PDF(Pubmed)
Abstract：
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.
摘要：
Hermansky-Pudlak综合征2型（HPS2）是一种罕见的常染色体隐性遗传疾病，由AP3B1基因突变引起的，编码衔接蛋白复合物3的β3A亚基。这导致细胞内蛋白质的错误分选。HPS2的临床特征是严重的中性粒细胞减少症。目前的HPS2动物模型没有概括人类疾病。因此，我们使用HPS2患者的诱导多能干细胞(iPSCs)研究粒细胞生成.CD15POS细胞发育减少，但HPS2来源的CD15POS细胞分化为分段CD11b+CD16hi中性粒细胞。这些HPS2嗜中性粒细胞对其循环对应物进行表型检查，显示CD63表达增加，脱粒能力受损，和完整的NADPH氧化酶活性。最明显的是在HPS2iPSC培养的最后几天中性粒细胞产量的降低。虽然中性粒细胞的活力是正常的,CD15NEG巨噬细胞容易吞噬中性粒细胞，导致HPS2中性粒细胞输出受限。在这个iPSC模型中，在嗜中性粒细胞成熟过程中，HPS2嗜中性粒细胞的发育受到较慢的发育速度和巨噬细胞介导的清除的影响。
