Pub Date : 2024-11-01DOI: 10.1016/j.xfss.2024.08.002
Alexander M. Quaas M.D., Ph.D. , Alan S. Penzias M.D. , Eli Y. Adashi M.D., M.S.
Human embryonic aneuploidy may represent one of the final frontiers in assisted reproductive technology, primarily secondary to oocyte aneuploidy. Mammalian oocytes possess unique characteristics predisposing them to much higher rates of aneuploidy than sperm or most somatic cells. Some of these characteristics are age-independent, whereas others result from reproductive aging and environmental toxicity. A detailed understanding of these properties may lead to novel diagnostic and therapeutic tools designed to detect and prevent oocyte and embryonic aneuploidy to overcome this ultimate barrier to success in assisted reproductive technology.
{"title":"Embryonic aneuploidy — the true “last barrier in assisted reproductive technology”?","authors":"Alexander M. Quaas M.D., Ph.D. , Alan S. Penzias M.D. , Eli Y. Adashi M.D., M.S.","doi":"10.1016/j.xfss.2024.08.002","DOIUrl":"10.1016/j.xfss.2024.08.002","url":null,"abstract":"<div><div>Human embryonic aneuploidy may represent one of the final frontiers in assisted reproductive technology, primarily secondary to oocyte aneuploidy. Mammalian oocytes possess unique characteristics predisposing them to much higher rates of aneuploidy than sperm or most somatic cells. Some of these characteristics are age-independent, whereas others result from reproductive aging and environmental toxicity. A detailed understanding of these properties may lead to novel diagnostic and therapeutic tools designed to detect and prevent oocyte and embryonic aneuploidy to overcome this ultimate barrier to success in assisted reproductive technology.</div></div>","PeriodicalId":73012,"journal":{"name":"F&S science","volume":"5 4","pages":"Pages 303-305"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To determine if engineered high-mobility group AT-hook 2 (HMGA2) overexpressing uterine primary myometrial cells recapitulate the transcriptional and epigenomic features of HMGA2-subtype leiomyomas.
Design
Isolated primary, “normal” myometrial cells from three patients were engineered to overexpress HMGA2 to determine how HMGA2 establishes transcriptomic and epigenomic features of HMGA2-overexpressing leiomyoma.
Setting
Academic research laboratory.
Patient(s)
Primary myometrial cells were isolated from normal myometrium obtained from three patients undergoing hysterectomy.
Intervention(s)
Not applicable.
Main Outcome Measure(s)
Determined genome-wide transcriptomic and epigenomic features of engineered HMGA2-overexpressing uterine primary myometrial cells.
Result(s)
Engineered HMGA2-V5-overexpressing primary myometrial cells approximated the HMGA2 expression level observed in HMGA2-overexpression subtype leiomyoma. High-mobility group AT-hook 2-V5 expression resulted in differential expression of 1,612 genes (false discovery rate [FDR] < 0.05) that were found to be enriched in pathways associated with leiomyoma formation, including extracellular matrix organization. Comparative gene expression analysis between HMGA2-V5 engineered primary cells and HMGA2-overexpression subtype leiomyoma revealed significant overlap of differentially expressed genes. Mechanistically, HMGA2-V5 overexpression resulted in 41,323 regions with differential H3K27ac deposition (FDR < 0.05) and 205,605 regions of altered chromatin accessibility (FDR < 0.05). Transcription factor binding site analysis implicated the AP-1 family of transcription factors.
Conclusion(s)
High-mobility group AT-hook 2 overexpression induces leiomyoma-like transcriptomic and epigenomic modulations in myometrial cells.
{"title":"Engineered uterine primary myometrial cells with high-mobility group AT-hook 2 overexpression display a leiomyoma-like transcriptional and epigenomic phenotype","authors":"Priyanka Saini Ph.D. , Austin G. Holmes Ph.D. , Jian-Jun Wei M.D. , J. Brandon Parker Ph.D. , Debabrata Chakravarti Ph.D.","doi":"10.1016/j.xfss.2024.07.008","DOIUrl":"10.1016/j.xfss.2024.07.008","url":null,"abstract":"<div><h3>Objective</h3><div>To determine if engineered high-mobility group AT-hook 2 (HMGA2) overexpressing uterine primary myometrial cells recapitulate the transcriptional and epigenomic features of HMGA2-subtype leiomyomas.</div></div><div><h3>Design</h3><div>Isolated primary, “normal” myometrial cells from three patients were engineered to overexpress HMGA2 to determine how HMGA2 establishes transcriptomic and epigenomic features of HMGA2-overexpressing leiomyoma.</div></div><div><h3>Setting</h3><div>Academic research laboratory.</div></div><div><h3>Patient(s)</h3><div>Primary myometrial cells were isolated from normal myometrium obtained from three patients undergoing hysterectomy.</div></div><div><h3>Intervention(s)</h3><div>Not applicable.</div></div><div><h3>Main Outcome Measure(s)</h3><div>Determined genome-wide transcriptomic and epigenomic features of engineered HMGA2-overexpressing uterine primary myometrial cells.</div></div><div><h3>Result(s)</h3><div>Engineered HMGA2-V5-overexpressing primary myometrial cells approximated the HMGA2 expression level observed in HMGA2-overexpression subtype leiomyoma. High-mobility group AT-hook 2-V5 expression resulted in differential expression of 1,612 genes (false discovery rate [FDR] < 0.05) that were found to be enriched in pathways associated with leiomyoma formation, including extracellular matrix organization. Comparative gene expression analysis between HMGA2-V5 engineered primary cells and HMGA2-overexpression subtype leiomyoma revealed significant overlap of differentially expressed genes. Mechanistically, HMGA2-V5 overexpression resulted in 41,323 regions with differential H3K27ac deposition (FDR < 0.05) and 205,605 regions of altered chromatin accessibility (FDR < 0.05). Transcription factor binding site analysis implicated the AP-1 family of transcription factors.</div></div><div><h3>Conclusion(s)</h3><div>High-mobility group AT-hook 2 overexpression induces leiomyoma-like transcriptomic and epigenomic modulations in myometrial cells.</div></div>","PeriodicalId":73012,"journal":{"name":"F&S science","volume":"5 4","pages":"Pages 352-368"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141794185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.xfss.2024.08.004
Virpi Töhönen Ph.D. , Per Antonson Ph.D. , Nageswara Rao Boggavarapu Ph.D. , Heba Ali M.Sc. , Leticia Apolinario Motaholi Ph.D. , Jan-Åke Gustafsson Ph.D. , Mukesh Varshney Ph.D. , Kenny A. Rodriguez-Wallberg Ph.D. , Shintaro Katayama Ph.D. , Ivan Nalvarte Ph.D. , Jose Inzunza Ph.D.
Objective
To study the role of estrogen receptor β in follicle development and maturation and the response to gonadotropin stimulation aiming at superovulation.
Design
Experimental study and transcriptomic analysis.
Setting
Karolinka Institutet, medical university.
Animal(s)
Healthy wild-type (WT) and estrogen receptor β knockout (Esr2-KO) female mice undergoing superovulation at 4 weeks, 7 weeks, and 6 months of age.
Intervention(s)
Not applicable.
Main Outcome Measure(s)
Oocyte yield after superovulation, transcriptomic profiling of cumulus-granulosa cell complexes and oocytes, and immunohistochemical analyses.
Result(s)
Superovulation of estrogen receptor β (ERβ) knockout mice resulted in reduced oocyte yield at 6 months of age compared with WT mice, but younger mice had similar yields. RNA-seq analysis of cumulus cells from superovulated WT and Esr2-KO mice identified genes and pathways associated with among others adhesion, proliferation, Wnt-signaling, and placed ERβ in bipotential granulosa cell cluster. Loss of ERβ increased expression of the other estrogen receptors Esr1 and Gper1.
Conclusion(s)
Our results show that ERβ has an important role in regulating ovulation in response to exogenous gonadotropins in 6-month-old mice, but not in younger mice. Our transcriptomic and immunohistochemical observations suggest a dysregulation of the granulosa cell communication and lack of tight coordination between granulosa cell replication and antrum expansion. A significant upregulation of other estrogen receptors may support a compensatory mechanism sustaining fertility during younger age in Esr2-KO mice.
{"title":"Transcriptomic profiling of the oocyte-cumulus-granulosa cell complex from estrogen receptor β knockout mice","authors":"Virpi Töhönen Ph.D. , Per Antonson Ph.D. , Nageswara Rao Boggavarapu Ph.D. , Heba Ali M.Sc. , Leticia Apolinario Motaholi Ph.D. , Jan-Åke Gustafsson Ph.D. , Mukesh Varshney Ph.D. , Kenny A. Rodriguez-Wallberg Ph.D. , Shintaro Katayama Ph.D. , Ivan Nalvarte Ph.D. , Jose Inzunza Ph.D.","doi":"10.1016/j.xfss.2024.08.004","DOIUrl":"10.1016/j.xfss.2024.08.004","url":null,"abstract":"<div><h3>Objective</h3><div>To study the role of estrogen receptor β in follicle development and maturation and the response to gonadotropin stimulation aiming at superovulation.</div></div><div><h3>Design</h3><div>Experimental study and transcriptomic analysis.</div></div><div><h3>Setting</h3><div>Karolinka Institutet, medical university.</div></div><div><h3>Animal(s)</h3><div>Healthy wild-type (WT) and estrogen receptor β knockout (<em>Esr</em>2-KO) female mice undergoing superovulation at 4 weeks, 7 weeks, and 6 months of age.</div></div><div><h3>Intervention(s)</h3><div>Not applicable.</div></div><div><h3>Main Outcome Measure(s)</h3><div>Oocyte yield after superovulation, transcriptomic profiling of cumulus-granulosa cell complexes and oocytes, and immunohistochemical analyses.</div></div><div><h3>Result(s)</h3><div>Superovulation of estrogen receptor β (ERβ) knockout mice resulted in reduced oocyte yield at 6 months of age compared with WT mice, but younger mice had similar yields. RNA-seq analysis of cumulus cells from superovulated WT and <em>Esr</em>2-KO mice identified genes and pathways associated with among others adhesion, proliferation, Wnt-signaling, and placed ERβ in bipotential granulosa cell cluster. Loss of ERβ increased expression of the other estrogen receptors <em>Esr1</em> and <em>Gper1</em>.</div></div><div><h3>Conclusion(s)</h3><div>Our results show that ERβ has an important role in regulating ovulation in response to exogenous gonadotropins in 6-month-old mice, but not in younger mice. Our transcriptomic and immunohistochemical observations suggest a dysregulation of the granulosa cell communication and lack of tight coordination between granulosa cell replication and antrum expansion. A significant upregulation of other estrogen receptors may support a compensatory mechanism sustaining fertility during younger age in <em>Esr2</em>-KO mice.</div></div>","PeriodicalId":73012,"journal":{"name":"F&S science","volume":"5 4","pages":"Pages 306-317"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142019771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To determine whether tertiary lymphoid structures (TLSs), which reflect organized immune cell aggregates present in non-lymphoid tissues, are consistent features of endometriosis lesions.
Design
Detailed histopathological analysis of endometrial and lesion tissue from patients with endometriosis and controls was performed. Multiplex immunofluorescence on select samples was then conducted to identify canonical cell populations present within TLSs: CD3+ and CD8+ T-cells, CD79a+ B-cells, CD208+ dendritic cells, CD21+ follicular dendritic cells, and PNAd+ high endothelial venules.
Patient(s)
Patients with histologically confirmed endometriosis (N = 113; 44.3 ± 6.0) and control individuals (N = 110; 44.6 ± 7.1).
Intervention
Not applicable.
Main Outcome Measure(s)
Detection of TLSs as characterized by the presence of all canonical cell types that constitute TLS and structure morphology.
Result(s)
Of the selected samples (N = 18; 6 ectopic/eutopic/control), mature TLSs were identified in 3 ectopic tissue samples present on the ovary and fallopian tube, with immature TLSs (lacking follicular dendritic cell networks and high endothelial venules) present throughout eutopic and control endometrial samples.
Conclusion
These findings demonstrate the presence of TLSs across various endometriosis phenotypes, prompting further research into their significance within disease pathophysiology and the prognostic implications for patients.
{"title":"Tertiary lymphoid structures in endometriosis","authors":"Katherine B. Zutautas M.Sc. , Priyanka Yolmo B.Tech. , Minqi Xu M.D. , Timothy Childs M.D. , Madhuri Koti D.V.M., Ph.D. , Chandrakant Tayade D.V.M., Ph.D.","doi":"10.1016/j.xfss.2024.10.001","DOIUrl":"10.1016/j.xfss.2024.10.001","url":null,"abstract":"<div><h3>Objective</h3><div>To determine whether tertiary lymphoid structures (TLSs), which reflect organized immune cell aggregates present in non-lymphoid tissues, are consistent features of endometriosis lesions.</div></div><div><h3>Design</h3><div>Detailed histopathological analysis of endometrial and lesion tissue from patients with endometriosis and controls was performed. Multiplex immunofluorescence on select samples was then conducted to identify canonical cell populations present within TLSs: CD3<sup>+</sup> and CD8<sup>+</sup> T-cells, CD79a<sup>+</sup> B-cells, CD208<sup>+</sup> dendritic cells, CD21<sup>+</sup> follicular dendritic cells, and PNAd<sup>+</sup> high endothelial venules.</div></div><div><h3>Patient(s)</h3><div>Patients with histologically confirmed endometriosis (N = 113; 44.3 ± 6.0) and control individuals (N = 110; 44.6 ± 7.1).</div></div><div><h3>Intervention</h3><div>Not applicable.</div></div><div><h3>Main Outcome Measure(s)</h3><div>Detection of TLSs as characterized by the presence of all canonical cell types that constitute TLS and structure morphology.</div></div><div><h3>Result(s)</h3><div>Of the selected samples (N = 18; 6 ectopic/eutopic/control), mature TLSs were identified in 3 ectopic tissue samples present on the ovary and fallopian tube, with immature TLSs (lacking follicular dendritic cell networks and high endothelial venules) present throughout eutopic and control endometrial samples.</div></div><div><h3>Conclusion</h3><div>These findings demonstrate the presence of TLSs across various endometriosis phenotypes, prompting further research into their significance within disease pathophysiology and the prognostic implications for patients.</div></div>","PeriodicalId":73012,"journal":{"name":"F&S science","volume":"5 4","pages":"Pages 335-341"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142382619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.xfss.2024.07.006
Emmanuel N. Paul Ph.D., Tyler J. Carpenter B.S., Laura A. Pavliscak B.S., Abigail Z. Bennett B.S., Maria Ariadna Ochoa-Bernal Ph.D., Asgerally T. Fazleabas Ph.D., Jose M. Teixeira Ph.D.
Objective
To study the possible role for HMGA2 overexpression in differentiated myometrial cells and its potential to induce a stem cell-like or dedifferentiating phenotype and drive fibroid development.
Design
Myometrial cells were immortalized and transduced with an HMGA2 lentivirus to produce HMGA2hi cells. In vitro stem cell assays were conducted, and ribonucleic acid from HMGA2hi and control cells as well as fibroid-free myometrial and HMGA2 fibroid (HMGA2F) tissues were submitted for ribonucleic acid sequencing.
Setting
University research laboratory.
Patient(s)
Women who underwent hysterectomy for symptomatic uterine fibroids or other gynecological conditions.
Intervention(s)
Not applicable.
Main Outcome Measure(s)
In vitro stem cell-like properties from myometrial cell lines. Ribonucleic acid sequencing and collagen production of HMGA2-overexpressing primary leiomyoma tissue and cell lines.
Result(s)
HMGA2hi cells had enhanced self-renewal capacity, decreased proliferation, and a greater ability to differentiate into other mesenchymal cell types. HMGA2hi cells exhibited a stem cell-like signature and shared transcriptomic similarities with HMGA2F. Moreover, dysregulated extracellular matrix pathways were observed in both HMGA2hi cells and HMGA2F.
Conclusion(s)
Our findings show that HMGA2 overexpression may drive myometrial cells to dedifferentiate into a more plastic phenotype and provide evidence for an alternative mechanism for fibroid etiology, suggesting that fibroids arise not only from a mutated stem cell but also from a mutated differentiated myometrial cell.
{"title":"HMGA2 overexpression induces plasticity in myometrial cells and a transcriptomic profile more similar to that of uterine fibroids","authors":"Emmanuel N. Paul Ph.D., Tyler J. Carpenter B.S., Laura A. Pavliscak B.S., Abigail Z. Bennett B.S., Maria Ariadna Ochoa-Bernal Ph.D., Asgerally T. Fazleabas Ph.D., Jose M. Teixeira Ph.D.","doi":"10.1016/j.xfss.2024.07.006","DOIUrl":"10.1016/j.xfss.2024.07.006","url":null,"abstract":"<div><h3>Objective</h3><div>To study the possible role for <em>HMGA2</em> overexpression in differentiated myometrial cells and its potential to induce a stem cell-like or dedifferentiating phenotype and drive fibroid development.</div></div><div><h3>Design</h3><div>Myometrial cells were immortalized and transduced with an <em>HMGA2</em> lentivirus to produce HMGA2hi cells. In vitro stem cell assays were conducted, and ribonucleic acid from HMGA2hi and control cells as well as fibroid-free myometrial and <em>HMGA2</em> fibroid (HMGA2F) tissues were submitted for ribonucleic acid sequencing.</div></div><div><h3>Setting</h3><div>University research laboratory.</div></div><div><h3>Patient(s)</h3><div>Women who underwent hysterectomy for symptomatic uterine fibroids or other gynecological conditions.</div></div><div><h3>Intervention(s)</h3><div>Not applicable.</div></div><div><h3>Main Outcome Measure(s)</h3><div>In vitro stem cell-like properties from myometrial cell lines. Ribonucleic acid sequencing and collagen production of <em>HMGA2</em>-overexpressing primary leiomyoma tissue and cell lines.</div></div><div><h3>Result(s)</h3><div>HMGA2hi cells had enhanced self-renewal capacity, decreased proliferation, and a greater ability to differentiate into other mesenchymal cell types. HMGA2hi cells exhibited a stem cell-like signature and shared transcriptomic similarities with HMGA2F. Moreover, dysregulated extracellular matrix pathways were observed in both HMGA2hi cells and HMGA2F.</div></div><div><h3>Conclusion(s)</h3><div>Our findings show that <em>HMGA2</em> overexpression may drive myometrial cells to dedifferentiate into a more plastic phenotype and provide evidence for an alternative mechanism for fibroid etiology, suggesting that fibroids arise not only from a mutated stem cell but also from a mutated differentiated myometrial cell.</div></div>","PeriodicalId":73012,"journal":{"name":"F&S science","volume":"5 4","pages":"Pages 369-378"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141705225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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