Dr. von Hauner Childrens' Hospital, University Hospital Ludwig Maximillian's University, Department of Pediatric Hematology/Oncology, 80337 Munich, Germany.
The Ohio State University College of Medicine, Department of Internal Medicine, Division of Hematology, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA.
Cell Rep. 2023 May 30;42(5):112528. doi: 10.1016/j.celrep.2023.112528. Epub 2023 May 18.
Altered hematopoietic stem cell (HSC) fate underlies primary blood disorders but microenvironmental factors controlling this are poorly understood. Genetically barcoded genome editing of synthetic target arrays for lineage tracing (GESTALT) zebrafish were used to screen for factors expressed by the sinusoidal vascular niche that alter the phylogenetic distribution of the HSC pool under native conditions. Dysregulated expression of protein kinase C delta (PKC-δ, encoded by prkcda) increases the number of HSC clones by up to 80% and expands polyclonal populations of immature neutrophil and erythroid precursors. PKC agonists such as cxcl8 augment HSC competition for residency within the niche and expand defined niche populations. CXCL8 induces association of PKC-δ with the focal adhesion complex, activating extracellular signal-regulated kinase (ERK) signaling and expression of niche factors in human endothelial cells. Our findings demonstrate the existence of reserve capacity within the niche that is controlled by CXCL8 and PKC and has significant impact on HSC phylogenetic and phenotypic fate.
造血干细胞（HSC）命运的改变是原发性血液疾病的基础，但控制这种命运改变的微环境因素还知之甚少。使用经过基因编码的合成靶基因谱系追踪（GESTALT）斑马鱼的基因组编辑，筛选出表达于窦状血管龛中的因子，这些因子在天然条件下改变了 HSC 库的系统发生分布。蛋白激酶 C 德尔塔（PKC-δ，由 prkcda 编码）的失调表达将 HSC 克隆的数量增加了多达 80%，并扩大了不成熟中性粒细胞和红细胞前体的多克隆群体。PKC 激动剂（如 cxcl8）增加了 HSC 在龛内竞争居住的能力，并扩大了特定龛种群。CXCL8 诱导 PKC-δ 与焦点黏附复合物的关联，激活细胞外信号调节激酶（ERK）信号，并在人内皮细胞中表达龛内因子。我们的研究结果表明，龛内存在由 CXCL8 和 PKC 控制的储备能力，对 HSC 的系统发生和表型命运有重大影响。
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