GSE191029
Microenvironmental Control of Hematopoietic Niche Capacity via CXCL8 and Protein Kinase C
Altered hematopoietic stem cell (HSC) fate underlies primary blood disorders but microenvironmental factors controlling HSC fate 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-d, encoded by prkcda) increased the number of HSC clones by approximately 50% 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-d with the focal adhesion complex, activating MEK/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 PKC and has significant impact on HSC phylogenetic and phenotypic fate. Overall design: Single Cell RNA-seq and Single Cell ATAC-seq from zebrafish embryos and zebrafish kidney marrow.  Bulk RNA-seq and bulk ATAC-seq from HUVEC cells transduced with adenovirus E4ORF1.