Stepwise reprogramming of the bone marrow niche with particular focus on stromal cell populations implicated as playing a role in MF. In the bone marrow (BM) niche under normal (healthy) conditions, HSC function is tightly controlled by a specialized microenvironment comprising sympathetic neurons, Nes⁺, LepR⁺, and Gli1⁺ MSCs and OBCs. These stromal cell subsets, megakaryocytes,^77,83  growth factors, and cytokines control the proliferation and maintenance of the HSCs. In prefibrotic stages of PMF, hematopoietic stem and progenitor cells acquire genetic alterations in MPNs (MPN clone). The MPN clone gives rise to mutant dysplastic megakaryocytes that contribute to a proinflammatory environment that damages sensitive elements of the microenvironment such as Nes⁺ MSCs, Schwann cells, and their associated nerve terminals and thus contributes to the loss of normal hematopoiesis. Megakaryocytes derived from the malignant MPN clone significantly contribute to the reprogramming of stromal cells. Stromal cell subsets lose their hematopoiesis support (eg, loss of CXCL12 and increased cellular stress through accumulation of ROS and maintain a profibrotic environment that favors the malignant hematopoietic clone and leads to a vicious circle that results in bone marrow fibrosis and continuous production of extracellular matrix proteins, inflammation, loss of normal hematopoiesis, and expansion of the MPN clone. In the fibrotic phase, stromal cell subsets acquire an abnormal phenotype and start proliferating, detaching, and migrating from their normal niches; they can be found in abundance in the marrow cavity where they differentiate into myofibroblasts under the influence of CXCL4 secreted by megakaryocytes. They also start expressing CXCL4, which further negatively affects normal hematopoiesis and induces myofibroblast differentiation. The inflammatory environment created by the MPN clone, mutant megakaryocytes, and functionally and transcriptionally reprogrammed stromal cells (myofibroblasts) leads to a self-reinforcing niche. It remains unclear how this self-reinforcing niche is interrupted through HSCT. The posttransplant phase raises numerous open questions as indicated by the question marks. Detailed histopathologic studies on posttransplant bone marrow biopsies indicate resolution of bone marrow fibrosis but it remains an open question whether the reprogrammed stroma in bone marrow fibrosis regains its function and whether the stromal reprogramming is a reversible process after HSCT. Megakaryocytes in posttransplant bone marrows show atypical microforms exhibiting a dysplastic aspect that might be the result of an altered interaction between stromal cells (recipient bone marrow) and donor megakaryocytes that have not completely recovered their functionality. This disturbed interaction can in turn negatively affect regenerating hematopoiesis, in line with delayed hematopoiesis recovery in patients with bone marrow fibrosis after HSCT. Another open question is whether nerve fibers and nestin⁺ stromal cell subsets are able to recover after HSCT. Future studies will shed light on regenerative processes in the bone marrow microenvironment after HSCT and answer the question of whether the reprogrammed self-reinforcing niche in bone marrow fibrosis is reversible. Cytokines and growth factors are highlighted in gray. ANGPT1, angiopoietin; CAR, cxcl12-abundant reticular cells; CXCL12, C-X-C motif chemokine 12; CXCL4, C-X-C motif chemokine 4 (or platelet factor 4); ECM, extracellular matrix; FGF1, fibroblast growth factor 1; GFP, green fluorescent protein; IL6, interleukin 6 SCF, stem cell factor; TPO, thrompoietin.