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.