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 CD15^POS cells was reduced, but HPS2-derived CD15^POS cells differentiated into segmented CD11b⁺CD16^hi 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^NEG 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.

中文翻译：

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骨髓定向减少，巨噬细胞对干细胞衍生的 HPS2 中性粒细胞的摄取增加。

Hermansky-Pudlak 综合征 2 型 (HPS2) 是一种罕见的常染色体隐性遗传疾病，由编码接头蛋白复合物 3 的 β3A 亚基的 AP3B1 基因突变引起。这会导致细胞内蛋白质的错误分类。HPS2 的临床特征是严重的中性粒细胞减少症。目前的 HPS2 动物模型不能概括人类疾病。因此，我们使用 HPS2 患者的诱导多能干细胞 (iPSC) 来研究粒细胞生成。向 CD15 ^POS细胞的发育减少，但 HPS2 衍生的 CD15 ^POS细胞分化为分段的 CD11b ⁺ CD16 ^hi中性粒细胞。这些 HPS2 中性粒细胞的表型与循环中的中性粒细胞相似，显示 CD63 表达增加、脱颗粒能力受损和 NADPH 氧化酶活性完整。最引人注目的是 HPS2 iPSC 培养的最后几天中性粒细胞产量的下降。尽管中性粒细胞活力正常，但 CD15 ^NEG巨噬细胞很容易吞噬中性粒细胞，导致 HPS2 中中性粒细胞输出有限。在此 iPSC 模型中，HPS2 中性粒细胞发育受到较慢的发育速率和中性粒细胞成熟过程中巨噬细胞介导的清除的影响。