RT Journal Article
SR Electronic
T1 Reduced myeloid commitment and increased uptake by macrophages of stem cell–derived HPS2 neutrophils
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202302263
DO 10.26508/lsa.202302263
VO 7
IS 4
A1 Webbers, Steven DS
A1 Aarts, Cathelijn EM
A1 Klein, Bart
A1 Koops, Dané
A1 Geissler, Judy
A1 Tool, Anton TJ
A1 van Bruggen, Robin
A1 van den Akker, Emile
A1 Kuijpers, Taco W
YR 2024
UL http://www.life-science-alliance.org/content/7/4/e202302263.abstract
AB 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.