WIN18,446 enhances spermatogonial stem cell homing and fertility after germ cell transplantation by increasing blood-testis barrier permeability
Spermatogonial stem cells (SSCs) possess a unique ability to recolonize the seminiferous tubules. Upon microinjection into the adluminal compartment of the seminiferous tubules, SSCs transmigrate through the blood-testis barrier (BTB) to the basal compartment of the tubule and reinitiate spermatogen...
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| Format: | Article |
| Language: | English |
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The Society for Reproduction and Development
2023-10-01
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| Series: | The Journal of Reproduction and Development |
| Subjects: | |
| Online Access: | https://www.jstage.jst.go.jp/article/jrd/69/6/69_2023-074/_pdf/-char/en |
| _version_ | 1797392202434871296 |
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| author | Hiroko MORIMOTO Mito KANATSU-SHINOHARA Takashi SHINOHARA |
| author_facet | Hiroko MORIMOTO Mito KANATSU-SHINOHARA Takashi SHINOHARA |
| author_sort | Hiroko MORIMOTO |
| collection | DOAJ |
| description | Spermatogonial stem cells (SSCs) possess a unique ability to recolonize the seminiferous tubules. Upon microinjection into the adluminal compartment of the seminiferous tubules, SSCs transmigrate through the blood-testis barrier (BTB) to the basal compartment of the tubule and reinitiate spermatogenesis. It was recently discovered that inhibiting retinoic acid signaling with WIN18,446 enhances SSC colonization by transiently suppressing spermatogonia differentiation, thereby promoting fertility restoration. In this study, we report that WIN18,446 increases SSC colonization by disrupting the BTB. WIN18,446 altered the expression patterns of tight junction proteins (TJPs) and disrupted the BTB in busulfan-treated mice. WIN18,446 upregulated the expression of FGF2, one of the self-renewal factors for SSCs. While WIN18,446 enhanced SSC colonization in busulfan-treated wild-type mice, it did not increase colonization levels in busulfan-treated Cldn11-deficient mice, which lack the BTB, indicating that the enhancement of SSC colonization in wild-type testes depended on the loss of the BTB. Serial transplantation analysis revealed impaired self-renewal caused by WIN18,446, indicating that WIN18,446-mediated inhibition of retinoic acid signaling impaired SSC self-renewal. Strikingly, WIN18,446 administration resulted in the death of 45% of busulfan-treated recipient mice. These findings suggest that TJP modulation is the primary mechanism behind enhanced SSC homing by WIN18,446 and raise concerns regarding the use of WIN18,446 for human SSC transplantation. |
| first_indexed | 2024-03-08T23:43:47Z |
| format | Article |
| id | doaj.art-7ad7ba5e83cc409e81df7dee78f7fbf7 |
| institution | Directory Open Access Journal |
| issn | 0916-8818 1348-4400 |
| language | English |
| last_indexed | 2024-03-08T23:43:47Z |
| publishDate | 2023-10-01 |
| publisher | The Society for Reproduction and Development |
| record_format | Article |
| series | The Journal of Reproduction and Development |
| spelling | doaj.art-7ad7ba5e83cc409e81df7dee78f7fbf72023-12-14T02:46:14ZengThe Society for Reproduction and DevelopmentThe Journal of Reproduction and Development0916-88181348-44002023-10-0169634735510.1262/jrd.2023-074jrdWIN18,446 enhances spermatogonial stem cell homing and fertility after germ cell transplantation by increasing blood-testis barrier permeabilityHiroko MORIMOTO0Mito KANATSU-SHINOHARA1Takashi SHINOHARA2Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, JapanDepartment of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, JapanDepartment of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, JapanSpermatogonial stem cells (SSCs) possess a unique ability to recolonize the seminiferous tubules. Upon microinjection into the adluminal compartment of the seminiferous tubules, SSCs transmigrate through the blood-testis barrier (BTB) to the basal compartment of the tubule and reinitiate spermatogenesis. It was recently discovered that inhibiting retinoic acid signaling with WIN18,446 enhances SSC colonization by transiently suppressing spermatogonia differentiation, thereby promoting fertility restoration. In this study, we report that WIN18,446 increases SSC colonization by disrupting the BTB. WIN18,446 altered the expression patterns of tight junction proteins (TJPs) and disrupted the BTB in busulfan-treated mice. WIN18,446 upregulated the expression of FGF2, one of the self-renewal factors for SSCs. While WIN18,446 enhanced SSC colonization in busulfan-treated wild-type mice, it did not increase colonization levels in busulfan-treated Cldn11-deficient mice, which lack the BTB, indicating that the enhancement of SSC colonization in wild-type testes depended on the loss of the BTB. Serial transplantation analysis revealed impaired self-renewal caused by WIN18,446, indicating that WIN18,446-mediated inhibition of retinoic acid signaling impaired SSC self-renewal. Strikingly, WIN18,446 administration resulted in the death of 45% of busulfan-treated recipient mice. These findings suggest that TJP modulation is the primary mechanism behind enhanced SSC homing by WIN18,446 and raise concerns regarding the use of WIN18,446 for human SSC transplantation.https://www.jstage.jst.go.jp/article/jrd/69/6/69_2023-074/_pdf/-char/enblood testis barrierhomingspermatogoniawin18,446 |
| spellingShingle | Hiroko MORIMOTO Mito KANATSU-SHINOHARA Takashi SHINOHARA WIN18,446 enhances spermatogonial stem cell homing and fertility after germ cell transplantation by increasing blood-testis barrier permeability The Journal of Reproduction and Development blood testis barrier homing spermatogonia win18,446 |
| title | WIN18,446 enhances spermatogonial stem cell homing and fertility after germ cell transplantation by increasing blood-testis barrier permeability |
| title_full | WIN18,446 enhances spermatogonial stem cell homing and fertility after germ cell transplantation by increasing blood-testis barrier permeability |
| title_fullStr | WIN18,446 enhances spermatogonial stem cell homing and fertility after germ cell transplantation by increasing blood-testis barrier permeability |
| title_full_unstemmed | WIN18,446 enhances spermatogonial stem cell homing and fertility after germ cell transplantation by increasing blood-testis barrier permeability |
| title_short | WIN18,446 enhances spermatogonial stem cell homing and fertility after germ cell transplantation by increasing blood-testis barrier permeability |
| title_sort | win18 446 enhances spermatogonial stem cell homing and fertility after germ cell transplantation by increasing blood testis barrier permeability |
| topic | blood testis barrier homing spermatogonia win18,446 |
| url | https://www.jstage.jst.go.jp/article/jrd/69/6/69_2023-074/_pdf/-char/en |
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