Synergistic cooperation between progranulin and Jak2/Stat3 signaling determines definitive myeloid cell fate

Abstract Perturbations in cell fate choices result in loss of tissue homeostasis and diseases like cancer and developmental disorders. A better comprehension of the molecular mechanisms that drive cell fate determination is necessary to reveal novel therapeutic interventions. The JAK/STAT signaling pathway is a cornerstone to cancer progression, including hematopoietic malignancies. However, little is known about the molecular regulators of this pathway, and how they enable hematopoietic cell state transitions in homeostatic conditions and disease. In this study, we found in vivo that progranulin (GRN), a gene associated to human frontotemporal dementia, is critical to determine myeloid cell fate through the regulation of the JAK2/STAT3 pathway. Through the generation of inducible stat3 and progranulin a (grna) zebrafish, in conjunction with knockout ablation models, FACS sorting, transcriptomic profiling, rescue experiments, and CUT&RUN, we demonstrate in vivo that Stat3 induces grna expression,which in turns increases stat3 expression and reinforces myeloid fate commitment over erythroid differentiation. In addition, in vivo lineage tracing experiments coupled with live imaging and tissue-specific ablations show that the Grna/Stat3 axis operates during definitive, but not primitive myelopoiesis. This distinct molecular requirement during developmental myelopoiesis helped identify key functional differences between macrophages from different embryonic origins. Particularly, we found that definitive myeloid cells are the main contributors of tissue repair and organogenesis, while primitive myeloid cells are functionally inefficient in these contexts. Finally, successful myeloid differentiation of a human myelogenous leukemia line was only achieved when the JAK2/STAT3 pathway was co-stimulated with GRN, showing high conservation during human myelopoiesis and the critical role of GRN during myeloid fate determination. This discovery reveals a new mechanism to control hematopoietic lineage commitment in homeostatic conditions, and uncovers progranulin as a potential target to correct hematological malignancies with faulty IL-6/JAK2/STAT3 activation.