Microenvironmental Control of Hematopoietic Stem Cell Fate via CXCL8 and Protein Kinase C

Altered hematopoietic stem cell (HSC) fate underlies primary blood disorders but microenvironmental factors controlling this are poorly understood. Genetically barcoded 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-delta, encoded by prkcda) increased the number of HSC clones by up to 80% and expanded polyclonal populations of immature neutrophil and erythroid precursors. PKC agonists such as cxcl8 augmented HSC competition for residency within the niche and expanded defined niche populations. CXCL8 induced association of PKC-delta with the focal adhesion complex, activating ERK signaling and expression of niche factors in human endothelial cells. Our findings demonstrate the existence of reserve capacity within the niche which is controlled by CXCL8 and PKC and has significant impact on HSC phylogenetic and phenotypic fate.

异化的造血干细胞（HSC）命运是原发性血液疾病之根源，然而调控此过程的微环境因素尚缺乏深入理解。本研究采用基因条形码标记的 GESTALT 斑马鱼，旨在筛选出在原位条件下影响 HSC 群体系统发育分布的窦状血管微环境中的表达因子。蛋白质激酶 C δ（PKC-δ，由 prkcda 编码）的失调性表达使得 HSC 克隆数量增加高达 80%，并扩展了未成熟中性粒细胞和红细胞前体的多克隆种群。PKC 激动剂如 cxcl8 加强了 HSC 在微环境中的居留竞争，并扩展了特定的微环境种群。CXCL8 诱导 PKC-δ 与焦点粘附复合物的结合，激活了 ERK 信号传导以及人内皮细胞中微环境因子的表达。我们的研究揭示了微环境中存在储备能力，这种能力受 CXCL8 和 PKC 的调控，并对 HSC 的系统发育和表型命运产生显著影响。