Effect of hydroxychloroquine and chloroquine on syncytial differentiation and autophagy in primary human trophoblasts
During placentation, cytotrophoblasts differentiate and fuse to form multinucleated cells (syncytiotrophoblasts) in a process that involves autophagy. Appropriate syncytial differentiation is essential for establishing a healthy pregnancy. In this study, we evaluated the effect of two chloroquine co...
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Published in | Biomedicine & pharmacotherapy Vol. 149; p. 112916 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
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Elsevier Masson SAS
01.05.2022
Elsevier |
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Abstract | During placentation, cytotrophoblasts differentiate and fuse to form multinucleated cells (syncytiotrophoblasts) in a process that involves autophagy. Appropriate syncytial differentiation is essential for establishing a healthy pregnancy. In this study, we evaluated the effect of two chloroquine compounds, hydroxychloroquine (HCQ) and chloroquine (CQ), on syncytial differentiation and autophagy in cultured primary human trophoblasts (PHTs). PHT cells were isolated from the human term placenta. Bafilomycin, a well-known autophagy inhibitor, was used as a positive control. Biochemical and morphological differentiation was assessed in syncytiotrophoblasts, and autophagy-related proteins and genes were evaluated. Affymetrix Human Gene 2.0 ST Array profiling was used to identify genes affected by HCQ during syncytial differentiation. Chloroquine compounds lowered the production of beta-human chorionic gonadotropin (β-hCG) and the fusion index in PHTs. Syncytial differentiation in PHT was associated with the increased expression of ATG4C mRNA (autophagy-related gene), and this expression was affected by CQ but not by HCQ. Microarray analysis revealed that HCQ or CQ affected several genes (MMP15, GPC3, CXCL10, TET-1, and S100A7) during syncytial differentiation, which were different from that of the syncytial differentiation suppression (Ham’s/Waymouth media) or autophagy inhibition (bafilomycin treatment). Using Kyoto Encyclopedia of Genes and Genomes analysis we identified that HCQ might affect JAK2 signaling in the syncytial differentiation of PHT. In conclusion, chloroquine compounds could mitigate biochemical and morphological syncytial trophoblast differentiation in cultured PHT cells through the JAK signaling pathway rather than the inhibition of autophagic activity.
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•Chloroquine compounds mitigate syncytial trophoblast differentiation.•Effect of hydroxychloroquine and chloroquine on syncytialization was modest compared to bafilomycin or Ham’s/Waymouth media.•Hydroxychloroquine can affect JAK2 signaling in relation to syncytial differentiation of PHTs. |
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AbstractList | During placentation, cytotrophoblasts differentiate and fuse to form multinucleated cells (syncytiotrophoblasts) in a process that involves autophagy. Appropriate syncytial differentiation is essential for establishing a healthy pregnancy. In this study, we evaluated the effect of two chloroquine compounds, hydroxychloroquine (HCQ) and chloroquine (CQ), on syncytial differentiation and autophagy in cultured primary human trophoblasts (PHTs). PHT cells were isolated from the human term placenta. Bafilomycin, a well-known autophagy inhibitor, was used as a positive control. Biochemical and morphological differentiation was assessed in syncytiotrophoblasts, and autophagy-related proteins and genes were evaluated. Affymetrix Human Gene 2.0 ST Array profiling was used to identify genes affected by HCQ during syncytial differentiation. Chloroquine compounds lowered the production of beta-human chorionic gonadotropin (β-hCG) and the fusion index in PHTs. Syncytial differentiation in PHT was associated with the increased expression of ATG4C mRNA (autophagy-related gene), and this expression was affected by CQ but not by HCQ. Microarray analysis revealed that HCQ or CQ affected several genes (MMP15, GPC3, CXCL10, TET-1, and S100A7) during syncytial differentiation, which were different from that of the syncytial differentiation suppression (Ham’s/Waymouth media) or autophagy inhibition (bafilomycin treatment). Using Kyoto Encyclopedia of Genes and Genomes analysis we identified that HCQ might affect JAK2 signaling in the syncytial differentiation of PHT. In conclusion, chloroquine compounds could mitigate biochemical and morphological syncytial trophoblast differentiation in cultured PHT cells through the JAK signaling pathway rather than the inhibition of autophagic activity. During placentation, cytotrophoblasts differentiate and fuse to form multinucleated cells (syncytiotrophoblasts) in a process that involves autophagy. Appropriate syncytial differentiation is essential for establishing a healthy pregnancy. In this study, we evaluated the effect of two chloroquine compounds, hydroxychloroquine (HCQ) and chloroquine (CQ), on syncytial differentiation and autophagy in cultured primary human trophoblasts (PHTs). PHT cells were isolated from the human term placenta. Bafilomycin, a well-known autophagy inhibitor, was used as a positive control. Biochemical and morphological differentiation was assessed in syncytiotrophoblasts, and autophagy-related proteins and genes were evaluated. Affymetrix Human Gene 2.0 ST Array profiling was used to identify genes affected by HCQ during syncytial differentiation. Chloroquine compounds lowered the production of beta-human chorionic gonadotropin (β-hCG) and the fusion index in PHTs. Syncytial differentiation in PHT was associated with the increased expression of ATG4C mRNA (autophagy-related gene), and this expression was affected by CQ but not by HCQ. Microarray analysis revealed that HCQ or CQ affected several genes (MMP15, GPC3, CXCL10, TET-1, and S100A7) during syncytial differentiation, which were different from that of the syncytial differentiation suppression (Ham’s/Waymouth media) or autophagy inhibition (bafilomycin treatment). Using Kyoto Encyclopedia of Genes and Genomes analysis we identified that HCQ might affect JAK2 signaling in the syncytial differentiation of PHT. In conclusion, chloroquine compounds could mitigate biochemical and morphological syncytial trophoblast differentiation in cultured PHT cells through the JAK signaling pathway rather than the inhibition of autophagic activity. [Display omitted] •Chloroquine compounds mitigate syncytial trophoblast differentiation.•Effect of hydroxychloroquine and chloroquine on syncytialization was modest compared to bafilomycin or Ham’s/Waymouth media.•Hydroxychloroquine can affect JAK2 signaling in relation to syncytial differentiation of PHTs. |
ArticleNumber | 112916 |
Author | Choi, Yun-Sun Roh, Cheong-Rae Kim, Jung-Sun Oh, Soo-young Hwang, Jae Ryoung Choi, Minji Sung, Ji-Hee Byun, Nagyeong Choi, Suk-Joo |
Author_xml | – sequence: 1 givenname: Minji surname: Choi fullname: Choi, Minji organization: Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea – sequence: 2 givenname: Nagyeong surname: Byun fullname: Byun, Nagyeong organization: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea – sequence: 3 givenname: Jae Ryoung surname: Hwang fullname: Hwang, Jae Ryoung organization: Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea – sequence: 4 givenname: Yun-Sun surname: Choi fullname: Choi, Yun-Sun organization: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea – sequence: 5 givenname: Ji-Hee surname: Sung fullname: Sung, Ji-Hee organization: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea – sequence: 6 givenname: Suk-Joo surname: Choi fullname: Choi, Suk-Joo organization: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea – sequence: 7 givenname: Jung-Sun surname: Kim fullname: Kim, Jung-Sun organization: Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea – sequence: 8 givenname: Soo-young surname: Oh fullname: Oh, Soo-young email: ohsymd@skku.edu organization: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea – sequence: 9 givenname: Cheong-Rae surname: Roh fullname: Roh, Cheong-Rae email: crroh@skku.edu organization: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea |
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CitedBy_id | crossref_primary_10_1021_acsnano_3c06229 crossref_primary_10_1016_j_isci_2024_109900 crossref_primary_10_1038_s42003_022_03856_1 crossref_primary_10_1111_aji_13835 crossref_primary_10_5468_ogs_23252 |
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Keywords | JAK-STAT Chloroquine RMA Trophoblast Autophagy CQ Syncytiotrophoblasts H/W Hydroxychloroquine RT-PCR HCQ β-hCG Differentiation PHT ELISA |
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Title | Effect of hydroxychloroquine and chloroquine on syncytial differentiation and autophagy in primary human trophoblasts |
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