Pub Date : 2024-07-09Epub Date: 2024-06-13DOI: 10.1016/j.stemcr.2024.05.008
Jakub Scaber, Iona Thomas-Wright, Alex J Clark, Yinyan Xu, Björn F Vahsen, Mireia Carcolé, Ruxandra Dafinca, Lucy Farrimond, Adrian M Isaacs, David L Bennett, Kevin Talbot
Induced pluripotent stem cell (iPSC)-derived motor neurons (MNs) from patients with amyotrophic lateral sclerosis (ALS) and the C9ORF72 hexanucleotide repeat expansion (HRE) have multiple cellular phenotypes, but which of these accurately reflect the biology underlying the cell-specific vulnerability of ALS is uncertain. We therefore compared phenotypes due to the C9ORF72 HRE in MNs with sensory neurons (SNs), which are relatively spared in ALS. The iPSC models were able to partially reproduce the differential gene expression seen between adult SNs and MNs. We demonstrated that the typical hallmarks of C9ORF72-ALS, including RNA foci and dipeptide formation, as well as specific axonal transport defects, occurred equally in MNs and SNs, suggesting that these in vitro phenotypes are not sufficient to explain the cell-type selectivity of ALS in isolation.
诱导多能干细胞(iPSC)衍生的运动神经元(MNs)来自肌萎缩性脊髓侧索硬化症(ALS)和C9ORF72六核苷酸重复扩增(HRE)患者,具有多种细胞表型,但其中哪些表型能准确反映ALS细胞特异性脆弱性的生物学基础尚不确定。因此,我们比较了C9ORF72 HRE在MNs和感觉神经元(SNs)中导致的表型,后者在ALS中相对幸免。iPSC 模型能够部分再现成年 SN 和 MN 之间的不同基因表达。我们证明了 C9ORF72-ALS 的典型特征,包括 RNA 病灶和二肽形成,以及特定的轴突运输缺陷,在 MNs 和 SNs 中同样发生,这表明这些体外表型不足以单独解释 ALS 的细胞类型选择性。
{"title":"Cellular and axonal transport phenotypes due to the C9ORF72 HRE in iPSC motor and sensory neurons.","authors":"Jakub Scaber, Iona Thomas-Wright, Alex J Clark, Yinyan Xu, Björn F Vahsen, Mireia Carcolé, Ruxandra Dafinca, Lucy Farrimond, Adrian M Isaacs, David L Bennett, Kevin Talbot","doi":"10.1016/j.stemcr.2024.05.008","DOIUrl":"10.1016/j.stemcr.2024.05.008","url":null,"abstract":"<p><p>Induced pluripotent stem cell (iPSC)-derived motor neurons (MNs) from patients with amyotrophic lateral sclerosis (ALS) and the C9ORF72 hexanucleotide repeat expansion (HRE) have multiple cellular phenotypes, but which of these accurately reflect the biology underlying the cell-specific vulnerability of ALS is uncertain. We therefore compared phenotypes due to the C9ORF72 HRE in MNs with sensory neurons (SNs), which are relatively spared in ALS. The iPSC models were able to partially reproduce the differential gene expression seen between adult SNs and MNs. We demonstrated that the typical hallmarks of C9ORF72-ALS, including RNA foci and dipeptide formation, as well as specific axonal transport defects, occurred equally in MNs and SNs, suggesting that these in vitro phenotypes are not sufficient to explain the cell-type selectivity of ALS in isolation.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11252479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141321677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-02DOI: 10.1016/j.stemcr.2024.06.007
David Pamies, Jason Ekert, Marie-Gabrielle Zurich, Olivier Frey, Sophie Werner, Monica Piergiovanni, Benjamin S Freedman, Adrian Kee Keong Teo, Hendrik Erfurth, Darwin R Reyes, Peter Loskill, Pelin Candarlioglu, Laura Suter-Dick, Shan Wang, Thomas Hartung, Sandra Coecke, Glyn N Stacey, Beren Atac Wagegg, Eva-Maria Dehne, Francesca Pistollato, Marcel Leist
{"title":"Recommendations on fit-for-purpose criteria to establish quality management for microphysiological systems and for monitoring their reproducibility.","authors":"David Pamies, Jason Ekert, Marie-Gabrielle Zurich, Olivier Frey, Sophie Werner, Monica Piergiovanni, Benjamin S Freedman, Adrian Kee Keong Teo, Hendrik Erfurth, Darwin R Reyes, Peter Loskill, Pelin Candarlioglu, Laura Suter-Dick, Shan Wang, Thomas Hartung, Sandra Coecke, Glyn N Stacey, Beren Atac Wagegg, Eva-Maria Dehne, Francesca Pistollato, Marcel Leist","doi":"10.1016/j.stemcr.2024.06.007","DOIUrl":"10.1016/j.stemcr.2024.06.007","url":null,"abstract":"","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11252524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141498980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-11DOI: 10.1016/j.stemcr.2024.05.007
{"title":"Year in review: 2023 to 2024.","authors":"","doi":"10.1016/j.stemcr.2024.05.007","DOIUrl":"https://doi.org/10.1016/j.stemcr.2024.05.007","url":null,"abstract":"","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141318304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-11Epub Date: 2024-05-23DOI: 10.1016/j.stemcr.2024.04.012
Jarny Choi, Suzanne K Butcher, Paul W Angel, Jack Bransfield, Jake Barry, Noel Faux, Bobbie Shaban, Priyanka Pillai, Aleks Michalewicz, Christine A Wells
Stemformatics.org has been serving the stem cell research community for over a decade, by making it easy for users to find and view transcriptional profiles of pluripotent and adult stem cells and their progeny, comparing data derived from multiple tissues and derivation methods. In recent years, Stemformatics has shifted its focus from curation to collation and integration of public data with shared phenotypes. It now hosts several integrated expression atlases based on human myeloid cells, which allow for easy cross-dataset comparisons and discovery of emerging cell subsets and activation properties. The atlases are designed for external users to benchmark their own data against a common reference. Here, we use case studies to illustrate how to find and explore previously published datasets of relevance and how in-vitro-derived cells can be transcriptionally matched to cells in the integrated atlas to highlight phenotypes of interest.
{"title":"Stemformatics data portal enables transcriptional benchmarking of lab-derived myeloid cells.","authors":"Jarny Choi, Suzanne K Butcher, Paul W Angel, Jack Bransfield, Jake Barry, Noel Faux, Bobbie Shaban, Priyanka Pillai, Aleks Michalewicz, Christine A Wells","doi":"10.1016/j.stemcr.2024.04.012","DOIUrl":"10.1016/j.stemcr.2024.04.012","url":null,"abstract":"<p><p>Stemformatics.org has been serving the stem cell research community for over a decade, by making it easy for users to find and view transcriptional profiles of pluripotent and adult stem cells and their progeny, comparing data derived from multiple tissues and derivation methods. In recent years, Stemformatics has shifted its focus from curation to collation and integration of public data with shared phenotypes. It now hosts several integrated expression atlases based on human myeloid cells, which allow for easy cross-dataset comparisons and discovery of emerging cell subsets and activation properties. The atlases are designed for external users to benchmark their own data against a common reference. Here, we use case studies to illustrate how to find and explore previously published datasets of relevance and how in-vitro-derived cells can be transcriptionally matched to cells in the integrated atlas to highlight phenotypes of interest.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11391030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141093919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-11Epub Date: 2024-05-16DOI: 10.1016/j.stemcr.2024.04.009
Qian Chen, Hiroyuki Hirai, Manwai Chan, Jilei Zhang, Minsu Cho, Scott H Randell, Preetish Kadur Lakshminarasimha Murthy, Jalees Rehman, Yuru Liu
Lung alveolar structure and function are maintained by subsets of alveolar type II stem cells (AT2s), but there is a need for characterization of these subsets and their associated niches. Here, we report a CD44high subpopulation of AT2s characterized by increased expression of genes that regulate immune signaling even during steady-state homeostasis. Disruption of one of these immune regulatory transcription factor STAT1 impaired the stem cell function of AT2s. CD44high cells were preferentially located near macro- blood vessels and a supportive niche constituted by LYVE1+ endothelial cells, adventitial fibroblasts, and accumulated hyaluronan. In this microenvironment, CD44high AT2 cells were more responsive to transformation by KRAS than general AT2 cells. Moreover, after bacterial lung injury, there was a significant increase of CD44high AT2s and niche components distributed throughout the lung parenchyma. Taken together, CD44high AT2 cells and their perivascular niche regulate tissue homeostasis and tumor formation.
{"title":"Characterization of perivascular alveolar epithelial stem cells and their niche in lung homeostasis and cancer.","authors":"Qian Chen, Hiroyuki Hirai, Manwai Chan, Jilei Zhang, Minsu Cho, Scott H Randell, Preetish Kadur Lakshminarasimha Murthy, Jalees Rehman, Yuru Liu","doi":"10.1016/j.stemcr.2024.04.009","DOIUrl":"10.1016/j.stemcr.2024.04.009","url":null,"abstract":"<p><p>Lung alveolar structure and function are maintained by subsets of alveolar type II stem cells (AT2s), but there is a need for characterization of these subsets and their associated niches. Here, we report a CD44<sup>high</sup> subpopulation of AT2s characterized by increased expression of genes that regulate immune signaling even during steady-state homeostasis. Disruption of one of these immune regulatory transcription factor STAT1 impaired the stem cell function of AT2s. CD44<sup>high</sup> cells were preferentially located near macro- blood vessels and a supportive niche constituted by LYVE1<sup>+</sup> endothelial cells, adventitial fibroblasts, and accumulated hyaluronan. In this microenvironment, CD44<sup>high</sup> AT2 cells were more responsive to transformation by KRAS than general AT2 cells. Moreover, after bacterial lung injury, there was a significant increase of CD44<sup>high</sup> AT2s and niche components distributed throughout the lung parenchyma. Taken together, CD44<sup>high</sup> AT2 cells and their perivascular niche regulate tissue homeostasis and tumor formation.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11390684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140959506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-11Epub Date: 2024-05-09DOI: 10.1016/j.stemcr.2024.04.007
Victor L Perez, Hazem M Mousa, Kiyoharu J Miyagishima, Amberlynn A Reed, An-Jey A Su, Thomas N Greenwell, Kia M Washington
Several gaps and barriers remain for transplanting stem cells into the eye to treat ocular disease, especially diseases of the retina. While the eye has historically been considered immune privileged, recent thinking has identified the immune system as both a barrier and an opportunity for eye stem cell transplantation. Recent approaches leveraging scaffolds or cloaking have been considered in other tissues beyond immune suppression. This perspective paper outlines approaches for transplantation and proposes opportunities to overcome barriers of the immune system in stem cell transplantation in the eye.
{"title":"Retinal transplant immunology and advancements.","authors":"Victor L Perez, Hazem M Mousa, Kiyoharu J Miyagishima, Amberlynn A Reed, An-Jey A Su, Thomas N Greenwell, Kia M Washington","doi":"10.1016/j.stemcr.2024.04.007","DOIUrl":"10.1016/j.stemcr.2024.04.007","url":null,"abstract":"<p><p>Several gaps and barriers remain for transplanting stem cells into the eye to treat ocular disease, especially diseases of the retina. While the eye has historically been considered immune privileged, recent thinking has identified the immune system as both a barrier and an opportunity for eye stem cell transplantation. Recent approaches leveraging scaffolds or cloaking have been considered in other tissues beyond immune suppression. This perspective paper outlines approaches for transplantation and proposes opportunities to overcome barriers of the immune system in stem cell transplantation in the eye.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140905092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-11Epub Date: 2024-05-16DOI: 10.1016/j.stemcr.2024.04.008
Soraya O Sandoval, Gerarda Cappuccio, Karina Kruth, Sivan Osenberg, Saleh M Khalil, Natasha M Méndez-Albelo, Krishnan Padmanabhan, Daifeng Wang, Mark J Niciu, Anita Bhattacharyya, Jason L Stein, André M M Sousa, Elisa A Waxman, Elizabeth D Buttermore, Dosh Whye, Carissa L Sirois, Aislinn Williams, Mirjana Maletic-Savatic, Xinyu Zhao
Human brain organoid models have emerged as a promising tool for studying human brain development and function. These models preserve human genetics and recapitulate some aspects of human brain development, while facilitating manipulation in an in vitro setting. Despite their potential to transform biology and medicine, concerns persist about their fidelity. To fully harness their potential, it is imperative to establish reliable analytic methods, ensuring rigor and reproducibility. Here, we review current analytical platforms used to characterize human forebrain cortical organoids, highlight challenges, and propose recommendations for future studies to achieve greater precision and uniformity across laboratories.
{"title":"Rigor and reproducibility in human brain organoid research: Where we are and where we need to go.","authors":"Soraya O Sandoval, Gerarda Cappuccio, Karina Kruth, Sivan Osenberg, Saleh M Khalil, Natasha M Méndez-Albelo, Krishnan Padmanabhan, Daifeng Wang, Mark J Niciu, Anita Bhattacharyya, Jason L Stein, André M M Sousa, Elisa A Waxman, Elizabeth D Buttermore, Dosh Whye, Carissa L Sirois, Aislinn Williams, Mirjana Maletic-Savatic, Xinyu Zhao","doi":"10.1016/j.stemcr.2024.04.008","DOIUrl":"10.1016/j.stemcr.2024.04.008","url":null,"abstract":"<p><p>Human brain organoid models have emerged as a promising tool for studying human brain development and function. These models preserve human genetics and recapitulate some aspects of human brain development, while facilitating manipulation in an in vitro setting. Despite their potential to transform biology and medicine, concerns persist about their fidelity. To fully harness their potential, it is imperative to establish reliable analytic methods, ensuring rigor and reproducibility. Here, we review current analytical platforms used to characterize human forebrain cortical organoids, highlight challenges, and propose recommendations for future studies to achieve greater precision and uniformity across laboratories.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140959579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-11Epub Date: 2024-05-30DOI: 10.1016/j.stemcr.2024.05.001
Jonathan Eintracht, Nicholas Owen, Philippa Harding, Mariya Moosajee
Genetic perturbations influencing early eye development can result in microphthalmia, anophthalmia, and coloboma (MAC). Over 100 genes are associated with MAC, but little is known about common disease mechanisms. In this study, we generated induced pluripotent stem cell (iPSC)-derived optic vesicles (OVs) from two unrelated microphthalmia patients and healthy controls. At day 20, 35, and 50, microphthalmia patient OV diameters were significantly smaller, recapitulating the "small eye" phenotype. RNA sequencing (RNA-seq) analysis revealed upregulation of apoptosis-initiating and extracellular matrix (ECM) genes at day 20 and 35. Western blot and immunohistochemistry revealed increased expression of lumican, nidogen, and collagen type IV, suggesting ECM overproduction. Increased apoptosis was observed in microphthalmia OVs with reduced phospho-histone 3 (pH3+) cells confirming decreased cell proliferation at day 35. Pharmacological inhibition of caspase-8 activity with Z-IETD-FMK decreased apoptosis in one patient model, highlighting a potential therapeutic approach. These data reveal shared pathophysiological mechanisms contributing to a microphthalmia phenotype.
影响早期眼部发育的遗传扰动可导致小眼症、无眼症和疣状胬肉(MAC)。有100多个基因与小眼球症有关,但人们对常见疾病的发病机制知之甚少。在这项研究中,我们从两名无血缘关系的小眼球症患者和健康对照组中生成了诱导多能干细胞(iPSC)衍生的视小泡(OV)。在第20、35和50天,小眼症患者的视小泡直径明显变小,再现了 "小眼 "表型。RNA测序(RNA-seq)分析显示,在第20天和第35天,凋亡启动基因和细胞外基质(ECM)基因上调。Western 印迹和免疫组化显示,lumican、nidogen 和胶原 IV 型的表达增加,表明 ECM 过度产生。第 35 天时,观察到小眼球 OV 细胞凋亡增加,磷酸组蛋白 3(pH3+)细胞减少,证实细胞增殖减少。用Z-IETD-FMK对caspase-8的活性进行药理抑制,减少了一个患者模型的细胞凋亡,突出了一种潜在的治疗方法。这些数据揭示了导致小眼症表型的共同病理生理机制。
{"title":"Disruption of common ocular developmental pathways in patient-derived optic vesicle models of microphthalmia.","authors":"Jonathan Eintracht, Nicholas Owen, Philippa Harding, Mariya Moosajee","doi":"10.1016/j.stemcr.2024.05.001","DOIUrl":"10.1016/j.stemcr.2024.05.001","url":null,"abstract":"<p><p>Genetic perturbations influencing early eye development can result in microphthalmia, anophthalmia, and coloboma (MAC). Over 100 genes are associated with MAC, but little is known about common disease mechanisms. In this study, we generated induced pluripotent stem cell (iPSC)-derived optic vesicles (OVs) from two unrelated microphthalmia patients and healthy controls. At day 20, 35, and 50, microphthalmia patient OV diameters were significantly smaller, recapitulating the \"small eye\" phenotype. RNA sequencing (RNA-seq) analysis revealed upregulation of apoptosis-initiating and extracellular matrix (ECM) genes at day 20 and 35. Western blot and immunohistochemistry revealed increased expression of lumican, nidogen, and collagen type IV, suggesting ECM overproduction. Increased apoptosis was observed in microphthalmia OVs with reduced phospho-histone 3 (pH3+) cells confirming decreased cell proliferation at day 35. Pharmacological inhibition of caspase-8 activity with Z-IETD-FMK decreased apoptosis in one patient model, highlighting a potential therapeutic approach. These data reveal shared pathophysiological mechanisms contributing to a microphthalmia phenotype.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11390689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141184634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Liver disease is a major global health challenge. There is a shortage of liver donors worldwide, and hepatocyte transplantation (HT) may be an effective treatment to overcome this problem. However, the present approaches for generation of hepatocytes are associated with challenges, and interspecies chimera-derived hepatocytes produced by interspecies blastocyst complementation (IBC) may be promising donor hepatocytes because of their more comprehensive hepatic functions. In this study, we isolated mouse hepatocytes from mouse-rat chimeric livers using IBC and found that interspecies chimera-derived hepatocytes exhibited mature hepatic functions in terms of lipid accumulation, glycogen storage, and urea synthesis. Meanwhile, they were more similar to endogenous hepatocytes than hepatocytes derived in vitro. Interspecies chimera-derived hepatocytes could relieve chronic liver fibrosis and reside in the injured liver after transplantation. Our results suggest that interspecies chimera-derived hepatocytes are a potentially reliable source of hepatocytes and can be applied as a therapeutic approach for HT.
{"title":"Functional mouse hepatocytes derived from interspecies chimeric livers effectively mitigate chronic liver fibrosis.","authors":"Cheng Huang, Haiping Jiang, Jingxi Dong, Liyuan Jiang, Jie Li, Jing Xu, Tongtong Cui, Leyun Wang, Xin Li, Guihai Feng, Ying Zhang, Tianda Li, Wei Li, Qi Zhou","doi":"10.1016/j.stemcr.2024.04.006","DOIUrl":"10.1016/j.stemcr.2024.04.006","url":null,"abstract":"<p><p>Liver disease is a major global health challenge. There is a shortage of liver donors worldwide, and hepatocyte transplantation (HT) may be an effective treatment to overcome this problem. However, the present approaches for generation of hepatocytes are associated with challenges, and interspecies chimera-derived hepatocytes produced by interspecies blastocyst complementation (IBC) may be promising donor hepatocytes because of their more comprehensive hepatic functions. In this study, we isolated mouse hepatocytes from mouse-rat chimeric livers using IBC and found that interspecies chimera-derived hepatocytes exhibited mature hepatic functions in terms of lipid accumulation, glycogen storage, and urea synthesis. Meanwhile, they were more similar to endogenous hepatocytes than hepatocytes derived in vitro. Interspecies chimera-derived hepatocytes could relieve chronic liver fibrosis and reside in the injured liver after transplantation. Our results suggest that interspecies chimera-derived hepatocytes are a potentially reliable source of hepatocytes and can be applied as a therapeutic approach for HT.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11390683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140905083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-11Epub Date: 2024-05-23DOI: 10.1016/j.stemcr.2024.04.011
Ioannis Bantounas, Kirsty M Rooney, Filipa M Lopes, Faris Tengku, Steven Woods, Leo A H Zeef, I-Hsuan Lin, Shweta Y Kuba, Nicola Bates, Sandra Hummelgaard, Katherine A Hillman, Silvia Cereghini, Adrian S Woolf, Susan J Kimber
Hepatocyte nuclear factor 1B (HNF1B) encodes a transcription factor expressed in developing human kidney epithelia. Heterozygous HNF1B mutations are the commonest monogenic cause of dysplastic kidney malformations (DKMs). To understand their pathobiology, we generated heterozygous HNF1B mutant kidney organoids from CRISPR-Cas9 gene-edited human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) reprogrammed from a family with HNF1B-associated DKMs. Mutant organoids contained enlarged malformed tubules displaying deregulated cell turnover. Numerous genes implicated in Mendelian kidney tubulopathies were downregulated, and mutant tubules resisted the cyclic AMP (cAMP)-mediated dilatation seen in controls. Bulk and single-cell RNA sequencing (scRNA-seq) analyses indicated abnormal Wingless/Integrated (WNT), calcium, and glutamatergic pathways, the latter hitherto unstudied in developing kidneys. Glutamate ionotropic receptor kainate type subunit 3 (GRIK3) was upregulated in malformed mutant nephron tubules and prominent in HNF1B mutant fetal human dysplastic kidney epithelia. These results reveal morphological, molecular, and physiological roles for HNF1B in human kidney tubule differentiation and morphogenesis illuminating the developmental origin of mutant-HNF1B-causing kidney disease.
{"title":"Human pluripotent stem cell-derived kidney organoids reveal tubular epithelial pathobiology of heterozygous HNF1B-associated dysplastic kidney malformations.","authors":"Ioannis Bantounas, Kirsty M Rooney, Filipa M Lopes, Faris Tengku, Steven Woods, Leo A H Zeef, I-Hsuan Lin, Shweta Y Kuba, Nicola Bates, Sandra Hummelgaard, Katherine A Hillman, Silvia Cereghini, Adrian S Woolf, Susan J Kimber","doi":"10.1016/j.stemcr.2024.04.011","DOIUrl":"10.1016/j.stemcr.2024.04.011","url":null,"abstract":"<p><p>Hepatocyte nuclear factor 1B (HNF1B) encodes a transcription factor expressed in developing human kidney epithelia. Heterozygous HNF1B mutations are the commonest monogenic cause of dysplastic kidney malformations (DKMs). To understand their pathobiology, we generated heterozygous HNF1B mutant kidney organoids from CRISPR-Cas9 gene-edited human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) reprogrammed from a family with HNF1B-associated DKMs. Mutant organoids contained enlarged malformed tubules displaying deregulated cell turnover. Numerous genes implicated in Mendelian kidney tubulopathies were downregulated, and mutant tubules resisted the cyclic AMP (cAMP)-mediated dilatation seen in controls. Bulk and single-cell RNA sequencing (scRNA-seq) analyses indicated abnormal Wingless/Integrated (WNT), calcium, and glutamatergic pathways, the latter hitherto unstudied in developing kidneys. Glutamate ionotropic receptor kainate type subunit 3 (GRIK3) was upregulated in malformed mutant nephron tubules and prominent in HNF1B mutant fetal human dysplastic kidney epithelia. These results reveal morphological, molecular, and physiological roles for HNF1B in human kidney tubule differentiation and morphogenesis illuminating the developmental origin of mutant-HNF1B-causing kidney disease.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141093918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}