ZNF467 nucleoplasmic condensates enhance human haematopoietic stem cell homing

Human hematopoietic stem cells (HSCs) possess a distinct gene expression profile distinguishing them from progenitor cells. Gaining insight into the distinctive features of these signature genes could accelerate the development of effective strategies to enhance the clinical efficacy of HSC transplantation. Research into genes specifically enriched in cord blood (CB) HSCs revealed high expression levels of ZNF467 in both freshly isolated human CB HSCs and ex-vivo cultured CB HSCs. ZNF467, originally identified from a mouse hematogenic endothelial cell line, has been linked to the regulation of adipogenesis and osteogenesis within the mouse bone marrow. However, its biological function in human tissues remains largely elusive. Although neither overexpression nor knockdown of full-length ZNF467 had dramatic effect on ex-vivo expansion of CB HSPCs,nucleoplasmic condensates of truncated ZNF467, resulting from ZNF467 with the amino acids (216-292)deletion,as npZNF467.Overexpression npZNF467 profoundly enhances the long-term reconstituting capacity of human cord blood HSCs.Overexpression of npZNF467 in HSC and progenitor cells induces a unique gene expression profile, notably upregulating genes associated with HSPC migration and adhesion. The npZNF467 condensates significantly amplify the homing efficiency of CB HSPCs, primarily through activating expression of MMP9 and ICAM1.Collectively,the enforced expression of npZNF467 condensate initiates a homing-related gene expression program, fostering both homing and long-term engraftment of human CB HSPCs.