Furthermore, in a mouse model of MPN expressing the human JAK2-V617F mutation, this effect was found to be caused by early glial and sympathetic nerve damage and apoptosis of nestin+ MSCs triggered by the mutant HSCs. In vivo depletion of nestin+ cells accelerated MPN progression. Conversely, MPN phenotype could be reversed by compensating for the sympathetic neuropathy by the treatment with a beta-3-sympathicomimetic drug. Mice with JAK2-V617F driven MPN treated with a beta-3-sympathicomimetic agonist not only restored nestin+ MSCs numbers, but also showed correction of thrombocytosis, neutrophilia, and bone marrow fibrosis, and efficiently reduced mutant hematopoietic progenitor numbers in bone marrow and peripheral blood. Thus, treatments with a beta-3 sympathicomimetic agonist corrected the damage inflicted by the MPN clone on the stem cell niche and led to a dramatic improvement of the MPN phenotype. Therefore, beta-3 sympathicomimetic agonists represent a promising novel therapeutic approach to MPN by targeting the stem cell niche rather than the MPN clone itself.