleukemia cells",
pages = "3663-3647",
number = "18",
volume = "286",
doi = "10.1111/febs.14927"
}

Bjelica, S., Diklić, M., Đikić, D., Kovačić, M., Subotički, T., Mitrović-Ajtić, O., Radojković, M., Čokić, V.,& Santibanez, J. F.. (2019). Hydroxyurea-induced senescent peripheral blood mesenchymal stromal cells inhibit bystander cell proliferation of JAK2V617F-positive human erythroleukemia cells. in FEBS Journal
Wiley, Hoboken., 286(18), 3647-3663.
https://doi.org/10.1111/febs.14927

Bjelica S, Diklić M, Đikić D, Kovačić M, Subotički T, Mitrović-Ajtić O, Radojković M, Čokić V, Santibanez JF. Hydroxyurea-induced senescent peripheral blood mesenchymal stromal cells inhibit bystander cell proliferation of JAK2V617F-positive human erythroleukemia cells. in FEBS Journal. 2019;286(18):3647-3663.
doi:10.1111/febs.14927 .

Bjelica, Sunčica, Diklić, Miloš, Đikić, Dragoslava, Kovačić, Marijana, Subotički, Tijana, Mitrović-Ajtić, Olivera, Radojković, Milica, Čokić, Vladan, Santibanez, Juan F., "Hydroxyurea-induced senescent peripheral blood mesenchymal stromal cells inhibit bystander cell proliferation of JAK2V617F-positive human erythroleukemia cells" in FEBS Journal, 286, no. 18 (2019):3647-3663,
https://doi.org/10.1111/febs.14927 . .