Structure of the TPOR complex guides design of analogs that bias hematopoiesis. TPOR complex structure-driven analogs of TPO

Thrombopoietin (TPO) is an essential cytokine for hematopoietic stem cell (HSC) maintenance and megakaryocyte differentiation. Using a high-resolution structure of the extracellular TPO-TPO receptor (TpoR) signaling complex, we guided the engineering of TPO variants (TPOmod) with a spectrum of signaling activities, from neutral antagonists to partial- and super-agonists. To demonstrate the functional uncoupling of the two primary roles of TPO and highlight the potential utilities of TPOmod in hematology research and clinical HSC transplantation, single cell RNAseq was performed on human HSCs cultured with three of these TPOmod variants and a wildtype TPO.