Steven Ds Webbers, Cathelijn Em Aarts, Bart Klein, Dané Koops, Judy Geissler, Anton Tj Tool, Robin van Bruggen, Emile van den Akker, Taco W Kuijpers
{"title":"干细胞衍生的 HPS2 中性粒细胞减少了髓细胞的承诺,增加了巨噬细胞的吸收。","authors":"Steven Ds Webbers, Cathelijn Em Aarts, Bart Klein, Dané Koops, Judy Geissler, Anton Tj Tool, Robin van Bruggen, Emile van den Akker, Taco W Kuijpers","doi":"10.26508/lsa.202302263","DOIUrl":null,"url":null,"abstract":"<p><p>Hermansky-Pudlak syndrome type 2 (HPS2) is a rare autosomal recessive disorder, caused by mutations in the <i>AP3B1</i> gene, encoding the β3A subunit of the adapter protein complex 3. This results in mis-sorting of proteins within the cell. A clinical feature of HPS2 is severe neutropenia. Current HPS2 animal models do not recapitulate the human disease. Hence, we used induced pluripotent stem cells (iPSCs) of an HPS2 patient to study granulopoiesis. Development into CD15<sup>POS</sup> cells was reduced, but HPS2-derived CD15<sup>POS</sup> cells differentiated into segmented CD11b<sup>+</sup>CD16<sup>hi</sup> neutrophils. These HPS2 neutrophils phenocopied their circulating counterparts showing increased CD63 expression, impaired degranulation capacity, and intact NADPH oxidase activity. Most noticeable was the decrease in neutrophil yield during the final days of HPS2 iPSC cultures. Although neutrophil viability was normal, CD15<sup>NEG</sup> macrophages were readily phagocytosing neutrophils, contributing to the limited neutrophil output in HPS2. In this iPSC model, HPS2 neutrophil development is affected by a slower rate of development and by macrophage-mediated clearance during neutrophil maturation.</p>","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 4","pages":""},"PeriodicalIF":3.3000,"publicationDate":"2024-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10796564/pdf/","citationCount":"0","resultStr":"{\"title\":\"Reduced myeloid commitment and increased uptake by macrophages of stem cell-derived HPS2 neutrophils.\",\"authors\":\"Steven Ds Webbers, Cathelijn Em Aarts, Bart Klein, Dané Koops, Judy Geissler, Anton Tj Tool, Robin van Bruggen, Emile van den Akker, Taco W Kuijpers\",\"doi\":\"10.26508/lsa.202302263\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Hermansky-Pudlak syndrome type 2 (HPS2) is a rare autosomal recessive disorder, caused by mutations in the <i>AP3B1</i> gene, encoding the β3A subunit of the adapter protein complex 3. This results in mis-sorting of proteins within the cell. A clinical feature of HPS2 is severe neutropenia. Current HPS2 animal models do not recapitulate the human disease. Hence, we used induced pluripotent stem cells (iPSCs) of an HPS2 patient to study granulopoiesis. Development into CD15<sup>POS</sup> cells was reduced, but HPS2-derived CD15<sup>POS</sup> cells differentiated into segmented CD11b<sup>+</sup>CD16<sup>hi</sup> neutrophils. These HPS2 neutrophils phenocopied their circulating counterparts showing increased CD63 expression, impaired degranulation capacity, and intact NADPH oxidase activity. Most noticeable was the decrease in neutrophil yield during the final days of HPS2 iPSC cultures. Although neutrophil viability was normal, CD15<sup>NEG</sup> macrophages were readily phagocytosing neutrophils, contributing to the limited neutrophil output in HPS2. In this iPSC model, HPS2 neutrophil development is affected by a slower rate of development and by macrophage-mediated clearance during neutrophil maturation.</p>\",\"PeriodicalId\":18081,\"journal\":{\"name\":\"Life Science Alliance\",\"volume\":\"7 4\",\"pages\":\"\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2024-01-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10796564/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Life Science Alliance\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.26508/lsa.202302263\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/4/1 0:00:00\",\"PubModel\":\"Print\",\"JCR\":\"Q1\",\"JCRName\":\"BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Life Science Alliance","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.26508/lsa.202302263","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/4/1 0:00:00","PubModel":"Print","JCR":"Q1","JCRName":"BIOLOGY","Score":null,"Total":0}
Reduced myeloid commitment and increased uptake by macrophages of stem cell-derived HPS2 neutrophils.
Hermansky-Pudlak syndrome type 2 (HPS2) is a rare autosomal recessive disorder, caused by mutations in the AP3B1 gene, encoding the β3A subunit of the adapter protein complex 3. This results in mis-sorting of proteins within the cell. A clinical feature of HPS2 is severe neutropenia. Current HPS2 animal models do not recapitulate the human disease. Hence, we used induced pluripotent stem cells (iPSCs) of an HPS2 patient to study granulopoiesis. Development into CD15POS cells was reduced, but HPS2-derived CD15POS cells differentiated into segmented CD11b+CD16hi neutrophils. These HPS2 neutrophils phenocopied their circulating counterparts showing increased CD63 expression, impaired degranulation capacity, and intact NADPH oxidase activity. Most noticeable was the decrease in neutrophil yield during the final days of HPS2 iPSC cultures. Although neutrophil viability was normal, CD15NEG macrophages were readily phagocytosing neutrophils, contributing to the limited neutrophil output in HPS2. In this iPSC model, HPS2 neutrophil development is affected by a slower rate of development and by macrophage-mediated clearance during neutrophil maturation.
期刊介绍:
Life Science Alliance is a global, open-access, editorially independent, and peer-reviewed journal launched by an alliance of EMBO Press, Rockefeller University Press, and Cold Spring Harbor Laboratory Press. Life Science Alliance is committed to rapid, fair, and transparent publication of valuable research from across all areas in the life sciences.