Reduced myeloid commitment and increased uptake by macrophages of stem cell-derived HPS2 neutrophils

• Published in: Life science alliance 2024-04, Vol.7 (4), p.e202302263
• Main Authors: Webbers, Steven Ds, Aarts, Cathelijn Em, Klein, Bart, Koops, Dané, Geissler, Judy, Tool, Anton Tj, van Bruggen, Robin, van den Akker, Emile, Kuijpers, Taco W
• Format: Article
• Language: English
• Subjects: Animals; Hermanski-Pudlak Syndrome - genetics; Hermanski-Pudlak Syndrome - metabolism; Humans; Macrophages - metabolism; Mutation; Neutrophils - metabolism
• ISSN: 2575-1077; 2575-1077
• DOI: 10.26508/lsa.202302263

Hermansky-Pudlak syndrome type 2 (HPS2) is a rare autosomal recessive disorder, caused by mutations in the 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 cells was reduced, but HPS2-derived CD15 cells differentiated into segmented CD11b CD16 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 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.